{
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   "id": "943eec30-eca9-499a-9262-e215ca349f64",
   "metadata": {
    "editable": true,
    "slideshow": {
     "slide_type": ""
    },
    "tags": []
   },
   "source": [
    "# Single sample intracellular signalling network inference\n",
    "\n",
    "In this notebook we showcase how to use the advanced CARNIVAL implementation available in CORNETO. This implementation extends the capabilities of the original CARNIVAL method by enabling advanced modelling and injection of knowledge for hypothesis generation. We will use a dataset consisting of 6 samples of hepatic stellate cells (HSC) where three of them were activated by the cytokine Transforming growth factor (TGF-β). \n",
    "\n",
    "In the first part, we will show how to estimate Transcription Factor activities from gene expression data, following the [Decoupler tutorial](https://decoupler-py.readthedocs.io/en/latest/notebooks/bulk.html) for functional analysis. Then, we will use the CARNIVAL method available in CORNETO to infer a network from TFs to receptors, assuming that we don't really know which treatment was used."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 1,
   "id": "95502198-c8a0-4d71-a5e9-709bad72ec00",
   "metadata": {},
   "outputs": [],
   "source": [
    "# --- Saezlab tools ---\n",
    "# https://decoupler-py.readthedocs.io/\n",
    "import gzip\n",
    "import os\n",
    "import shutil\n",
    "import tempfile\n",
    "import urllib.request\n",
    "\n",
    "import decoupler as dc\n",
    "import numpy as np\n",
    "\n",
    "# https://omnipathdb.org/\n",
    "import omnipath as op\n",
    "\n",
    "# Additional packages\n",
    "import pandas as pd\n",
    "\n",
    "# --- Additional libs ---\n",
    "# Pydeseq for differential expression analysis\n",
    "from pydeseq2.dds import DefaultInference, DeseqDataSet\n",
    "from pydeseq2.ds import DeseqStats\n",
    "\n",
    "# https://saezlab.github.io/\n",
    "import corneto as cn"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 2,
   "id": "5bb37ac8-1631-4cae-a462-c23ff2ae8171",
   "metadata": {},
   "outputs": [],
   "source": [
    "max_time = 300\n",
    "seed = 0"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "id": "04892cd1-a822-4cfb-ba15-29c647928f92",
   "metadata": {},
   "outputs": [
    {
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       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th>GeneName</th>\n",
       "      <th>DDX11L1</th>\n",
       "      <th>WASH7P</th>\n",
       "      <th>MIR6859-1</th>\n",
       "      <th>MIR1302-11</th>\n",
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       "      <td>438</td>\n",
       "      <td>480</td>\n",
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       "      <td>31860</td>\n",
       "      <td>2033</td>\n",
       "      <td>89559</td>\n",
       "      <td>282</td>\n",
       "      <td>448</td>\n",
       "    </tr>\n",
       "    <tr>\n",
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       "      <td>0</td>\n",
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       "      <td>243</td>\n",
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       "<p>6 rows × 64253 columns</p>\n",
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      "text/plain": [
       "GeneName       DDX11L1  WASH7P  MIR6859-1  MIR1302-11  MIR1302-9  FAM138A  \\\n",
       "25_HSCs-Ctrl1        0       9         10           1          0        0   \n",
       "26_HSCs-Ctrl2        0      12         14           0          0        0   \n",
       "27_HSCs-Ctrl3        0      14         10           0          0        0   \n",
       "31_HSCs-TGFb1        0      11         16           0          0        0   \n",
       "32_HSCs-TGFb2        0       5          8           0          0        0   \n",
       "33_HSCs-TGFb3        0      12          5           0          0        0   \n",
       "\n",
       "GeneName       OR4G4P  OR4G11P  OR4F5  RP11-34P13.7  ...  MT-ND4  MT-TH  \\\n",
       "25_HSCs-Ctrl1       0        0      0            33  ...   93192    342   \n",
       "26_HSCs-Ctrl2       0        0      0            66  ...  114914    355   \n",
       "27_HSCs-Ctrl3       0        0      0            52  ...  155365    377   \n",
       "31_HSCs-TGFb1       0        0      0            54  ...  110866    373   \n",
       "32_HSCs-TGFb2       0        0      0            44  ...   45488    239   \n",
       "33_HSCs-TGFb3       0        0      0            32  ...   70704    344   \n",
       "\n",
       "GeneName       MT-TS2  MT-TL2  MT-ND5  MT-ND6  MT-TE  MT-CYB  MT-TT  MT-TP  \n",
       "25_HSCs-Ctrl1     476     493   54466   17184   1302   54099    258    475  \n",
       "26_HSCs-Ctrl2     388     436   64698   21106   1492   62679    253    396  \n",
       "27_HSCs-Ctrl3     438     480   85650   31860   2033   89559    282    448  \n",
       "31_HSCs-TGFb1     441     481   60325   19496   1447   66283    172    341  \n",
       "32_HSCs-TGFb2     331     343   27442    9054    624   27535     96    216  \n",
       "33_HSCs-TGFb3     453     497   45443   13796   1077   43415    192    243  \n",
       "\n",
       "[6 rows x 64253 columns]"
      ]
     },
     "execution_count": 3,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We need to download the dataset, available at GEO GSE151251\n",
    "url = \"https://www.ncbi.nlm.nih.gov/geo/download/?acc=GSE151251&format=file&file=GSE151251%5FHSCs%5FCtrl%2Evs%2EHSCs%5FTGFb%2Ecounts%2Etsv%2Egz\"\n",
    "\n",
    "adata = None\n",
    "with tempfile.TemporaryDirectory() as tmpdirname:\n",
    "    # Path for the gzipped file in the temp folder\n",
    "    gz_file_path = os.path.join(tmpdirname, \"counts.txt.gz\")\n",
    "\n",
    "    # Download the file\n",
    "    with urllib.request.urlopen(url) as response:\n",
    "        with open(gz_file_path, \"wb\") as out_file:\n",
    "            shutil.copyfileobj(response, out_file)\n",
    "\n",
    "    # Decompress the file\n",
    "    decompressed_file_path = gz_file_path[:-3]  # Removing '.gz' extension\n",
    "    with gzip.open(gz_file_path, \"rb\") as f_in:\n",
    "        with open(decompressed_file_path, \"wb\") as f_out:\n",
    "            shutil.copyfileobj(f_in, f_out)\n",
    "\n",
    "    adata = pd.read_csv(decompressed_file_path, index_col=2, sep=\"\\t\").iloc[:, 5:].T\n",
    "\n",
    "adata"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "ed7df83c-ccf2-43ab-95d7-be55d36669be",
   "metadata": {},
   "source": [
    "## Data preprocessing\n",
    "\n",
    "We will use AnnData and PyDeseq2 to pre-process the data and compute differential expression between control and tretament"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 4,
   "id": "0c49ddc4-55d7-49f3-bd40-487c7535fbda",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "C:\\Users\\pablo\\miniconda3\\envs\\corneto-dev-mini\\Lib\\site-packages\\anndata\\_core\\anndata.py:1756: UserWarning: Variable names are not unique. To make them unique, call `.var_names_make_unique`.\n",
      "  utils.warn_names_duplicates(\"var\")\n",
      "C:\\Users\\pablo\\miniconda3\\envs\\corneto-dev-mini\\Lib\\site-packages\\anndata\\utils.py:261: UserWarning: Suffix used (-[0-9]+) to deduplicate index values may make index values difficult to interpret. There values with a similar suffixes in the index. Consider using a different delimiter by passing `join={delimiter}`Example key collisions generated by the make_index_unique algorithm: ['SNORD116-1', 'SNORD116-2', 'SNORD116-3', 'SNORD116-4', 'SNORD116-5']\n",
      "  warnings.warn(\n"
     ]
    },
    {
     "data": {
      "text/plain": [
       "AnnData object with n_obs × n_vars = 6 × 64253"
      ]
     },
     "execution_count": 4,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "from anndata import AnnData\n",
    "\n",
    "adata = AnnData(adata, dtype=np.float32)\n",
    "adata.var_names_make_unique()\n",
    "adata"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "id": "34ee8218-6f15-4b09-a44d-150970c83c45",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
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       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
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       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>condition</th>\n",
       "      <th>sample_id</th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>25_HSCs-Ctrl1</th>\n",
       "      <td>control</td>\n",
       "      <td>25</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>26_HSCs-Ctrl2</th>\n",
       "      <td>control</td>\n",
       "      <td>26</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>27_HSCs-Ctrl3</th>\n",
       "      <td>control</td>\n",
       "      <td>27</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>31_HSCs-TGFb1</th>\n",
       "      <td>treatment</td>\n",
       "      <td>31</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>32_HSCs-TGFb2</th>\n",
       "      <td>treatment</td>\n",
       "      <td>32</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>33_HSCs-TGFb3</th>\n",
       "      <td>treatment</td>\n",
       "      <td>33</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "</div>"
      ],
      "text/plain": [
       "               condition sample_id\n",
       "25_HSCs-Ctrl1    control        25\n",
       "26_HSCs-Ctrl2    control        26\n",
       "27_HSCs-Ctrl3    control        27\n",
       "31_HSCs-TGFb1  treatment        31\n",
       "32_HSCs-TGFb2  treatment        32\n",
       "33_HSCs-TGFb3  treatment        33"
      ]
     },
     "execution_count": 5,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# Process treatment information\n",
    "adata.obs[\"condition\"] = [\n",
    "    \"control\" if \"-Ctrl\" in sample_id else \"treatment\" for sample_id in adata.obs.index\n",
    "]\n",
    "\n",
    "# Process sample information\n",
    "adata.obs[\"sample_id\"] = [sample_id.split(\"_\")[0] for sample_id in adata.obs.index]\n",
    "\n",
    "# Visualize metadata\n",
    "adata.obs"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "id": "92c0ad7c-acb6-49b8-b537-0f772a631b9a",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "AnnData object with n_obs × n_vars = 6 × 19713\n",
       "    obs: 'condition', 'sample_id'"
      ]
     },
     "execution_count": 6,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# Obtain genes that pass the thresholds\n",
    "genes = dc.filter_by_expr(\n",
    "    adata, group=\"condition\", min_count=10, min_total_count=15, large_n=1, min_prop=1\n",
    ")\n",
    "\n",
    "# Filter by these genes\n",
    "adata = adata[:, genes].copy()\n",
    "adata"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "id": "290781e0-acef-440f-a0a6-1ff123d41a8e",
   "metadata": {},
   "outputs": [],
   "source": [
    "# Estimation of differential expression\n",
    "\n",
    "inference = DefaultInference()\n",
    "dds = DeseqDataSet(\n",
    "    adata=adata,\n",
    "    design_factors=\"condition\",\n",
    "    refit_cooks=True,\n",
    "    inference=inference,\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 8,
   "id": "96b44f6e-9b7e-4252-a0ec-8b8134361865",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Fitting size factors...\n",
      "... done in 0.01 seconds.\n",
      "\n",
      "Fitting dispersions...\n",
      "... done in 11.68 seconds.\n",
      "\n",
      "Fitting dispersion trend curve...\n",
      "... done in 1.20 seconds.\n",
      "\n",
      "Fitting MAP dispersions...\n",
      "... done in 10.25 seconds.\n",
      "\n",
      "Fitting LFCs...\n",
      "... done in 5.81 seconds.\n",
      "\n",
      "Calculating cook's distance...\n",
      "... done in 0.03 seconds.\n",
      "\n",
      "Replacing 0 outlier genes.\n",
      "\n"
     ]
    }
   ],
   "source": [
    "# Compute LFCs\n",
    "dds.deseq2()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 9,
   "id": "ec048254-a549-4b29-8da5-f66a0882621b",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Running Wald tests...\n",
      "... done in 2.97 seconds.\n",
      "\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Log2 fold change & Wald test p-value: condition treatment vs control\n",
      "                  baseMean  log2FoldChange     lfcSE      stat    pvalue  \\\n",
      "GeneName                                                                   \n",
      "WASH7P           10.349784       -0.011129  0.651922 -0.017071  0.986380   \n",
      "MIR6859-1        10.114621        0.000625  0.657581  0.000950  0.999242   \n",
      "RP11-34P13.7     45.731312        0.078209  0.324512  0.241005  0.809551   \n",
      "RP11-34P13.8     29.498379       -0.065178  0.393711 -0.165549  0.868512   \n",
      "CICP27          106.032659        0.150594  0.223024  0.675239  0.499524   \n",
      "...                    ...             ...       ...       ...       ...   \n",
      "MT-ND6        17914.984474       -0.435304  0.278796 -1.561372  0.118436   \n",
      "MT-TE          1281.293477       -0.332495  0.288073 -1.154204  0.248416   \n",
      "MT-CYB        54955.449372       -0.313285  0.286900 -1.091966  0.274848   \n",
      "MT-TT           204.692221       -0.485882  0.220606 -2.202488  0.027631   \n",
      "MT-TP           345.049755       -0.460675  0.161701 -2.848936  0.004387   \n",
      "\n",
      "                  padj  \n",
      "GeneName                \n",
      "WASH7P        0.991409  \n",
      "MIR6859-1     0.999520  \n",
      "RP11-34P13.7  0.877381  \n",
      "RP11-34P13.8  0.917121  \n",
      "CICP27        0.637374  \n",
      "...                ...  \n",
      "MT-ND6        0.211001  \n",
      "MT-TE         0.380057  \n",
      "MT-CYB        0.411271  \n",
      "MT-TT         0.061644  \n",
      "MT-TP         0.012217  \n",
      "\n",
      "[19713 rows x 6 columns]\n"
     ]
    }
   ],
   "source": [
    "stat_res = DeseqStats(\n",
    "    dds, contrast=[\"condition\", \"treatment\", \"control\"], inference=inference\n",
    ")\n",
    "\n",
    "stat_res.summary()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 10,
   "id": "0f868f1b-faf1-47a0-b14f-1fae209a5697",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
       "<div>\n",
       "<style scoped>\n",
       "    .dataframe tbody tr th:only-of-type {\n",
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       "    }\n",
       "\n",
       "    .dataframe tbody tr th {\n",
       "        vertical-align: top;\n",
       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>baseMean</th>\n",
       "      <th>log2FoldChange</th>\n",
       "      <th>lfcSE</th>\n",
       "      <th>stat</th>\n",
       "      <th>pvalue</th>\n",
       "      <th>padj</th>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>GeneName</th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>WASH7P</th>\n",
       "      <td>10.349784</td>\n",
       "      <td>-0.011129</td>\n",
       "      <td>0.651922</td>\n",
       "      <td>-0.017071</td>\n",
       "      <td>0.986380</td>\n",
       "      <td>0.991409</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>MIR6859-1</th>\n",
       "      <td>10.114621</td>\n",
       "      <td>0.000625</td>\n",
       "      <td>0.657581</td>\n",
       "      <td>0.000950</td>\n",
       "      <td>0.999242</td>\n",
       "      <td>0.999520</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>RP11-34P13.7</th>\n",
       "      <td>45.731312</td>\n",
       "      <td>0.078209</td>\n",
       "      <td>0.324512</td>\n",
       "      <td>0.241005</td>\n",
       "      <td>0.809551</td>\n",
       "      <td>0.877381</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>RP11-34P13.8</th>\n",
       "      <td>29.498379</td>\n",
       "      <td>-0.065178</td>\n",
       "      <td>0.393711</td>\n",
       "      <td>-0.165549</td>\n",
       "      <td>0.868512</td>\n",
       "      <td>0.917121</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>CICP27</th>\n",
       "      <td>106.032659</td>\n",
       "      <td>0.150594</td>\n",
       "      <td>0.223024</td>\n",
       "      <td>0.675239</td>\n",
       "      <td>0.499524</td>\n",
       "      <td>0.637374</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>...</th>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>MT-ND6</th>\n",
       "      <td>17914.984474</td>\n",
       "      <td>-0.435304</td>\n",
       "      <td>0.278796</td>\n",
       "      <td>-1.561372</td>\n",
       "      <td>0.118436</td>\n",
       "      <td>0.211001</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>MT-TE</th>\n",
       "      <td>1281.293477</td>\n",
       "      <td>-0.332495</td>\n",
       "      <td>0.288073</td>\n",
       "      <td>-1.154204</td>\n",
       "      <td>0.248416</td>\n",
       "      <td>0.380057</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>MT-CYB</th>\n",
       "      <td>54955.449372</td>\n",
       "      <td>-0.313285</td>\n",
       "      <td>0.286900</td>\n",
       "      <td>-1.091966</td>\n",
       "      <td>0.274848</td>\n",
       "      <td>0.411271</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>MT-TT</th>\n",
       "      <td>204.692221</td>\n",
       "      <td>-0.485882</td>\n",
       "      <td>0.220606</td>\n",
       "      <td>-2.202488</td>\n",
       "      <td>0.027631</td>\n",
       "      <td>0.061644</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>MT-TP</th>\n",
       "      <td>345.049755</td>\n",
       "      <td>-0.460675</td>\n",
       "      <td>0.161701</td>\n",
       "      <td>-2.848936</td>\n",
       "      <td>0.004387</td>\n",
       "      <td>0.012217</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "<p>19713 rows × 6 columns</p>\n",
       "</div>"
      ],
      "text/plain": [
       "                  baseMean  log2FoldChange     lfcSE      stat    pvalue  \\\n",
       "GeneName                                                                   \n",
       "WASH7P           10.349784       -0.011129  0.651922 -0.017071  0.986380   \n",
       "MIR6859-1        10.114621        0.000625  0.657581  0.000950  0.999242   \n",
       "RP11-34P13.7     45.731312        0.078209  0.324512  0.241005  0.809551   \n",
       "RP11-34P13.8     29.498379       -0.065178  0.393711 -0.165549  0.868512   \n",
       "CICP27          106.032659        0.150594  0.223024  0.675239  0.499524   \n",
       "...                    ...             ...       ...       ...       ...   \n",
       "MT-ND6        17914.984474       -0.435304  0.278796 -1.561372  0.118436   \n",
       "MT-TE          1281.293477       -0.332495  0.288073 -1.154204  0.248416   \n",
       "MT-CYB        54955.449372       -0.313285  0.286900 -1.091966  0.274848   \n",
       "MT-TT           204.692221       -0.485882  0.220606 -2.202488  0.027631   \n",
       "MT-TP           345.049755       -0.460675  0.161701 -2.848936  0.004387   \n",
       "\n",
       "                  padj  \n",
       "GeneName                \n",
       "WASH7P        0.991409  \n",
       "MIR6859-1     0.999520  \n",
       "RP11-34P13.7  0.877381  \n",
       "RP11-34P13.8  0.917121  \n",
       "CICP27        0.637374  \n",
       "...                ...  \n",
       "MT-ND6        0.211001  \n",
       "MT-TE         0.380057  \n",
       "MT-CYB        0.411271  \n",
       "MT-TT         0.061644  \n",
       "MT-TP         0.012217  \n",
       "\n",
       "[19713 rows x 6 columns]"
      ]
     },
     "execution_count": 10,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "results_df = stat_res.results_df\n",
    "results_df"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "f3f0ed74-4941-482f-a453-1fcb396ab2e9",
   "metadata": {},
   "source": [
    "## Prior knowledge with Decoupler and Omnipath"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 11,
   "id": "5fe1c1bc-69a2-4514-8c58-f19688ceaee4",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
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       "\n",
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       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>source</th>\n",
       "      <th>target</th>\n",
       "      <th>weight</th>\n",
       "      <th>PMID</th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>0</th>\n",
       "      <td>MYC</td>\n",
       "      <td>TERT</td>\n",
       "      <td>1</td>\n",
       "      <td>10022128;10491298;10606235;10637317;10723141;1...</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>1</th>\n",
       "      <td>SPI1</td>\n",
       "      <td>BGLAP</td>\n",
       "      <td>1</td>\n",
       "      <td>10022617</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>2</th>\n",
       "      <td>SMAD3</td>\n",
       "      <td>JUN</td>\n",
       "      <td>1</td>\n",
       "      <td>10022869;12374795</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>3</th>\n",
       "      <td>SMAD4</td>\n",
       "      <td>JUN</td>\n",
       "      <td>1</td>\n",
       "      <td>10022869;12374795</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>4</th>\n",
       "      <td>STAT5A</td>\n",
       "      <td>IL2</td>\n",
       "      <td>1</td>\n",
       "      <td>10022878;11435608;17182565;17911616;22854263;2...</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>...</th>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>43173</th>\n",
       "      <td>NFKB</td>\n",
       "      <td>hsa-miR-143-3p</td>\n",
       "      <td>1</td>\n",
       "      <td>19472311</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>43174</th>\n",
       "      <td>AP1</td>\n",
       "      <td>hsa-miR-206</td>\n",
       "      <td>1</td>\n",
       "      <td>19721712</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>43175</th>\n",
       "      <td>NFKB</td>\n",
       "      <td>hsa-miR-21-5p</td>\n",
       "      <td>1</td>\n",
       "      <td>20813833;22387281</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>43176</th>\n",
       "      <td>NFKB</td>\n",
       "      <td>hsa-miR-224-5p</td>\n",
       "      <td>1</td>\n",
       "      <td>23474441;23988648</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>43177</th>\n",
       "      <td>AP1</td>\n",
       "      <td>hsa-miR-144</td>\n",
       "      <td>1</td>\n",
       "      <td>23546882</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "<p>43178 rows × 4 columns</p>\n",
       "</div>"
      ],
      "text/plain": [
       "       source          target  weight  \\\n",
       "0         MYC            TERT       1   \n",
       "1        SPI1           BGLAP       1   \n",
       "2       SMAD3             JUN       1   \n",
       "3       SMAD4             JUN       1   \n",
       "4      STAT5A             IL2       1   \n",
       "...       ...             ...     ...   \n",
       "43173    NFKB  hsa-miR-143-3p       1   \n",
       "43174     AP1     hsa-miR-206       1   \n",
       "43175    NFKB   hsa-miR-21-5p       1   \n",
       "43176    NFKB  hsa-miR-224-5p       1   \n",
       "43177     AP1     hsa-miR-144       1   \n",
       "\n",
       "                                                    PMID  \n",
       "0      10022128;10491298;10606235;10637317;10723141;1...  \n",
       "1                                               10022617  \n",
       "2                                      10022869;12374795  \n",
       "3                                      10022869;12374795  \n",
       "4      10022878;11435608;17182565;17911616;22854263;2...  \n",
       "...                                                  ...  \n",
       "43173                                           19472311  \n",
       "43174                                           19721712  \n",
       "43175                                  20813833;22387281  \n",
       "43176                                  23474441;23988648  \n",
       "43177                                           23546882  \n",
       "\n",
       "[43178 rows x 4 columns]"
      ]
     },
     "execution_count": 11,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# Retrieve CollecTRI gene regulatory network (through Omnipath)\n",
    "collectri = dc.get_collectri(organism=\"human\", split_complexes=False)\n",
    "collectri"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 12,
   "id": "c749a42b-ecd9-4f33-acd4-242cb8237d8d",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
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       "\n",
       "    .dataframe thead th {\n",
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       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th>GeneName</th>\n",
       "      <th>WASH7P</th>\n",
       "      <th>MIR6859-1</th>\n",
       "      <th>RP11-34P13.7</th>\n",
       "      <th>RP11-34P13.8</th>\n",
       "      <th>CICP27</th>\n",
       "      <th>FO538757.2</th>\n",
       "      <th>AP006222.2</th>\n",
       "      <th>RP4-669L17.10</th>\n",
       "      <th>MTND1P23</th>\n",
       "      <th>MTND2P28</th>\n",
       "      <th>...</th>\n",
       "      <th>MT-ND4</th>\n",
       "      <th>MT-TH</th>\n",
       "      <th>MT-TS2</th>\n",
       "      <th>MT-TL2</th>\n",
       "      <th>MT-ND5</th>\n",
       "      <th>MT-ND6</th>\n",
       "      <th>MT-TE</th>\n",
       "      <th>MT-CYB</th>\n",
       "      <th>MT-TT</th>\n",
       "      <th>MT-TP</th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>treatment.vs.control</th>\n",
       "      <td>-0.017071</td>\n",
       "      <td>0.00095</td>\n",
       "      <td>0.241005</td>\n",
       "      <td>-0.165549</td>\n",
       "      <td>0.675239</td>\n",
       "      <td>-1.645412</td>\n",
       "      <td>2.041302</td>\n",
       "      <td>-0.376843</td>\n",
       "      <td>-1.994386</td>\n",
       "      <td>-0.498507</td>\n",
       "      <td>...</td>\n",
       "      <td>-1.435973</td>\n",
       "      <td>0.754913</td>\n",
       "      <td>1.139002</td>\n",
       "      <td>1.167032</td>\n",
       "      <td>-1.242582</td>\n",
       "      <td>-1.561372</td>\n",
       "      <td>-1.154204</td>\n",
       "      <td>-1.091966</td>\n",
       "      <td>-2.202488</td>\n",
       "      <td>-2.848936</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "<p>1 rows × 19713 columns</p>\n",
       "</div>"
      ],
      "text/plain": [
       "GeneName                WASH7P  MIR6859-1  RP11-34P13.7  RP11-34P13.8  \\\n",
       "treatment.vs.control -0.017071    0.00095      0.241005     -0.165549   \n",
       "\n",
       "GeneName                CICP27  FO538757.2  AP006222.2  RP4-669L17.10  \\\n",
       "treatment.vs.control  0.675239   -1.645412    2.041302      -0.376843   \n",
       "\n",
       "GeneName              MTND1P23  MTND2P28  ...    MT-ND4     MT-TH    MT-TS2  \\\n",
       "treatment.vs.control -1.994386 -0.498507  ... -1.435973  0.754913  1.139002   \n",
       "\n",
       "GeneName                MT-TL2    MT-ND5    MT-ND6     MT-TE    MT-CYB  \\\n",
       "treatment.vs.control  1.167032 -1.242582 -1.561372 -1.154204 -1.091966   \n",
       "\n",
       "GeneName                 MT-TT     MT-TP  \n",
       "treatment.vs.control -2.202488 -2.848936  \n",
       "\n",
       "[1 rows x 19713 columns]"
      ]
     },
     "execution_count": 12,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "mat = results_df[[\"stat\"]].T.rename(index={\"stat\": \"treatment.vs.control\"})\n",
    "mat"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 13,
   "id": "ad5a1f0e-e15d-49b8-bb47-47819e02fd99",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Running ulm on mat with 1 samples and 19713 targets for 655 sources.\n"
     ]
    },
    {
     "data": {
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       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>ABL1</th>\n",
       "      <th>AHR</th>\n",
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       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>treatment.vs.control</th>\n",
       "      <td>-2.181499</td>\n",
       "      <td>-1.556123</td>\n",
       "      <td>-1.824668</td>\n",
       "      <td>-1.983679</td>\n",
       "      <td>-2.673171</td>\n",
       "      <td>0.235021</td>\n",
       "      <td>-3.93546</td>\n",
       "      <td>0.870591</td>\n",
       "      <td>1.649556</td>\n",
       "      <td>-0.612672</td>\n",
       "      <td>...</td>\n",
       "      <td>-0.063138</td>\n",
       "      <td>2.123082</td>\n",
       "      <td>1.887668</td>\n",
       "      <td>-1.141122</td>\n",
       "      <td>1.571889</td>\n",
       "      <td>1.277879</td>\n",
       "      <td>-0.116911</td>\n",
       "      <td>1.92635</td>\n",
       "      <td>0.91651</td>\n",
       "      <td>-2.744753</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "<p>1 rows × 655 columns</p>\n",
       "</div>"
      ],
      "text/plain": [
       "                          ABL1       AHR      AIRE       AP1     APEX1  \\\n",
       "treatment.vs.control -2.181499 -1.556123 -1.824668 -1.983679 -2.673171   \n",
       "\n",
       "                            AR   ARID1A    ARID3A    ARID3B    ARID4A  ...  \\\n",
       "treatment.vs.control  0.235021 -3.93546  0.870591  1.649556 -0.612672  ...   \n",
       "\n",
       "                        ZNF362    ZNF382    ZNF384    ZNF395    ZNF436  \\\n",
       "treatment.vs.control -0.063138  2.123082  1.887668 -1.141122  1.571889   \n",
       "\n",
       "                        ZNF699     ZNF76  ZNF804A    ZNF91      ZXDC  \n",
       "treatment.vs.control  1.277879 -0.116911  1.92635  0.91651 -2.744753  \n",
       "\n",
       "[1 rows x 655 columns]"
      ]
     },
     "execution_count": 13,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "tf_acts, tf_pvals = dc.run_ulm(mat=mat, net=collectri, verbose=True)\n",
    "tf_acts"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 14,
   "id": "657ee3c1-4ad9-42f5-b566-de15547f5084",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "image/png": 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",
      "text/plain": [
       "<Figure size 300x600 with 2 Axes>"
      ]
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "dc.plot_barplot(\n",
    "    acts=tf_acts, contrast=\"treatment.vs.control\", top=25, vertical=True, figsize=(3, 6)\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 15,
   "id": "65226927-8da1-4555-88c1-c213f7ac46d4",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "1201"
      ]
     },
     "execution_count": 15,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We obtain ligand-receptor interactions from Omnipath, and we keep only the receptors\n",
    "# This is our list of a prior potential receptors from which we will infer the network\n",
    "unique_receptors = set(\n",
    "    op.interactions.LigRecExtra.get(genesymbols=True)[\n",
    "        \"target_genesymbol\"\n",
    "    ].values.tolist()\n",
    ")\n",
    "len(unique_receptors)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 53,
   "id": "6b6634d6-09b3-486e-984a-b382c20d41f8",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "<Axes: xlabel='log2FoldChange', ylabel='stat'>"
      ]
     },
     "execution_count": 53,
     "metadata": {},
     "output_type": "execute_result"
    },
    {
     "data": {
      "image/png": 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",
      "text/plain": [
       "<Figure size 640x480 with 1 Axes>"
      ]
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "df_de_receptors = results_df.loc[results_df.index.intersection(unique_receptors)]\n",
    "df_de_receptors = df_de_receptors.sort_values(by=\"stat\", ascending=False)\n",
    "df_de_receptors.plot.scatter(x=\"log2FoldChange\", y=\"stat\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 56,
   "id": "2ceda357-2783-457e-a6ab-091b02630650",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
       "<div>\n",
       "<style scoped>\n",
       "    .dataframe tbody tr th:only-of-type {\n",
       "        vertical-align: middle;\n",
       "    }\n",
       "\n",
       "    .dataframe tbody tr th {\n",
       "        vertical-align: top;\n",
       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>baseMean</th>\n",
       "      <th>log2FoldChange</th>\n",
       "      <th>lfcSE</th>\n",
       "      <th>stat</th>\n",
       "      <th>pvalue</th>\n",
       "      <th>padj</th>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>GeneName</th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "      <th></th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>CDH6</th>\n",
       "      <td>28262.296983</td>\n",
       "      <td>3.019806</td>\n",
       "      <td>0.077417</td>\n",
       "      <td>39.007075</td>\n",
       "      <td>0.000000e+00</td>\n",
       "      <td>0.000000e+00</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>CRLF1</th>\n",
       "      <td>7919.672343</td>\n",
       "      <td>3.341644</td>\n",
       "      <td>0.087997</td>\n",
       "      <td>37.974317</td>\n",
       "      <td>0.000000e+00</td>\n",
       "      <td>0.000000e+00</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>FZD8</th>\n",
       "      <td>2719.781498</td>\n",
       "      <td>3.843015</td>\n",
       "      <td>0.102696</td>\n",
       "      <td>37.421427</td>\n",
       "      <td>1.751855e-306</td>\n",
       "      <td>1.817595e-303</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>CDH2</th>\n",
       "      <td>7111.507547</td>\n",
       "      <td>2.809461</td>\n",
       "      <td>0.081929</td>\n",
       "      <td>34.291273</td>\n",
       "      <td>1.058818e-257</td>\n",
       "      <td>6.138964e-255</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>DYSF</th>\n",
       "      <td>441.449511</td>\n",
       "      <td>4.593250</td>\n",
       "      <td>0.182207</td>\n",
       "      <td>25.208911</td>\n",
       "      <td>3.198723e-140</td>\n",
       "      <td>5.680759e-138</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>INHBA</th>\n",
       "      <td>24329.359641</td>\n",
       "      <td>2.598613</td>\n",
       "      <td>0.104321</td>\n",
       "      <td>24.909787</td>\n",
       "      <td>5.828479e-137</td>\n",
       "      <td>9.655193e-135</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>CELSR1</th>\n",
       "      <td>492.324435</td>\n",
       "      <td>3.517315</td>\n",
       "      <td>0.154495</td>\n",
       "      <td>22.766506</td>\n",
       "      <td>9.849205e-115</td>\n",
       "      <td>1.303070e-112</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>PDGFC</th>\n",
       "      <td>5481.167075</td>\n",
       "      <td>1.894857</td>\n",
       "      <td>0.083811</td>\n",
       "      <td>22.608707</td>\n",
       "      <td>3.558087e-113</td>\n",
       "      <td>4.676039e-111</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>VDR</th>\n",
       "      <td>1450.304353</td>\n",
       "      <td>2.555007</td>\n",
       "      <td>0.116782</td>\n",
       "      <td>21.878467</td>\n",
       "      <td>4.166147e-106</td>\n",
       "      <td>4.977410e-104</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>HHIP</th>\n",
       "      <td>379.064034</td>\n",
       "      <td>6.005841</td>\n",
       "      <td>0.287374</td>\n",
       "      <td>20.899036</td>\n",
       "      <td>5.463696e-97</td>\n",
       "      <td>5.439689e-95</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>IGF1</th>\n",
       "      <td>361.189076</td>\n",
       "      <td>6.462656</td>\n",
       "      <td>0.311795</td>\n",
       "      <td>20.727232</td>\n",
       "      <td>1.967869e-95</td>\n",
       "      <td>1.910966e-93</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>NPTN</th>\n",
       "      <td>12640.971164</td>\n",
       "      <td>1.418676</td>\n",
       "      <td>0.079355</td>\n",
       "      <td>17.877480</td>\n",
       "      <td>1.766413e-71</td>\n",
       "      <td>1.095010e-69</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>EFNB2</th>\n",
       "      <td>3320.076805</td>\n",
       "      <td>1.560331</td>\n",
       "      <td>0.087847</td>\n",
       "      <td>17.761861</td>\n",
       "      <td>1.395299e-70</td>\n",
       "      <td>8.385834e-69</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>ITGB3</th>\n",
       "      <td>6530.314159</td>\n",
       "      <td>1.364767</td>\n",
       "      <td>0.078772</td>\n",
       "      <td>17.325469</td>\n",
       "      <td>3.022208e-67</td>\n",
       "      <td>1.673505e-65</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>TGFB1</th>\n",
       "      <td>8948.243694</td>\n",
       "      <td>1.335271</td>\n",
       "      <td>0.077618</td>\n",
       "      <td>17.203057</td>\n",
       "      <td>2.518840e-66</td>\n",
       "      <td>1.367876e-64</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>IL21R</th>\n",
       "      <td>259.221468</td>\n",
       "      <td>3.227903</td>\n",
       "      <td>0.192097</td>\n",
       "      <td>16.803541</td>\n",
       "      <td>2.298997e-63</td>\n",
       "      <td>1.180212e-61</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>ITGA1</th>\n",
       "      <td>26223.832504</td>\n",
       "      <td>1.310351</td>\n",
       "      <td>0.079830</td>\n",
       "      <td>16.414270</td>\n",
       "      <td>1.511887e-60</td>\n",
       "      <td>7.251541e-59</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>FAP</th>\n",
       "      <td>7231.157483</td>\n",
       "      <td>1.750901</td>\n",
       "      <td>0.115188</td>\n",
       "      <td>15.200426</td>\n",
       "      <td>3.513274e-52</td>\n",
       "      <td>1.413412e-50</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>EGF</th>\n",
       "      <td>144.262044</td>\n",
       "      <td>3.733301</td>\n",
       "      <td>0.251634</td>\n",
       "      <td>14.836246</td>\n",
       "      <td>8.540295e-50</td>\n",
       "      <td>3.194589e-48</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>ITGA11</th>\n",
       "      <td>12471.033668</td>\n",
       "      <td>3.673199</td>\n",
       "      <td>0.250314</td>\n",
       "      <td>14.674378</td>\n",
       "      <td>9.407359e-49</td>\n",
       "      <td>3.390261e-47</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "</div>"
      ],
      "text/plain": [
       "              baseMean  log2FoldChange     lfcSE       stat         pvalue  \\\n",
       "GeneName                                                                     \n",
       "CDH6      28262.296983        3.019806  0.077417  39.007075   0.000000e+00   \n",
       "CRLF1      7919.672343        3.341644  0.087997  37.974317   0.000000e+00   \n",
       "FZD8       2719.781498        3.843015  0.102696  37.421427  1.751855e-306   \n",
       "CDH2       7111.507547        2.809461  0.081929  34.291273  1.058818e-257   \n",
       "DYSF        441.449511        4.593250  0.182207  25.208911  3.198723e-140   \n",
       "INHBA     24329.359641        2.598613  0.104321  24.909787  5.828479e-137   \n",
       "CELSR1      492.324435        3.517315  0.154495  22.766506  9.849205e-115   \n",
       "PDGFC      5481.167075        1.894857  0.083811  22.608707  3.558087e-113   \n",
       "VDR        1450.304353        2.555007  0.116782  21.878467  4.166147e-106   \n",
       "HHIP        379.064034        6.005841  0.287374  20.899036   5.463696e-97   \n",
       "IGF1        361.189076        6.462656  0.311795  20.727232   1.967869e-95   \n",
       "NPTN      12640.971164        1.418676  0.079355  17.877480   1.766413e-71   \n",
       "EFNB2      3320.076805        1.560331  0.087847  17.761861   1.395299e-70   \n",
       "ITGB3      6530.314159        1.364767  0.078772  17.325469   3.022208e-67   \n",
       "TGFB1      8948.243694        1.335271  0.077618  17.203057   2.518840e-66   \n",
       "IL21R       259.221468        3.227903  0.192097  16.803541   2.298997e-63   \n",
       "ITGA1     26223.832504        1.310351  0.079830  16.414270   1.511887e-60   \n",
       "FAP        7231.157483        1.750901  0.115188  15.200426   3.513274e-52   \n",
       "EGF         144.262044        3.733301  0.251634  14.836246   8.540295e-50   \n",
       "ITGA11    12471.033668        3.673199  0.250314  14.674378   9.407359e-49   \n",
       "\n",
       "                   padj  \n",
       "GeneName                 \n",
       "CDH6       0.000000e+00  \n",
       "CRLF1      0.000000e+00  \n",
       "FZD8      1.817595e-303  \n",
       "CDH2      6.138964e-255  \n",
       "DYSF      5.680759e-138  \n",
       "INHBA     9.655193e-135  \n",
       "CELSR1    1.303070e-112  \n",
       "PDGFC     4.676039e-111  \n",
       "VDR       4.977410e-104  \n",
       "HHIP       5.439689e-95  \n",
       "IGF1       1.910966e-93  \n",
       "NPTN       1.095010e-69  \n",
       "EFNB2      8.385834e-69  \n",
       "ITGB3      1.673505e-65  \n",
       "TGFB1      1.367876e-64  \n",
       "IL21R      1.180212e-61  \n",
       "ITGA1      7.251541e-59  \n",
       "FAP        1.413412e-50  \n",
       "EGF        3.194589e-48  \n",
       "ITGA11     3.390261e-47  "
      ]
     },
     "execution_count": 56,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We will take the top 20 receptors that increased the expression after treatment\n",
    "df_top_receptors = df_de_receptors.head(20)\n",
    "df_top_receptors"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "4071c630-59d4-4928-b2f1-283eba931d06",
   "metadata": {},
   "source": [
    "## Inferring intracellular signalling network with CARNIVAL and CORNETO\n",
    "\n",
    "CORNETO is a unified framework for knowledge-driven network inference. It includes a very flexible implementation of CARNIVAL that expands its original capabilities. We will see how to use it under different assumptions to extract a network from a prior knowledge network and a set of potential receptors + our estimated TFs"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 57,
   "id": "3b2b7222-cc3c-4981-aa82-1f17ee546214",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [],
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     },
     "metadata": {},
     "output_type": "display_data"
    },
    {
     "data": {
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NiNJCR6EUay17X/1lgrEQI5GiBtY5aYDqiNsuNyohqlKK9Zb8hSV3CWWCkRMjkWJ4PBm3dY5DKcY1KmD9BZ7clJu4lCLQ094Zy+cxywTrUI2Rdu8mUky4dY6KGOOarGdHiOmWloY+v1R9urjqzs2/G1RjHQnfkXXvJlLUyDqXlpdD/65KUoxrsl4t0k1AiCqJEX+/OBU+UGeZYCS9GIkUNbLOq2ur2n1QHeyySYipJiFElRY66oCL7d+yvjJB5cRIpNgA1lmFWtTFLgONlnLTrBZaompUSoxEinVY56jL+qIiRV3sciNHmJtZKUpSjcq6dxMp1mGdGzEVRxe73MyEqFIpwgHEfbOTpBqV9WIkUgxpnWGbUxpesWHVok52udFTbuImRhnduDVRjUqIkc68YKiuY8SdmyiTFHWxyyYhplta6ExrIgtdp2qUToxEig1onYMQoy52WSgFIsRIlKJOwRZJqtEkxhyRYrTWGXeinErrXAzZPizpdtkkxBQRYiRKMSnEGFA1ghhflNFyjEgxhErU1Tr7VYo62WWgGVNu4lSKSbDQIVWjlF6MRIr+kagGEE7EqJNdbvYIc5zEqGuwxUs1+hh/UDcxEilqYp2bzS4TIcZroeES4ho5W5+r8DX+oC5iJFJsMOtspxR1s8uUckMWut4bhTn+wEU1ghhDtRyjM7MBrbOVGHWyyyYhUoQ5fqVo3iyTDB+q8UCYXoxEigGsc2s6WdZ5oKNbG7sslh6IEEkpRq8aAzepJVIMYJ3bEmKdcXJAIY5092uzT5Ryox8x4jxpBGL0oRoDESORYhDrrHjYfaFcqvs1cFJg/dBUiDqMQKWUG7LQGqhG3927iRTdrfOYaZ1BiLpf18NdfSLCrEtUkSLMSbDQ7Q13vFxUo6/u3USKPq1zq8bWGSS4fWATG+rq3fBYXEqxxYgwEyHqjaSm5gRRjTVK27MXI5GiJta5HvsDu4wTwAlRE6NIuSG7nAj7XFGL2YY9dlCNGLVaQ/yuxEik6GydQYj9ulpncxC9Tuk2AEWYk2WfzRtro99UutvaWRffLDcYEOMBIsVg2K+rdTaDKX4H0UelFCnCnEy12MhK0Yo2rhZrRq0es2s5RqSYMOscNpiimhgpwpxctQinoWM3bjWfdd2oVdtejESKCbHOOHGdgilxgwIqybfQPe2dTXU8zZZk/LraQIxEihpZ55JDP0Ws+dw2vMU1mBKHUsSRaSVCTLx9Ns+xZkOlJVkHFz6tJjH2EylqZp1Xa4jLrEyRFUyRSYwt1NShoZQi7LNOAbsobzZdbVkEYvq56Hj2n/77/62fzmoX65zNxGedcZLewu2yTrXLN8iaUm4a00J3NO2xxRp9WyZzkH97ikhRE+tsBYgQhCh78VuGUqSUm8a10B2t2eY+vvjX0tKfoVPN3jrj/Isj6gyrrHJ9B8QY9uKilJvGVorNkprjeG3wfyurq7SmWGOdDzJL1Dl6W5rSdsGbUm4aXynCQjZLao6dWFjlhDi3tDBNpKiRdb6pd1D5RL+gFpqaOjQXGrFBhNf1sLK6wlbXVtnMwiy7trQwRaR4QyX2x2mdh7r6RMb9YqkYyYlAhEj2uZktNKwyiBAbsFBcEhvHy0SKNxBbBctAZ2/VNht/mNhBc1Sa00I3Q76iaZVNcYBrDiqRY/Z//qf/e5LO+pitM07CXks1gQ5KkeaokFpsVHVoWmUTKJi4ev2a+d9Jcf7TaRafdcb6DWxzLaJQi07ESCk3RIqNqBaFVV5dXfezZU6QF65dsZLkS0SKMVrntnSrLSFGpRadCJEizM1tn82bdSNZZajDWhEAIrw0f9VKiMI6EynGZJ2ReoNIsxMBxWGhKeWGlKKJRij5qw2k1GJmYa6218Bk9fok63zDOqcisM5ehAggLcfpjymbGCnCTMRohySX/NUGUmoxt7TAhUeh9scvESnaWecI6ntGevpF6o0X5guFaCwzESJZaBskseTPLpCy0YUV2OzifO2Pq9aZSLHGOmcVW2esIaKPmx8slYvKLyxsOoxAJeinFJMWgbYLpNQCgRXYZhtMrHNzTW6dc1brnFZ4NHrbuwJF9VStK4IIU1CHtH5IcAFK/pIw5c8pkGJHmjWBFSuOEylGbJ1BhkFbgJVXlqWX/NmRIelEss9u56326tDn2jtyER2aOOe5dZ4mUryBJ1VbZ6TeoGIlDGSpRVMdOt1pCWSfk2Sh/apDE9cK191yfyc3iIcmt857VFpnTA3zijSrJkUvq0yUSGoxKaToJ5BSi5qKFU/r3OxKUal1RurNSM9AXbl/9VS2uKlDIkZSi37PYV1aifkJpNj9DipWXLDBOjc7KSq1zmbXm3oRRi0GDaSQhSZSdELcU/6CWmUrXAIrjta5aUlRtXXGGqIs6xFELQZRhwSyz34QZ75ikEBKLWCZC+WS19OO2/2wWccRKLPOtV1volKKZt5hqLsxcQwpRQfEsa4oKlLqqOhCgjaCKx6wtc7NbJ+VWGe3Jg9h4afkr968Q7LPpBa9bvRJUIcAAisOCdq+VGJTkqLVOsM2y7LOZk2zCjipRVl2mSiR1GLcarGetUMroc5cn/NLqhNEijbWWZZK9NPkoR4sFAtS7TIRI5FiMFJU20qsXnVowiVBuxbT3DrniRRtrLOs9URUq7QpLImqVYoqyvTIQpN9doKqVmIy1KEJjwRt39a56UiRW+c9VuucknBO9Xd0K19zQclfeWVFaXSZKJGUohtktxJDzqGs9niIMnskaNdikkjRRiXKsM6wFX2cFFUDtvziwlWlyoCUIqlFN8hKzamqQ0m3YbPRQwC4Wmeg2VJypKXiqIg02ymBFi5n8XVJcTduosTkqsUo/nYygi0gMNk3Xx8J2oGsc1MpRcM652RY50oJX7/S9v0pYZVb1lkkIkZCXBa6nlZiMtcOrfCZoB3IOjebfZZmnUGIaPag6iRPgwxtdnFRceNZstBkn2WrRVmR5VogqOIjQTuwdW42UpRinYN0zw6rDp2wVFI7ooAokZSiG4KsK6pSh4CPzjehrTPQFGuKsqwzoswqIs242fux4qqn/IkTmDpyJ1ItRqHy/SpFFWuH1tcOkKBdiwlf4oSssz+oCqykAs5arqedGCnFxkRUF7HXuqJKdWgiQIJ2LSa5dZ4lUrSxztkQ2thsFitbHTqtHbpBdbBlldYVCSHUoqq1QysCJmjX4iXdbjJaWGfMdA5KQjKaxdarDtdb6AJdmYQN9jkq1K4rRqEOgTrWEatKkUjRxjq3hrDOMkv4wqpDK/x0zalLKRLHJI8UI3wvq32OQh2a7+PRQVuadW4WUrwRdQ6YRSOzhK8edbhRLaqz0JSWQ2rRDe2ZVtbV1h6JOjQRIkE7tHVueFLk1vlAWOssq4RPhjqshcpgiyBG4pjEIYoL2STBoa6eyD5XyATt0Na5GZTi/jDWWVakWaY6tGKpREnchGiBc8I8L7KZttDVLcEcUSFMgnZd1rkZSDGwdZZRwqdCHVpR6ZqzTEqRoNw+i9EAqxvzDlU3ng3QQVuqdW5oUjSsc39Q64zUm3pK+FSpwygtNJFiAklRwWvakWGVFFvVNZ6tM0Hbitmg1rnRlWJg61zPWFLV6jBKC032ubnVoqkO3SC7v6IVUIghE7Trts6NToqBrHM9JXxRqUMrFqljDkHBxeymDtef8yklPQCwhigxF/eluI5j4q0zIs1hAitRq8Nai1GUczcltUjwpQ43CAnJajFEB21X68xV4mSYX2xUpejbOoeNNMehDmtB64oEGfbZrzrcICYkriuG6KDtaZ3jVNzaWmecI261zmZNcxByi1Md1kJlKzFSigkkRRYs4BJGHa53WFmWljTQChUrkqtjXgr7iw1HirXW2VnpBa9p1kEdWqG0soU4pmHVolOaTVhirBczC7OyAit1W+dGVYq+rDMUot9Is07qkCw0wUstehGiTBdQ70xonL8KzuHJen65oUiRq0QoxIMmkTkpxSCpN7qpw40WmlJzCN5KUaY6tKKe3gASOt9It86NqBQ903D8NnnQWR2ut9AK1xWJYxpCKaogw6obCznQygysKOiyU5d1bkRSdLXOIEM/TR50V4dWIC1HVckfKcVkE2O9gRS/6AmhFkGIy6srKnZnot4XaBhSNKzzASfrjNSbgc7ehlCHUVnoNVKLibXQKtVhLYKuK84tLcjofOOE4/W+QCMpRUfr7KfJA6bopRI6tEnl6FNSiwRvUvQfgcZyz+zivKpdyXPrPE2k6MM6u81prqrDBH/whcISXZkEgeXV1cjn7EB0+FGLEjvfOGFSyudpdOsMy+xUo5lkdWiFypI/Gk+QDKwZhLhmsdBRwmtdUWLnG6XWuZGUoq11xt2rt72zIdWhnS0h+0yEyGIiRS8LLbHzjVLr3EikWLXO7a0tBjna1zQ3ijqsxXVK4m5KwCovO0SYoyRGdON2KvlDYCWCKZSTsl4o8aRotc4poQAraxxD3X3ryA/fN5o6XK8UKdjSbFjBeFGN/jZ2XXMUB1akW+dGUYo3rLORQ2qtWAEvphKYZhMGqkr+iBL1wzJyED0IMXILXdM1B3mIigMr0q1zo5DikzckfAvrbe+qrm+YSdgtTXKhqMxXJOiB6vqhT4UYJTFa1xUVVqzY4XmZL5ZoUuTWOce/jJnWuSvbJobXJzUJu34LTcGWpiDEAL8TJSmi3M/M9EBNs+LAihWTMl8s6UrxwI27VJpt6h5o2ECKHygt+SNOihVuARWd0N7aJhSi6tnkFkxz65wnUrSxzjcP9LNMOsVamvziUWahSS3GSoj1BFSiVIuXF2ajiDRbcVz2CyaWFA3rvAffZzNp1p3N0tXD1JX8ESXGAxkR5qhI8eriPDs3NxP1IZqU/YJJVopV69zR1jpNl08Fqkr+iBTjIcTVBCh0BFPOzl5iF7htbstkonxr6dY56aRYtc6zi4VD/MshuozUlfyRfY4WsmuYVanF4nKJnZo5z+aLsdTfH1fxopkknjBW68yR/8Z3vwmlOP33X/1f2crq6rF0KsW6WtsZvjalhS4VWDbTqkQtNvuarWrgGK8EjDD7JUXZNzbY5QtyJ/DFbp2TrBQP2N0t/ubv/vcJKEacVNeKi6ywXGrKC0tVyR+pRfWEuKyAEGWrRbiRc9dm4iZEJdY5yaT4pOX7CesDhyb+3YRppZfKJSHrV5vsYkbJX0RJswRJSErKDezy+1cusrml63HvyvOqXjhxpFhjnae5dd5wt7ASI0qNoBqL0SWSakOM0i9c4i5lhBhFDXO9ShFECEJ0c2BOfUuTYp2TqhQP2llnB2J8zrR9SFVpJtWoIl+R7LN8RN3UIQwxmnYZ24qHA8mkIwlTTHLrPEukaG+dXe8WnBgPW+11M6lGag6RDELU/SatkV224iWVL54oUuTWGbY552adbYjxkJUYTdW4UCo0tPJBuZ+qkj9C/YhjbEBQpYgbq5ddjgmTKl88aUrxST/W2YsYTdKY46qxkYmDLLR+UB1hlkWMF+evsg9mL3na5TgIUaV1TiIpHgh7tzCIcbL2AodibFTVqMJCEyUmmxD9OIz8zHl2JZrGsNpZ50SRYhjrbMeN+F27E6ERVeMiKUVtoFPKjZNSxE0UhFiPXY6gznpS9RskSSmGss41ahGye9yOGE3ViPXGRrnwVZT8ESWGI8QVzc+py9fnpNhlzEZKsnVOGimGts5+iREAiVzjd0xEqslCEzHWixVNCdFUdLhxvn/1IrsczdgA7a1zYkixxjpPhbTOvokRJwpyGhtBNS4p6G1HFto/IeqacoOb/9XFBfbupQ+j7n8YFrNcJU4QKUq0zi7EmHc7cZKuGlWU/BEleiOulBu/7uHM1Uvs0vVZHaPLjtY5qjdKCikeUHFwDGJ8Anchp+c0gmqUHXAhpeh+w9A5wjxz/Ro7O3tZnNcJG+n2UlRvpD0p1ljnSW6dpS60cmKEhR7v7uv0tBtJVY2y8xWJEpNHiCDBMzZrhy3JmGcE6xyZUkxCP8WnVN8tQIynXniBFRaL7PL5WXb+zGW2MLfoqBrRq7Aj05aUE0rJmhH1Vqw9N/SNMOOGjsoUu2UUFX0Wk2ydk0KKB6I6OO2dWXbzrTeJDQT5wXsXBEni+9qTrLyywrraslF2BanrokAOZqvEYn1cSC0tRIu6EyIawV6cdzZXCbHQL0X5ZrGQotH+K2fzUN4aWebPAyH2q7LOXgR5+z23iA2qEeoR23J5JZGqERa6tUMiKRIXCugaYRadbeau+ErJ0lwtRmqdIyFFTmwgtTG+PWh83ePxfHyZNrZcXHcLK7DeeHtfhSAvn7/KLp+bFV9BkElRjQgU9XZ0ESk2ASHinEQwxW+FluakOBn1GyojRU5uIMAnDfvbH/DX93iRZ1wY3jwgNsZ2CGI8//6M+Kq7ahRT/nrlvZ64iJrYPusaUEGLL9jlIGlYMi20gml+kYsh6We1QYbPGKpQNmCtD3MbLf3uceqFF0Kf41CMpoK8cmFOW9U4OrRZ6kCrTCrVdMEWVYOlZNhlkGHYvof4fVlq8fTMOWnXO7fOOxKrFA2bDDJ8WuH+wk6/yN9rin89VG9li7SD2Jpmm7cPiw0EOTNbZDOnLrLS7KJWqlH2lL9mC7aYKTe6ATYZdrmeOndNLfRkHG8qJU/RyCV8XTEhWgEV+jp/34O6/RU7BvvZbR/fxT75rx5gn/ivHmQ77t/FuoZ6tNg3Ff0VmwW6DpaqdLa5UHfjD02j0MfjeNO6j4RBTMdiPHATXDEeitM+V+8wbW2sc/Nm28fmL15l5954h81dmmelpfjGIdxx03Z5Jw9XF5kmUIq6ptzALl+V2PdQloWWZJ9jsc512+eAhDhryOGXWSX1Zsrm9WCPoTqfZfYpO3Y4aFj3Q1Gm7GwgiFSKdWzaZG+7uMJIrxbZ1jtvEtvSfIFd/mCWXbs4z5ZL0fZwhFrsaMtKs8+NHmzRMcIsOttcuSi9LZxmFnoytms5AkIE+T0fJDjCXxtTtvstROrHJotyvbDEWK9ShEKEUrRDcWaGla+vXwBPt7cLEr1y+iKb4duV0xciIciBzh420tMv7fUaOdiiIyGijt2sXVbymSWUsUpSinu5UpyO4xiHWlP0SYh5g6TGAxLiQbY+YRvWeIePO4epMCNH+9CQIyEuczKsJUQrBkc3sZ0P3MPu+28eFl/7twwovqgS0SYqdujY5QbNHFC/vKqws40mgbN8XIQYihSNoIoXIU6A6e0ssg/st3wvcpQQZeYbutkcYi4dbQwrHSkxtnZ1sUyXfVL0aqnEClwl+sWmndvYrfty7J7xO9j23VtZ3yb5ARpYLpkXVaN1zNGxqYNTM4cGJsXJON88ECkaa3cvejwNa3uh1veM1zdrnWdrFSb/P8jWtQcix9NGeaD6g8fVYduAvbLDOuLSxYuhXjedSbPBrX0sd+/N7K4/u12sQ3b0tEu1YDJJhAhRrV1+99I5JfN2bEnR+Bczjsf55kGVIvIQcx6EOFHH/ng2f+CvD1m9lzl0zTZwzCBYdScPAivDw+KrHUCIaxJSONo6WtnILYPsjvt3CILcfNuI+Fk9kDmioHHm2eiXchOFXdZQLU7HaZ0DkaJRqfK0QkK0tc4OxGh2zXZSoyBEpTa6fWSEtTiUNBWvXhXWWTZAhjfdOizIESQJsgxDkEukFDcQok4pN1HaZQ1J8Xjcxz+IUnzG5bGj9RKil3UOQYwHjRQf+eTU18fSWfu0FhFYmVc/Mxd2GrYaBHnbvlFht2G7/QAVEDLHuSaZGHUbLIU1XyRjL8acaB+jhZ6M+2/gixQNlTjm8DAGSR2RsC+B+yYaVvpoSCIPhUxHhyBF2zs8V4dQiVGje6BTBGbufeSjbNdD97KR27Z4EqRUtZhQC61byg0SsTF3WYf54zGpRVjnfFKU4pNutlnSvviyzjbE+Byr5EI6qUVpa4sIrGSHhuyJYXWVFS5flrKOGOokTqVY+/AwG9qxmd0x9lG278tjIsUHKT92kLqumEBC1CnlBnYZuYduzWCbhBSP6/DZPUnRIJWDDg9PyGjKUGOd8yG64LipxYPSSGdw0DGwggTt1eX47vBIBLfuW6YtI1J87vrsXrbn0T1CSVoj2ItNqhR1izCbdlnFfO4EEuOkDp/bj1IcC0lGSq1zjVqcclGL+2XsYHZgwDFBuzQ3x5aX4jupvZLH18pFseZoRrCxFpntbpNWJpYUStSNEHWyy7akGO26ohbWWQiKgLZ2HatLbN21X4KEPu5A4GP17lxrT49jgjbIEKQYF4Imj5spPtjWSmts5coyW11YZSuL5boJR+dyP50izEFGBcSuFKM7ZMd1+dx+SNGpA3bdHXGN6pha6xw2RwkK85jD+4yFrK4RNcpZpwRtbpeLASpWpMv8OpPHW9paWDbXI6z38rUCK5yZZaUL86EIUufeijoRYtBRAToQY0TLI5O6fGY/9tmJFKfCviknKVSdnGKVHownZLymkaIzFfAzuJ8QRvDCkXRiDqy4JY8HDfpkettZ9+7NbPChnax333bWOtLOWtL+SU5XC61Tyg26Yutsl2O00FO6WGdPUnTJ85sNa535a0LNObUGQ7S4nka1Lzv8PFQEujZ4YUVJUYK2X3glj68Uwjd+yG7uYdkd3ax9dxdry7WzdK+3odAx2KJLyg3s8vlrV8SWNESk/o/r9Jm9lKITKYayuEYHnIMeT3vWyIsMA6echnsDk45L8ALJ2W6db1QDdj6q5HEQIohREOR2Z4LUjRJ1SbkxB9GHnZ3SJMQ4qdPnjXrus99k6qdCWulpGUrRK3gRR4J29Q/W0SECP1HvG6x0eiAjtrUVbkmvLvOtzFaXVtcRY9yrijoNlgozWU9XUlToBCa5dZ7V6fNGTYo5n88bi+uAeCVoh+18E8W+RZU8DoLMDLeKTUSwr1UIcq0Qb7BFl8FS9U7W044U1d7qXtLt82Y0/Tv0x/LHN4IXTpDV+SbsvumYPI4IdpUgC1yhcQW5Nr8iyDJaItIjoAK7fG5uRvqogLiRakmpUryTun1WXUkxH8ebugYvQDoxBlayLmuccSePVwmyPcVatrSx9nuGWMtKhpU+mGOls3Nsrbyi9H11IcRGsctOFlrBmoR21rkeUgyr5HBXOODzeWEwFpZkPYMXMQZWRPJ4R4f9vsWcPG67r8Z6bMfdm8RWvrDAt3nxVTZB6hBhbjS77Gaj1+Qy40s6fk4vUnQKXOwJ+X5HfZDiLAtfPtjn8PPTfi5m2xM+5sCKzsnjfve19aZulhlqZ2uDK2z1SomtLfBL6xq32av1XWA6EGKj2mUntSg54DKp4+d0TckxEqJt5a1RjRIIRrWK25wV0SOxjlGloZWiLenE3Pkmxa28rsnjGy4Yn4nuLf0Zlr2zn3V+agvL3tHPMiNdod5Ph5QbKEMVo0a1ttANbp09SdFDLYaag2I0o8U4AbPll7kd5tuOsGV+lpnRQT6DK0CIcXa+aXepWIk7ebwWvhPd+YWVam0VuTuZTZ2s62NbWd/Dt7POezazTH+H942Kxd/UwZqM3YjrhxER43FdP6OfNcWXHRQYeiweCUmMeYMEZcKJpGfDEC3W6eqpCqmbEDVOHq9nX9OtG8cntGQzrO2WfrGtLpXF2mMxzwmnpgZbh5QblOihdrlZ1OGGv5WcdcVZrhIndf2MfpSi087n6qg8UYGnHH4+Fdiaad75Js41znr31SmYVT0hO1pZNjfAOj42wjo+fhNr3drFWtrTWgyWQlcb9D5sVkL0qxTbMq1hOSUZpGiorLzDw8/o8CGM8sGcw8OBIlziQo6z8w1XUromj2/Y14CJ7rDXLem0/9fvSLO2W/tY576bWOeeEZbd2s1aMqlYPiuiy1CIzWaXwxBjyps4X9L58/lNyTnuQIBjmLEcolO2TELsdyHn2SADtURg5cqVyIIXH+TPs7deP8muzS6I/2fb29itu0bZ3Q7R5jiTxzdcGCES3VOt4UezpnvaWAe22/tZeWaJlS8XxNe1ZbXHo9ntsgILrbV1DkKKzxn21C4/ETOWp+qIGNeLZ11U4vNBXiiq4EWptMxe+cEv2enTlzY89u5b77NfnHidPfaVh9nI5sHqz+NOHq9FmET3tMO648a7k/sF1zrUITa2NsBKFxc5QS4JglRhl9EMltShjVIMv6w4qfvn8+VFDMJzIhgQ5Ysx2uaDTnckg8z9EdXcXGTBix/+4Le2hGgCyvHbf/e9qoKMO3m8FmES3YNYZ99qmF+bbTd1sq7dQ6zv01tZ552DLNOfJbusgYVOqnX2TYoWteikBseMPolREuIYc+i0beBoEPUaVWDl5Mlz7Nw570BJsVBiP3jxJ9oFVsJ26fGtEsNepJmUIMi++25hgw/vFA1z0Tg3jF1GI1jMTyFIJ0XtrXMgUjQIxm2c6cGoiNEgRDd1OmWMPtUOf/j9Gd/P/eDUeXbp1Blt1hHr6dKTUkyK4j1aW8WW7mhlHTsG2cADtwqCxPfpTu/1TIouByDFcJ1zJpPw2QKF8oyAyqQXMcqctexgmU8w5/prL/KOFTMzwRSIaaFjvwg8uvS4JbrDNjv9nrT94++RtqkPB0FCNfbev431fOwmlt3WzVLtGbLLMsijJfDf9PlEfK4QvwPCcUuGFqQVpgzQgwz7DSXqpUYPSZwyGDuuzOhBim5derzGH6i2zqiSSXc4V8OsFouiTjzdzRXkbf2s95ObxTpk2+YutpxaI7scjYXOc+s8nYTPFZgUDRv9BHNeXwRAiK9zEntWhmo01OHrzHuUwaE404NUYHCoO/Z98OrS4zX+oJ5UHD/IdHY6KlGo1xVOihs+01AH67p7hG15dDe7dewedtPObcRyam10Yq7LUK3DoMQ4UY172FjgacNS44A8H6TczqhlRukeUoFyfhRskJzEuDA6OuIaea7F0FBPrPvr1qXHT6K7auuMKLhTVHttZYWt+OgzOTS6SWw77t/Frpy+wC6fOs+unLlMjOdTLfrsnHM8MZ+pTgW3xwcxrpPQrFJ2d5rZl9/h9UZZpdY6iP2umxBPvfBCJD0G3j8zw37wX/zdG3besYU98MDdykkPzRxqIZKvucrq2LzZltTMihWv3EmoODf7jBLBWlIDmS37SEFCF6E0f317Rlxjy4uL4rUcT37++xmb34fdLs4vsMunL7NL+Utscbax+yTWi5XV9cf4wrUZViiXaq3zjoZWihbFOM2JcYdBjH5ILGexwDJKBIWVDzvoPvI7ECeXXZ/Yzc5eXGBvvv6Op0K8//47lO/T/Nx19qtf/6IS6T5/RVTV3LxjM7t5Sz/76Kc/4j7+wEcyeVqRdXYKrFQv1ELBlRA9L4y2VrZ55xaxFa8X2dWzMxWCnFskFgyuFhO1pJWu9wVeOfmrwgM7P/kt/i2Swu6PcN9BhI+EbTW2wef/9V8fUb3DiN7iQr7trlGxFoMyPzts2TLA/uLze1hbm9ppEbDx3//Pv2ZnuWVcXKjYzJXlFXb18hw7feoC+/DMJbGvmcz600Qkui94B4BEeoxHkAXBmw3Ei+ax5bLbVSjWOB3XETlZ+yFs/L7deifI1EqoGf536OY3qZtu28wGtw2yVDrFysUyW1E8ZiFJsJb9XS8useX16vF/+Oc3XzvfFPbZxk7D9h5j/qf2hVWHR2XnIaq2z+gmU5vjh3Sb6Z//gb3+8zdZb383u3vvTrZtUxfr78kq/8MjNWjyxV96Pg+lhl/52/03FBi3lksXLvhTWx7WOax9xo3FKXjj13p72We74Ewtrl+Zr1hsvq2Ul1kzw2qha+xzoqyzuFHLfDHYWL7hACBtJ6+CDFmlEe1ziTrIDknPIMJb7xqtfD/Qze4b38OGRvoi2acf/vC3vp4HS21afawxFi75DxKpsM44lo7RbGMdMSp0Dfaw0b072L4Dn2B3fPpONjw6zNKZNGtGuKTnJC4bRIk/M4IeE0YqDWTGgTpeDvYYSZ+TMTadCH+yoJuMTSAjTkAlLsz7b6ALNXvXvbcGGn9Q6a4td14wlB0CQ04QhBjTiIIBbqux4f2vnL3CLr9/mV3lX5uGFJ075xxP2mdRumhlIUdEp2GtEYx5kFWi1XscCBDE97Lx/VQSidAKtzb9ceH8uWCHFGoxaAch6Qnbxjqio31bWqorsCJzPwdvHmLDt25ha6mMSPGZOX1RbA2vFDdyYmIStgORopEvmLN5KO+3csQgNq8SwYYD8vucqkBAMFHUA9sBrcuCIlCXHnMOi8wTFWt/DsoTQRnXwEzUBGFRtJt2bhNbcWFJEOOFP55h1682ZoqPTRQ6kde7H6UIC2yXPoP1vSOMYAsEVly7yczOxmarg1bJBI2Cy15LBMG4JmjHOEvHr6LNdnewrXffwjblhllh7jq32DPswnsXOVkWGuactyHF40n8HBlGkA4owDanWc1GNxmnBq1RACk/QTCaGwn2+SWSouh846So+QUoKlZiHnXqV9GauZPZ7na25c5tbPvH7mCLs4vswsmzQkUWFhbDdp/RgxSNfc+k0om1zkSKKk4Mo02/VzeZdIykCOW3+57tvtuY7d69PRbrLBK0XQIrYh1xVZ+uNkgVclK0Tha/a6iH3Tq0i916/y62MHONnfndKXb+nQ/YyvKqmHViRnXxVfy/ljRbNpJS3Gox25pFG7bELpURKUoGUm8c2/R7dJOJEh/72K3swqV5dvmCe9DlgQfvDlR/Lc06m51vnNYRi8VYZ3LbKlqX3Ek/NdjdQ73srrF72e17c+zCmUvs4vt8O3ORLdskiaNtl/XQpG3+D440iTJt3KRVkypIsbMty2YSap2JFGUrsL6+urrJRInukSH2r/7bL7BXvvcL25JDqEkQIhpYBFJLWTmJ52m3ihWHzjexqSM3RRsmd5ITy023bBLbculOduH9i+zC6Qvs0tkbzTdE30fLqsEK86+YQX6pVMu6/6dr/i8m8rVUaNKPSr3xeQVhTyTVOhMpyjyQ/CIGKdpexDGPTXXb18898efsvvG9YmBWqVBJuRnePMi2DrUHVrVBR5iaqJ1qCIiphntvF7XY6645bpf9qK4I/aKrol2uc80TJYbbbt8qNpQWXuQK8uw7Z9nVi+HHZyCfcGV1/T4FGYropFI5cU5xAs3z/x9O9LVMdCbBOnG77NqmP8KxqWH2FZU1ez+1vhtPmPnSQdcSi/wi//5/OsHe++PGtU00qEDS+LqphpoGVpwUrQisSLT4rdnWKkEuzS9xBXmBffjeeTZ/NdJGxLNcpU5zXoUSBDNPcZWaPzTxf+QbRuAQpdUpFNCm3yWwotNoUq99rdvyBsy7/PH3XmOn3vnQ8XFzquFffvURQYz1dr6R/nldUoVEYEXh372jp4PldufEtnhtkX347ofsLCfIwnVpa9Z5Y3vZ8v00J7/ZRr+miRTrhFuCNtYQlzWyem77KoNwg1jnt/9w2pUQqzcVbumx7vnEv3lYqwRtKG6nYxl17mRnbye7fe/tYrt2eU6oRwRqfBLktEF4bxjfz3Lim2rma5pIsR47gzb9XV321gmNSjUaTWruK4Iqb02f9Hz+aqm8zvLfd/9O1yh0UOv821+/4/u5sNKzF6+wnt5OPRS3Wy/HmC1+73Cf2HZ94o5KBPv0RfbhKdG1a8ogP7PBc0NZXl1I8ZmvP/q1Z5LwIb/x3W9KT+Bya9MftJuMclWDLj3Gvs5zS/rBqeCt7bxKA4NGnS9fDObCzvILfNfuUQ0YsaUSaXZK0NYld9KIYA9v6p34i2f+x0OMQEpR6flmrM3ZEiLa9AfoJhPFvlrLCXv6u0VnbXNf15ZXOGm2smtXF8QaHoIuaGNWqxTdSv2iGGE6r0nHa9cEbc1yJ1dKpentjz5KhEikqB5unW+CdpOJel+R5oINgJpFrSqe84sT0+zVE6+LRrfo64jos991sXQEjS2GN/XFfixFL0eHxHzdcif5/swuLy6O09Ua4u9MhyAY2l3mH6Pjc6BuMorhFljBSAFZQaAwZX07bt8akBT7Yz2Wbr0cdcudFPtTKDyx40tfmqUrlkhRKdD5ximwAnVY0ChB261LDxQNSFEKWYS0znvu9z+lcNc9o7EGWfD5MpoGVmz3p1g8PPrFL07RFUukqNw6uXW+8ZPsjGDFyZPnROdrL/h9XuB9lRwE8rLOiDL/6mdvrd8/rrpuuWP7hoRxJ4X4mfF7lZGdr8/oUrGiW+7kSrk8ccsXvvAcXbHhUc+aIoZHHWmGg+Sn842fwMp3//NvBNGhnvgvtjnXFC8sFNgrL78pvseYU3S0kbGvKoJAbqSIPMR/OfGG+B7R5oce2cfaO9ur6SwPPHIfy7ZnxVqmHbZtH2GfP/Apls0qGpPqY1yCa2AFUwM1yp3k+zK9vLh4mBFiI8WmQfvIiJTONyBDkCJGi5aKZebUXP90/oaSC9rL0G1fZQeBvOawbOWkBqUHQgRBvvStV9jnnvgztsmyBIGgzh6uGJE/OT87LyLgw5sG+LEajnQdEUni2IfL52fY3JV5NjTcw24e3cx27tlpr7g1a27L92e2fP06rSMSKaoHGic45eCJwEqAzjc779jCfvOb9yrEx4nxo9u3OVpnk0S7u9ul7Cv2U3YQyCvAAoX3V3/zMPvx919jb//+tCDHF47/s2hCcdtdt9x4XnvbOisdZEypDGDE7C+4Wi0WbtwwMAsb1n/kZ2+yz33pz2/UX4sdjHZqoDcjrrHy4uIhToh5umIlnNd0CKrYcEJ5dr4JWLECgjOrQn7/29O2z4GSNNcSg6hE2fvqyzr7jDo/9Pl97LOP3VdVZN/5Dz8SKUA6APuBMkIrIVqBoV2ov7Z28IlzaqDtzXlp6Whu//5JuoSJFJWSotOsZnFjrqPzjbk+iIvNeqFVVeKfKioRydJ+exl67WuYjjf1WmcrYOd3f/Ju0djBBNYRQY5OZBQF0LLMaT2z1lr/4MWfiO+1mRpoYKVYnLzlsceO0OVLpKgUomJlcFBJ5xsr0b1l09w1/+65qkr0MzDKa19BiCqqa3znJloGOb3y3V+sewg9HKHCcIOIA2+98a5/Aj11XrTq0iqwsrw8zVUiVawQKapH1iVBu96kZxAd1haBN18/uYEkTPXoVyW6JWgra1uG+l+fVSzmICcoLZAf1g+/8rf7q1U1pj3FZ48aqKcOpCzfPavNOcpvdLPlhYVDFFghUlQO0U3GZaSAjKRnk/BAgJfO3VBJ771dWWfs7mn3RYpuXXpUVtf4XUs0+w0iqmuOPECQBUGLz37x0yJFx7SnsNJRE2PQemo0xdWDEddwLh7mhDhNVyyRolJ4db6RNVIAhGdaY3SXFhfcUqlKCn4I0W1fVQVWglhnczQplKC5Hnf/+N5K1NmI3qLrzZf/7ReEeuy1NKqIzBEoyn9UjeVC4bnRxx+foCtWDSglx3IRR9n5BhYaI0ZNu2xdV9u5c4u7e/Xo0lNQ2aXHxwhTc5ATFCCsMQAyRE6iqbjN6O3IliF26H/61+I41M5jUQ3kUfppdGtix+1bYj9PV4rFqVu+8AVK0I6ZFHFHmrL5eb6RDkTHTTdF2vnmjju32c5dRsqO10hRty495lxpZWraSyVaBjmBEEGMsMuwzeKitplbAjJclwcYEfbct8s3KSKRPO6mFKvl8iy/oTxBtBUzKX7ju9/MNxoBOqkvO6hIejYVEixjbVqOl0p069ITxVxpr3EG5mhSa2AFyc/4qnpuSVDcnNssAj52I15rbfZDn/94rPsqKmhKpXEKrETgGukQuNyZFa/N7fnU7g0/y93mvK7m1qUnirnSIDunfoKCELNZ8bhdYEW3sjjxWTjBV+qvnYm+p6+T7f/rB+JViWtruKEcGn38cQqsaGKfmxKqkp6twDobqims/+8d6LElD7cE7ajmSrutJYpBTpwUnQIr4jPpUgVisfhmNQuIEaoR+7+2usbaWtOiIcWd94zGHpBZKRYntj/66ARdlZqQ4tcf/doY/zJm89AUt9ZTOn0Yvq9HHJYAjgR9LVVJz1aYEVdzZgoGwDupmg63wEpEc6WdchOxfyAZp8CKWxWI6jEGtp/DSBVCzbOpaDFfGnZa3GSKRW26aNNIAT2VIgjRaUDVlGafx2k/A5FiMcKRAnft2SlIEUoFRLJ6beOSkWuXnojmSjuOMPUIrHjOLWlpifQEEalCfEOJn6nSYaFNQtRq+aYyUoACKxGD1hRrELTzjQwLbX61W9tCLqJT5xuZIwXCWmdTddkFVsQ6okZzS8zRpAhufecffiR+Bsvsp9ltHMs3xkiBPF2V+inFqKzvCQebPh6VTVcdWLGDuZZlZ51RWRPFSAFfltOGmE3VZRtY4Re1Vu21UIPd2VmpnvmHH1UVLVSifoxIIwWIFDW5MxdiGk2KKHRtnp5r55uI50rbzWExVZdjYEWnuSXsRg02LLOpaLGOGHXCuB/QSAEiRS2weO5cbC2hagnRrfNNHHOlNwRYLKrLNrCi2dwSp8AKAl0agkYKxAxaUzTJRqOL2LVLTwxzpWvXE03VZRtYQYK2Ru21zBrsIIGVtfgULqJs1PmGlGLzAqrlremT1ZQckMuWLQPs4+MfY702jXpUVdcEsc6egRWN5h+bNdi2gRUkRC8v2waQ4lhCMXBoZN8+StAmUmw+YNTpd198ZcMIU5AMtj++dWbDHJM4gkC11lkkaPP/2wVWquuI2jBiJVUI7b7sAiuI2qccpvTFhKOcEGmkANnnJiVEY9SpE8z+gmbnnCiqa7xI0TWwYpBMjApr434bNdh2gRW7phQxY5IT4hG6OogUmxLojON3yL25BhZFdY3tyWHOYYHqQiswrrocAysakYxZg20XWIFl1qkpBas0W6GKFSLF5sWfTvrv34e1xkunzsR2EZvrbeZAeNvAimYkY9Zg2wVWdFvzZGtrCKg8wVUiBVaIFJsXC/PBOsVc/OBibPuaNiK3IJpEBFaMGmynwIpWTSmwP6XSYQqsECkSFJOoTJXYwjfYZsfASowk849//yP2LyfeuDE3xSOwottoUowU2PLAAxN0huuHeqLPDzp1pQmJnMPPnzQ69TQlBofiSTCGSsy4BFbiJBl0y758cVZsmPOS3dRfTRV65T/+bENgBfZ+VaM1z5VicZpGCjQmKY4x+1pl2TjYSAccQ6lOn/ZXoofhVl6jCZSdGF1djoGVuEnGHCGABrBo/iosPidxu8CKbs1tjZEC40Q9ZJ8JBnbfs933c++555bq1L/I4VCxogPJnDKCVTtu3ypaqkEl2gZWNGtKQSMFiBQJNrjl9purBOMGKMS9H9sR237aBlY0IBmoRHMdcdc9OWHxHQMrOjWlwFjXQoFGCjS4fSYEvQNxm9c2MMDuHhoSJAPigRKzU5P3339HJPtUXCqyt7ntfPet0+L/+FosFDcGVhjTgmSs1nlzbqtzYEWzphQYKUCzmokUCVY3WtP5Bmt0t931bwQxgoAwlgBduLcOZlmmJRriOXnyHHv1538SVTYmzFJDU3XpEFipEjgnwLd/XyHv2+/OOQdWymW2tLDIZi7OitnOsRNiqTTNVSIFVhqIFPNMv7EDiYNT55ve/kog5ebcFkFCqF6JYs0OhPjKy2+6Pgdkjea3GAKvQ+cb64zmu/budAysvPO7d0W6zvzcIvurv3k41kl85kgBWkdsIFL8xne/CclPsr8OtPX1ibUvXbCwUBAK0Q+gZP/r/+7zsU+0E6RoBFhAfrDLtYEVrC3+8z+9zM6+f9FCpOdiI0UjKEUjBcg+E6xAZBSkqBNO5y+ts8yulpWTDxQa8gHjts6mUsRSQ21g5Rcnprly/EN1jRZrjg9/fl989tmoWKGRAkSKBAtQHtfuMJo0VlI8HWyUwYdnLsVOilbr/O5b71cDK7D3x/6v/0+oRBOf+PTdfLsr1v3lhDhJIwWIFAkWiMAKJ0SnkQIYOoVJfUkA1uZ0sc6mejWBFmsmMLz+oUf2sZ7ezlj3dbVcnl5eWqLON0SKBCtAeK4jBTRKF/ECrGicKC+vrlOKJswoOfbvz8bvFcnccWNtZWW2fP06jRQgUiRYgbGkKJOzvcCNkQJYa4wLuds2s3Pn/HfxjjOtBWk3+XcuOD4Oq/zRj9+uRSAIDqC8uAhCpARtIkWCCTGa1MEWxzVSoHb/dn3yHvab1961TRzfoHg52cSmwIzmtu/98f0NDyHY8pkHP8KGhnu1+dtzy/xcbv9+GilApEioXsOpFOvYtMlRRcQ1UqB2//AVaSxm9xs3YI0uLhWGVmCl8ooIrFRJur1N7Puuu7ejSkSbv/1KoTA1+vjjlKBNpEiwwiQcO8Q1UsCK9pGR6v4hlQVArp+dYgQRghCjUomIHpsRZOT3bd02JKL37/7unepzkHpz3/he1ppJsRWNGj2slsv55ULhCboCiBQJVhJxCawUZ2Zib9mP/cPsEivMMj5UhZzNnxPkCCWGNJfRW4ZYW6v6aXcIloCYzTGvVkW491O7+eMzlS49X6rUYIumFBGPeXUD3x8EVqhipZlI8euPfu0g//JkA31mMXD8G9/9prSTuLWrSwRX7IALuBzzRWzdPyQ5X5udr3bqqZDP3ZXOMtb95kpM9TCqt/9wmv34e6/Z30g4Qb964nVBhF/52/0GA+nX+Yb/bQ9TYKX5lGKORdNMNgrk+faETEI0O9/Y2ipNAivYP/Qb/MELPxEW9bEvP1x9HHXWcUTC568tsp/++A1fShJEjga3unW+WV5amsjt3z9BNEL2OamYkk2IInDhkqBduHw51nVE7Fcp1cZ+/K0T1WAFlKHZ+aZ87Zpo0moCz0FUF89RjV/97M0b81U8gPI9pN1kmD5zpcVIgcceowRtIsXE4jlOhtIjg+h8YyUVK0CIcc8FeetP59lrr/5xXSClOryeW/oVrmQzlv3/BberxcLuahBGJU4FGPWK/b945oIWbcCEA6CRAg2NZui8fUgFIbp1voFljrNlPxKzJ1/8Jfvp1O82RJYRRDFtfbr1RqoNbDWs6ntvn45kH/2qRBNnz1zW4mSikQKkFJMMnLTjnBClL4KDDJ0633AFIapW4gA637z66p/YyT+ds1e2iCzfeTNbOn9eVIogObqqKo2+hLDQIMjONr3ulzpUrBgjBQ7TSAEixQmmT5PZp/h2wMfzpg1ClH43FxUr3Dbb2ioosJmZWA6MXRftWsA6m7Y+07m+nvnN109WvwcxfuTenNL9Rb1ykEYTw5vib79mjBSgzjfNToqcWPKsErWNDV9/9GvoEvqsT0Kc4PusZAG8dqTAOhGBwMqVK5EHVmZm5tkvXj25rpYZ6TVQe9ZKEODmLf0VW4/yOYt1hm22tt6a/vkflJPirt05EWzxS6BxryfSSIHmgfZrigYhnmD+5j8fVkWIwsJplKBtWmWsHZqEiJy+v/zqI6ynv6dKiIgmAxiVun1rRW0JQlxnnU+ue22xvnhOreLdc98u0UHbD9ABJ07QSAEiRZ0IEdPXT+Ea8niquX6ozNq4db5Bb0SsJUYFNIn91v/7U/aH35+pEt6ffXZvNcnZbNOPBO1rVysKcDR3Q2mlWltrrPM7G97j7d+rMwdYz+zs760OmnJDlKWGdqCRAmSfdSJEKMNjPp6K9cMnDJuvBEhudup8g6YEIMUoAVI01w5HR0fY2GfvZX3bt22YfzyyZbBqi/G8CiO1rCPF995+37b2+Y+/P61GoRmdb/AVhG2+N1Sj1cKDCNE9O86hU6KCplg8SiMFiBR1IESsHz7t46lo03RIRUCleg0bHbRtr5nlZVa4dCny44OZ0FdmFth99+8UjRM6N28WJGmdfwyVaCpGKEmTFNM1KrG2eSuUG17DnIkiW6Wh8w2UItYxzS49IHCz7NBUZzrUN4uRAo89doRogkgxTjKELHiR+SsrPMrJUPkJ69T5RrQCi6liBSR34IlPiu9F55tMhr3yn35SnX+MdUXAXFd0ss7WOcogUvy+UJdXKx1r8JhMUkRDCnS+Aemi5NBK4LqBRgo0L7RZUzTWD1/3QYhmQwflhNjuMKsZECMFYu58g1xJEI11/jEIEcR48cPLG6wzyN1KilaVuOdTu6vf3713Z/XxoEnWjoqbk2HK6NIDhVhL4DqBRgoQKepAiEi1QYQ55/HUPKsEVCZU7xM6y3iNFIhV4hsJ5Gj0YA2smO21fvez326wzrUBFrPUDr/TO3AjEnyXpczPbjZKmCUIs/oHzR1MBWsSuHakuLpKnW+IFGMlxCOGZfZaUZ/i214VFSobDorunW+46kICeW1gxaxZRkPb/KkLG6xz2qJ60aXGJLy7DGVoAkGPbbmbxPe//fU7dTJii1hHxFeQIdqBWQlcQzy37eGHJ4gamhexrSka64eILseakG2natw63+gwUgCBn9rAClr0AyBs5BguzBc2WGdR2lejEgFUulgjv4Io78mxs/kL7PLFWUGgYceGItJsF1jBhhuM0/JETJga2bePErRJKcZCiDnDLvshxENRESJgBi7soMNIATOBHJbZXJcz8/1EQ1tu7a9cWfC0zmjwCty6a7ttErU1wPLGr0+GO7n4e2KzC6wY+X86XQtYmqGRAoTolSInxDGfdllZQwc3wqlt2W9Ch5ECZgK5NbACQgSpWW39zp1bBBnOzy/ZWmeoP2yCFB2iy22cZHfdMyoi0LDZQXMWoQ7TxjrihsAKGitoNGPFwBNcJVJghRCtUjQSsk/4IEQQ4Y4oCRGEo/NIAXN0qjWwAst8c26zbUNbqMShoZ4qQVmts6kSvcaXmo+hccOHZwLkY7a0VBtO2AVWBCHqMlLAcCOcECmwQohWKXJCxPrhQR9PnWCVGuZI79qqZzWji421pZdIj2lrrZbhoUvNB/lz/P3K68gNCdrDI30iX7I2sGLOVREq1qWhbdph3W7Hzq1CEbqRIpoxlArlQKk5ghAdAiuYsaLTSAGcb5wQJ4gKCJGRoqWhwx4fTz+ssn45KGSOFEDgw9rJphbWEZ9WIKCCdU6nwIqfuuva9URY4U98+m5W8kF0j+z/VKBSO9fASrksNl2Azjc3feYzlKBNiI4UjYRsP3YZqhD1y1M6HRyZIwU2b+lnH/vYrTeUYibNWrs2BjjK1xfY2vINJTW0fatY5/yxZV2uGljhZOhVdy2ss00kHdbZT+PWIIQoAittbYkIrGCkQPn6dRopQIiOFI31w2eZv/XDQ1GuH/qB7JECW7YMiM2qqGCJa4EIt/m+SCBHPqJdYAV1134a2qYjSnkRgRVjKqBdYEWn0aSCoItFagVGsL+5KyJEkOExH4SIhg7juhFinCMFqn8Yy2hSu8CK37rrWuushhFvJGjbBlawjriqySQ+c6QAdb4hRKEUdWzoENhWxThSoMoxRodvJE3bBVb81l2DEO2ssx3MXMVL564E3l/R+Ya/j21gBbOaY55qaAWNFCBEphQt64dehBhZQ4fAIiKmkQK1gGUu812wC6wEqbsOohJNUrTrrehKiEbnG9vACifDuHM71xEijRQgRKUUjYYOfuxynlUCKlrmhOmQoG12vjlhE1gJmh6UVmydU0bnG8fASoTdyD0dQGWkAHW+IagnRU6IaAb7rI+nThmEqOVJaQ1wRAWsF2I+ipmKI0aQ7hoV5LIhsBKw7jpVM4dFhcV3q1gRx1KjwAp6I1LnG4JSUrRM2Dvo4+kTUdYvh7JWERIicg5f+cEvxViBWlgn8JmBFSBovqTSAItHYGVlcVGfBG1jpEBu//5JutwJykjRaOiAgIqfhOxDUfQ/TBJ++IPfuiZym0D3GmHrg6YH1YwwrWtJoVjekM9oJmjbBVZg8Vd1CqzQSAFCQAQOtFg6ZPuZsLeXCHE9UO7nhxBNW2p2vgmCtCTr/OPvv8Ze+tYrIgpePWHa2oQKtQZWEBVHYEW7BO1SKU8jBQhKlWKACXsiwsy3fqMrTqzQqVLGHEvqBx+cOs8uv3+OdXcFS8CWYZ3RAMKc3/KPx3/IHjnwKbaNW3moRGtgBXOlYfNh7XXqfCNGCtCsZoJKUgzQ0AEw8xV1QYsuOzIzE0z1zV+7HowUa0aYhsXW7SOiRvpfTrwhLPQkV4wPfP6TbO+nd1cDKwgAPfblhys2VaeKFU7QnBBppABBDSkGTMgmSAZGmVrLA31ZZ0n46MdvZ8Ob+tj3Jn8uiPGV7/+STb/6poiWW1OFdOt8wy3zc7n9+yfo7CGEQcqDEP1O2CMowuBQd+TWuVYxfvnfPladp2KmD+391O5KYEW3zjeFwtTo449TgjZBPilaGsLm6DDJgzkewC/MRrG+nHPNCFMpJwh/vb6RfpFuc7dlyt/rP/8D++C9D/VK0C6XZ5cLBRopQJBPisaEPT8VKoSAuHP3qO/n7rxji+igHZdKtHa+gU1G2k11QFahxL498V/qn/YnCbDvaAVGgRVCvcg4KMQHWaUChSDzDtTWxnZ9cjf74NxstWLFTSHef/8dgV5fZpswRKZSRoK2FUi/GdkyyL7z//xQrDMiEHP50iz7zPi9vvozqmHENQRWqGKFIO3cJ3CceuEFP80swh9ojE7dtKk60hOVIGbicy0QWPns5z4aSCXi9dt6e4PvVybDFkurIhHb2qLsNkz5G7C37shFnLs8KwIw5gAsdPL+xKfvCvz+rTb7LMryAszE4QoRnW8oH5FApJgkUmwfGhKT+KxA0AJEBEJCesvde3eybZu6WH9PNvDro4lExqhF9gsovdd+/hZ74zX7Eab3j+9l942vz9FHUMVcR8Tv/xRK8eIc2//XD4RSivWS4kqxOL39kUf20hlMUGafCfJhjiatBYhwZPOQIEUQIggobGOKMNYZ1Sqm0rMDlOy12XmxlmiSlXXfQIIPfX5fbMdVBFaWliiwQpCKFB0CxQfYGE2qVO5z62wdYeoHv/rZW66EaAJrn2L9U8PON8ZIgTydZQQixaSsTRjriKoB6xwUv/31Sd/P/QVXjFolaNNIAQKRYjigGodvr8f1/iBEp3EAyxLz+4Km4kAhBpnjjLXPpev65CPyYzdJIwUIRIohCJH5nzctHbDMKYd1vjCdbxzVqMMIUzeUisErUGYu6pH+h5ECfKNIM4FIMQJClJbjhtGkCK7YIehIAU/rHNEI056+rtj/rjRSgBAFlESfjSa0OYOU+i2kM6u6jVcdCnFOyl3GGE1qBxWDscJUsQxtClaohChzT29nrCcqjRQgJI4UjeYRT7FKrl/O5Xn4gtbwL8luQGvsw4sspnptczSpk52VPRgLg6OCWmeT5HbdM1rtl+iFj358Z7xnKY0UICSJFA1VeIwFS3zG9L8D/Hef4V8Pc3KclLAf5ojV2Oq1MZrUaR0Ra4jLkpsnpOqwzqhaOfXOOc+RpsNcVaKFWJxYLhSmaKQAISrUtaZoNI44xcJXgoBQX+Sv86JhexNLiBhN6lRRwlWO1HVEE2F7J8Jyd/R0ifZfXoQYtlJFFjBSAPmIdKkStFeKATtx+1GOOf6ah4LOhNaBENFJBqRo6/yWl1nh0iX5d7OQc1hE5xtO3uicjfZfAAZkWRUjOuLkdmxmd969PV7XTCMFCEkhRU5EKuqEBbnx1x73S4w+CVHpwjzW9dqHhx0fXwo4mjQQKQZmxMpoUhDgd/7hR9UZK+ZIgXWWFWNKY5zKRyMFCImxz4ZC9EuIU5Yt7+P5ILdjfqy00eLsdQ9CxLxppc0CQIhRBVbqtc6Zzk6xr5ixgoRs64wVnbCGihUaKUBIglLkRPS0D8sMAnzeLnhiBGXw+0+5kJkZQR73IESvqYIgRKVJvu0ugRWRoB2g/VUgQsR7BrTO5qxmc3i9dcaKhqw4TSMFCNorRYPQnnV5CtZ9YH3HnaLJ/Od5vh3h3+4Aabm81phBwNoSIhK07TrfAFCHBa4Slf3RAqpEWHyQt3V4PaLP5twVzTDLP984XZqEJNhnNyLCus9ev4nZ/HmzBmm5EdcztTZaF0IUnW+4SrQVOUjQvnxZ3ZsHHGFqBlZgl83h9Zi1IuatcJuq09ApA+Mj+/ZRYIWgNykaAY0xD4WYD/rmRvK2k00CIT5t2YcjOhCi6HzjElgBIa4qDFAEWktEYAXD64vlamAF6tDsjyiaxSoIAoUFP26HOSFSYIWQCKX4lNudHcov7A7w30W3k0m39zWCO894vNRh1YQItI+MiBb+dkAuYpgGsaqsMxQilCK6eyMFx1xHFARULCol7xCYuOn++6nzDSExpHjARZnJuLM7qkWj9ddBj98/ZJCrUqDzjVPvQlSryOp8I8M6Yz+xllhtEssBQkTEGWSIhHKNMO1yDhAIepGiYZ2dIsVHZeyEYb0nHB72auxwSHYNtR1QreLa+UZhYKVKdD7L+qBkU5wUoQ7NdUQEVm7Oba50rNZoVrOx/PIErSMSkqQUnUhpKsw6ogteCvE7kRCiZ2BFcuebekgRa54ZI0H723/3PfEzVKxgNKmuIwU4IebpUiToAj95ijkXFXlE4r6MBnw+LFfOzz4YaUDhHGvEnW/c9sNzDotRsYKv3/kPNoEVTohajRRYWjq67XOfm6LLkJA0UnTCGFM4EtSngvXbMzE0Kbp10A7S+aZUWmZ/+P0Z9qeTH7IvfOHjrK+93fG5MzPz7CevvMV27tzCdt6xRcx/9rOWaCZoI7DywanzIrDyuS/9ufgK4tYp/UaMFPjiF4/QJUhIon1uWjiNJhWqK0Tnm9/85j22MF9gp/PuDSJOnjwniBHPByH6sc4gTWwIqrz+8zfFz8wE7drRpHGDRgoQiBQTCKiurFsH7YCdb0Buo6Mj4vvf/+F9d1L807nKekJuZIN1Rs7hv/8/v83+8e9/xOavLVYet3S+gUoEsIZoJmijuYMuoJECBCLFBEKsI7p1vrl4MVRgxSQ5qEUoQTtARcJqA7DPgqAtaUCn3vlQfK3ObG5pEY0esH74gxd+Uu18A5UobCoIUaPACo0UIBApJhBuo0nrCayA5Ew7/F7evhTw9OmKAu3uaWdbtgxUrXGVFE9WSBENYDE3BYQIYkTqTTVB2+h8o+Gs5udopABBd/gJtORZpfNNU8BzNGmdnW+gFmGPsfZnqrkq4XKV9/bvTlWeZ1ht6whTWGdTKe7aPVoNrGANEc0egL/86iOVwEq5rFdgpVCYos43hIYgRSMPcKIZDkYUo0mhFkGKIECTyExY/3/PPbdUrLOFoE1CBG67e1SQ9wf589V1RF0DKzRSgED2OaGE6DqaVFIHbVhiWGNhod9eP03vremT4uvQUA/r7m53tM4jmwdY/6ZB0fkGjR4ABFWqCdpIE9JnHZFGChCIFBNpm4eGHNcRZXe+Ma0xLHSxUKlBvjY7L3ILTTUp/jiWEaZW63zX3jsqCdqWzjfVwAonxLOnL7Aff/+1+AmRRgoQGtE+NztKc3PSrSisMRK5rZbZap2RsC1I0ck633XL+sCK0UF7aW6evTo1zX7760oDiOGRGMeTVipWJmikAIFIsYEA1QVSlA1YY1hkpOXAAgslaEzTg4qsJmzbWudBoSjNzjco4UPnm3ffOl1JySlWgisYS9rT1xnfsSsUMFKAErQJRIqNAtWdb3beuY3N/OztjdbayGWsHWFqKsVsR1s1sHL/+F42smWQffvY96rWG9h1zyj7zPi9sc1rXi2XZ1eKRRopQCBSbBRE0fkGgZFXa0gRFnjXR3YIu74uwGKxzib5wUID//DvX6qqTCjDhz+/j23dPhLfsVtZQdoSBVYIRIqNhNLVq8o734AAQWzWtUST6NZZZ64W8+9d2PD7l85dWfe7n/j03Xy7K+a7yRoIEYGVKTqLCESKPmFpWlvbvBbKAlHKWUndvEMBnW9UjSatxa27RtcR2117d1YI0TLCFAna7/3pgw2/a65FbuOq8KFH9onqlrhRXlycyB04QCMFCESKPkgQ4wweZD5bjfHfYQZBQnEcj4okw3S+qddCY30Q9hfBEnTGRl21aZ0RfT71zrmqPV6nNLOt7DMP3SsqW3QAP3bTq+UyVawQiBRdiO0gqwye2hPyJcx+iU/z18qDHPn2XD1DsrwIMWjnGxmAZUYkuWqdjTksovMNVGJNgrc4MPfdxT7+yZ2xBVJqgcDK8tISrSMSiBRdyBCT93ISXzZnvOZT/PWfV0GOSxcuxPIHgGUGKe751O6KXTaizqLRA1ufvyiStB+9j20e6dGm0YPofFMooPNNni4nApHiRpv8LFPbjbvfIMcn+fthPstU0v8AsMxQibDPwjJzUoRCBDGCEGGdEZTZy0nzvvE9ooRPm0YPxkgB6nxDaCRIKfMz1OEJFt14AijHE/x9n22EP4LZ6ksoRaPzDQDrjN6IX/nb/YIQtet8QyMFCKQUbQkRxPR0iF/NG5sVQUkV6434nXFVa41RwzqcCpYaltm0qZGOJvVoKEEjBQhEivaEeIx5D6o3AauLMaZTbtFk/po5gxwRrT7AnGdOV7nDUI2JIsb3/vgBe+fd1zasGYIIxRgB4/8mQUU9q9ltzZJGChAaGS0REOIE346GmRHN36PfIEY/gZvpehTjqRdeOGK8j3K88sqb1TksdsAaI2qasZYobOriIluT2KXHCow6SFnGHZgoX7vmSJZlTojU6IFApBjcMmPx/XAYMnR4Tz+kFZoYoyLFV1/9U7VDjhugFkGMKPlTWV0TiBRRsbK4+Bx10CY0MgIHWjg5HfBBiCDDJ2QRImAMtN/LNq5D1lrpY7oe7IWFgi9CBJCmc+bkGeXlhkFAIwUIRIobCTHnQTpQaHs5gSkp9TLWIvcaitAJB/h+Pq3jwXazzHZ45828Nvu+UizSSAECkaINQIj9LoQ4rrokz7DG4x7E+IxB4FrBaayp4/Mvzmmx3+g6ThUrBCJFe9s8FichBiDGfh1ttDnPOUlA+zSa1UwgUrSHW6L04ag721iI0Um9jBk5jNpgcKg70PPb4q5tppECBCJFV5XoZEcnjTGokcMgRrcE4md0OtjmwCq/2LFza6z7SyMFCESKznjSxTbHetFwYkTqz6SLWszpcrBv3rFFlO35wfCm/ljbgq2USrMUWCEQKdqrRDOB2g7Pa1JF4pYmckCHA41Rpe3Dw6LO2Wz+4AS0BHvo8x+PVyVWZjXn6RIhECkGIxUtuiwb+ZATAVVupOjYtEkQI6pU0ODBLOWrBTpp/9WTnxVKMc6bDI0UIDQr/NQ+P+jw8wnNao1RV33Q5ud7oHbj3Nf2oaF1M5xBjKhWuW98rxgrcPbUeTa8eVBM5utsSykr6fOJiZF9+2ikAIGUogvGHH7+sk4fxFhbdCK+PXHtV2tXF8vwzQ7mCAK0BbP2VIwR0x5LEQQCkSJziTpr+HmmAxK72oPL1WGWq8SEQATNuEqkBG0CkaITjG7atheQpm26tFGvWD/sGB52fHx1WbtEbhAiJWgTiBQ9Hu8PqMjiRt7h5w9GvSPtIyOsJWO/ZFteWGBMkxkrBo5yQqSRAgQCkzSOIAGkGCmyAwOiJZcdlq9fZ6vFouPvRh1kwUgBTohH6FIgEBqTFGNHpqODtfb02FvmUokVZ2erc53jxkqhkC9du0YVKwQCkaKig+kSWEFjhcLlyyxlmcESJ8RIgUKBOt8QCA1OirFlPIuKlcFB8dUOxZkZEVzRQSWKWc1LS4ep8w2BII8U+zX9PE7R8rzqN87WJGhbUZqbAwmJWc6xkyI63xQKz1HnGwIhBCm6DJvfo+nnceqgcFrlm2INEWuJdgAZghSBtAYqke/PNI0UIBDqU4q2a0669So0MBa1UsTwekSbbUUZt8uwzdXnOkSko8JKsTi7UiqN02lPINRHik5qcb9OH8RoEZZzeFjJ2lkqkxGdb2wJcXWVLV2+LL4CWGtsiTHIYowUGKfACoFQPyk6VYkc0OyzHHRSiSq6gputwJwCK6WrV9dN4otzLZFGChAIcknRqdIhx9XZQU1UIgI/TwVUunUBltkpsFKen2fl69fX22yH56pnRBopQCBIJUWjV6GTwtCl3T9GmjpFxI/LfjO3zjcrxSIrcpVYqyrjss4YKbBaLlNghUCQqBSB513UYqwzlo21xKdcrLNUpeiZoH3p0oafx6USzZECtI5IIMgnRbdehc+4dNOJAm6zqI/KfCPR+WbTJsfHly5erAZWaok0cteMBG0aKUAgqCFFo02Yk1oUM5aNdb2oVSLGro65qMQJme8nOt+4VaxYAitVIuW22el31DHiGtY0aaQAgaBQKYIYjzDnfD8oxRNREqMR5HGz7lLX0bw639QGVuK0znxfJnMHDtBIAQJBJSkacOuoEhkxGoR4zM3uG+MJpACBFdfONzWBlXUHOOJUHFSsrC4vU+cbAiEKUjSCFkd9EGNOISEe8yDEPJM4ixrrgW1OFStG5xu7dcQ4rPNquYzAyiEKrBAI0SlF00ZPeRDj65y8pCZ3g2j59jpzTtIGQAZPyBqV4NX5BoToNlYgyrI+EVgpFChBm0CoE5mQv/cEFCFzbgwBC/0iJzGhLOtJizHsONYO/eREjsusXvHqfLNSKLj+fmQNICoJ2kdz+/fTSAECoV4xVCdZuRGjFSBFJFFP+lVxhtLc76EMrQrxcD3R5lMvvHDESrxtfX1iswM639jlI66T4JwQWx0SvE0VmbJRkuVr1wLve/n69anRxx+nRg8EQpykGIIYTUwbm107rz7jtcYCvN6sDIVoJUV0vnHKR0RgxSkfcZ0E7+x0jTzLIkWMFOC2eS+tIxII8dpnAag+ToxQKM/6VHTMID1Zyd4gwkMyLbNX55vClSuehBiVdaaRAgSCfNQdGgUx8g3R3sPMuepFBZ5jktcQvTrfOCVo21lndNlWCRopQCBoSooWcgRJ7WXOXXVkYdogw8OyoswmvDrfiJECPqA8YbsyUoA63xAICqBEzhhdubE+NyaZDJ+XXbpn4vxPf3oknc3aRrjR+WbpwgWfR7SFZR0CNOuIs441xeXFxelbHntsL52+BIJ8ZFS8qJGCM2XpYINIci7ES+UN5XlcRaPYWpKyFWXLy56R5nWvo3gtkUYKEAgJVIoO6hGkaAZZ7mX2nW1gh98wyHDK6OUYCS699toRZpMLuXj+vK91RBNIw/FT2hdGKSJRvLywsJfWEQmEhClFB/WYtyi/RMBvYMVqnVXVOouRAouLFFghEBQjRYfAHm6dbyK3zuZIAep8QyAQKcYBqMOCZTSpb1JUVOtMIwUIBCLF2GB2vgkKVXNYaKQAgUCkGCu8Ot84HkgF1plGChAI0SNDh6CC8vz8LMjQq/ONo3WWnbBdGSlwlEYKEAhEirEAHavDEqIK62yMFDhCfxkCQWNSNHINc06Pyx4n6rEvYy4P54PmOIYlRBUqkUYKEAjJUYoYA+BERlPMvSO3bKDXotPgKhDijqh2ROYIUxopQCDEC9+BFqPpqxMhijEAEe87ZsU4JTJjdEEk1lP2HBZjNCklaBMIupMiq/RMdMIh2R1rvGC8n5vFfCqKyYKSrfNznBAn6LQkEDQnRWP9LufwsNRxogGJcZo5TxfsZ+5zoeUcQHmpOFMj+/ZRgjaBkBCl+JSLbY77QkbpW97hsScTYp3zMSw/EAiEMKRoWFCncaXPR9nJxsVGO6nFnOxRq4qs8xNcJVJghUBIiFI84KHSYofReNaJnPdrToqHOCFSYIVASBApOpHKRNTBFQ8cd/j5mJIDJ2cOywQnxAk6DQmEZJGiE6m8pNlnmXSx0DklpFgH0PmGEyIlaBMISSJFYz3RKa1lSqcPYkSinSy0dFKsp3ciRgqU5uZopACBkECl6DSfeVoz61zdrygsdD3WebVcRhkftQIjEBJKik4qUdcL+o1IDlpIlShGClRmNU/RqUcgNJZSfLlpjxhXiKGizjRSgEBoCFJMGpSntoRdS6SRAgQCkWIcyOlonWmkAIHQ+KTYp+nnUdsAIsQIU3TzXl5cPEQjBQiExiDFKYef72nGgxXYOmMdcXERIwUm6VQjEBpbKeY0/TwPOvxcikoL2kyWRgoQCA1Gii7jBZRUiUjAHlWkiG44qYz/RuXLS0t5GilAIDSmUnQilDGdPggnaRBif0By93+gAlhnY6QABVYIhAYlRSdCeVKzz+LU81FKmo7f3ETMaqaRAgRCY5OiU+OHMV0stEfPx+MyrLOvEaaVBG0aKUAgNDIpGqMGnGzgM5p8jqeZczpO3ZFfv9a5vLg4NfrFL1KCNoHQ4ErRjVgOesxfjkIl5lys85SMzuDpbNbzOVwhzq6WyzRSgEBoElI86vLYsSim5rm9v4tKPFq3dfYxh2WlVEI7sHEKrBAITUKKhtqacHgYSu3ZmFQi3nfMRSVO1a0SPQIsCKwYw+spsEIgNJFSNFXXrIuNPhYxIR5k7iNMj0o5QG7riQisFAoTuf37J+hUIhCajBQNtehGNJERo0GIbu/1nAyV6GWdl5eWpkcff5wStAmEJlWKIEb0ApzyIkaVa4yGZXYjxGlZKtHNOmOkwEqpRIEVAqGZSdEAiCDvRox8O2FUmMgkQ5QWnvCwzLD3h2SNSnAiRctIgTydQgRCYyHUoBGD8EBQXorwqGFlQ5OUoTpBhE/5eL8njLzKwDj1wgtjxmeq3C1aW1lrV9eG52GkQHlh4TB10CYQiBTDEiMIEUT1vDFxL8jrP2koTz92HApxIuznqSXFTGfnRqW4tiY634x+8YtkmwkEIsW6iNFKkFOsMmAqX2PD8Rp4vXuNr7kAr3m4HkK0I8VsX9+GiX0IrFA+IoFApOiHGI+xeBrP5g3LXHeOoJUU7awzRgosLy6OUz4igdDYqHtGi0FIGOw+EfG+w5LvlUGIGw5KTW6iZaQAESKBQEoxkGocM1RjTuE+5w27LLXFf1UpcsssrLOJtTVWmp8/Sh20CQQixXrI8SCrdNCRSY4gw6P1rh16kSKCKwiymCgvLKDzzTidKgRCcyCj4kUN4prg5Igeh4ggHwj5Umbk+iXZytCPdTZGClCkmUAgpahEPUKJYUN0ud9QkbkaJZg3iBDRaSkNHQIpxZaWE6Z1xkiB8vXrFFghEIgUmxMgRW6dT8A6o/NNaX7+EHXQJhCaDyk6BJaDgWRtGilAIBApEhjLtLeLEablxcVpGilAIBApEil2d282RgpQpJlAaGL8/wIMAOou9sefLFO2AAAAAElFTkSuQmCC\" style=\"width: 100%; max-width:100px;\" />\n",
       "            </td>\n",
       "            <td>\n",
       "            <table>\n",
       "                <tr><td>Installed version:</td><td style='text-align:left'>v1.0.0.dev1 (latest: v1.0.0.dev0)</td></tr><tr><td>Available backends:</td><td style='text-align:left'>CVXPY v1.5.3</td></tr><tr><td>Default backend (corneto.opt):</td><td style='text-align:left'>CVXPY</td></tr><tr><td>Installed solvers:</td><td style='text-align:left'>GUROBI, SCIP, SCIPY</td></tr><tr><td>Graphviz version:</td><td style='text-align:left'>v0.20.3</td></tr><tr><td>Installed path:</td><td style='text-align:left'>C:\\Users\\pablo\\Documents\\work\\projects\\corneto\\corneto</td></tr><tr><td>Repository:</td><td style='text-align:left'><a href=https://github.com/saezlab/corneto>https://github.com/saezlab/corneto</a></td></tr>\n",
       "            </table>\n",
       "            </td>\n",
       "        </tr>\n",
       "        </table>"
      ],
      "text/plain": [
       "<IPython.core.display.HTML object>"
      ]
     },
     "metadata": {},
     "output_type": "display_data"
    }
   ],
   "source": [
    "cn.info()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 58,
   "id": "653e2ae6-a86a-4433-aca9-e783662e0848",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
       "<div>\n",
       "<style scoped>\n",
       "    .dataframe tbody tr th:only-of-type {\n",
       "        vertical-align: middle;\n",
       "    }\n",
       "\n",
       "    .dataframe tbody tr th {\n",
       "        vertical-align: top;\n",
       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>source</th>\n",
       "      <th>target</th>\n",
       "      <th>source_genesymbol</th>\n",
       "      <th>target_genesymbol</th>\n",
       "      <th>is_directed</th>\n",
       "      <th>is_stimulation</th>\n",
       "      <th>is_inhibition</th>\n",
       "      <th>consensus_direction</th>\n",
       "      <th>consensus_stimulation</th>\n",
       "      <th>consensus_inhibition</th>\n",
       "      <th>curation_effort</th>\n",
       "      <th>references</th>\n",
       "      <th>sources</th>\n",
       "      <th>n_sources</th>\n",
       "      <th>n_primary_sources</th>\n",
       "      <th>n_references</th>\n",
       "      <th>references_stripped</th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>0</th>\n",
       "      <td>Q13976</td>\n",
       "      <td>Q13507</td>\n",
       "      <td>PRKG1</td>\n",
       "      <td>TRPC3</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>True</td>\n",
       "      <td>9</td>\n",
       "      <td>HPRD:14983059;KEA:14983059;ProtMapper:14983059...</td>\n",
       "      <td>HPRD;HPRD_KEA;HPRD_MIMP;KEA;MIMP;PhosphoPoint;...</td>\n",
       "      <td>15</td>\n",
       "      <td>8</td>\n",
       "      <td>2</td>\n",
       "      <td>14983059;16331690</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>1</th>\n",
       "      <td>Q13976</td>\n",
       "      <td>Q9HCX4</td>\n",
       "      <td>PRKG1</td>\n",
       "      <td>TRPC7</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>3</td>\n",
       "      <td>SIGNOR:21402151;TRIP:21402151;iPTMnet:21402151</td>\n",
       "      <td>SIGNOR;TRIP;iPTMnet</td>\n",
       "      <td>3</td>\n",
       "      <td>3</td>\n",
       "      <td>1</td>\n",
       "      <td>21402151</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>2</th>\n",
       "      <td>Q13438</td>\n",
       "      <td>Q9HBA0</td>\n",
       "      <td>OS9</td>\n",
       "      <td>TRPV4</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>3</td>\n",
       "      <td>HPRD:17932042;SIGNOR:17932042;TRIP:17932042</td>\n",
       "      <td>HPRD;SIGNOR;TRIP</td>\n",
       "      <td>3</td>\n",
       "      <td>3</td>\n",
       "      <td>1</td>\n",
       "      <td>17932042</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>3</th>\n",
       "      <td>P18031</td>\n",
       "      <td>Q9H1D0</td>\n",
       "      <td>PTPN1</td>\n",
       "      <td>TRPV6</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>True</td>\n",
       "      <td>11</td>\n",
       "      <td>DEPOD:15894168;DEPOD:17197020;HPRD:15894168;In...</td>\n",
       "      <td>DEPOD;HPRD;IntAct;Lit-BM-17;SIGNOR;SPIKE_LC;TRIP</td>\n",
       "      <td>7</td>\n",
       "      <td>6</td>\n",
       "      <td>2</td>\n",
       "      <td>15894168;17197020</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>4</th>\n",
       "      <td>P63244</td>\n",
       "      <td>Q9BX84</td>\n",
       "      <td>RACK1</td>\n",
       "      <td>TRPM6</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>True</td>\n",
       "      <td>True</td>\n",
       "      <td>False</td>\n",
       "      <td>True</td>\n",
       "      <td>2</td>\n",
       "      <td>SIGNOR:18258429;TRIP:18258429</td>\n",
       "      <td>SIGNOR;TRIP</td>\n",
       "      <td>2</td>\n",
       "      <td>2</td>\n",
       "      <td>1</td>\n",
       "      <td>18258429</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "</div>"
      ],
      "text/plain": [
       "   source  target source_genesymbol target_genesymbol  is_directed  \\\n",
       "0  Q13976  Q13507             PRKG1             TRPC3         True   \n",
       "1  Q13976  Q9HCX4             PRKG1             TRPC7         True   \n",
       "2  Q13438  Q9HBA0               OS9             TRPV4         True   \n",
       "3  P18031  Q9H1D0             PTPN1             TRPV6         True   \n",
       "4  P63244  Q9BX84             RACK1             TRPM6         True   \n",
       "\n",
       "   is_stimulation  is_inhibition  consensus_direction  consensus_stimulation  \\\n",
       "0           False           True                 True                  False   \n",
       "1            True          False                 True                   True   \n",
       "2            True           True                 True                   True   \n",
       "3           False           True                 True                  False   \n",
       "4           False           True                 True                  False   \n",
       "\n",
       "   consensus_inhibition  curation_effort  \\\n",
       "0                  True                9   \n",
       "1                 False                3   \n",
       "2                  True                3   \n",
       "3                  True               11   \n",
       "4                  True                2   \n",
       "\n",
       "                                          references  \\\n",
       "0  HPRD:14983059;KEA:14983059;ProtMapper:14983059...   \n",
       "1     SIGNOR:21402151;TRIP:21402151;iPTMnet:21402151   \n",
       "2        HPRD:17932042;SIGNOR:17932042;TRIP:17932042   \n",
       "3  DEPOD:15894168;DEPOD:17197020;HPRD:15894168;In...   \n",
       "4                      SIGNOR:18258429;TRIP:18258429   \n",
       "\n",
       "                                             sources  n_sources  \\\n",
       "0  HPRD;HPRD_KEA;HPRD_MIMP;KEA;MIMP;PhosphoPoint;...         15   \n",
       "1                                SIGNOR;TRIP;iPTMnet          3   \n",
       "2                                   HPRD;SIGNOR;TRIP          3   \n",
       "3   DEPOD;HPRD;IntAct;Lit-BM-17;SIGNOR;SPIKE_LC;TRIP          7   \n",
       "4                                        SIGNOR;TRIP          2   \n",
       "\n",
       "   n_primary_sources n_references references_stripped  \n",
       "0                  8            2   14983059;16331690  \n",
       "1                  3            1            21402151  \n",
       "2                  3            1            17932042  \n",
       "3                  6            2   15894168;17197020  \n",
       "4                  2            1            18258429  "
      ]
     },
     "execution_count": 58,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We get only interactions from SIGNOR http://signor.uniroma2.it/\n",
    "pkn = op.interactions.OmniPath.get(databases=[\"SIGNOR\"], genesymbols=True)\n",
    "pkn = pkn[pkn.consensus_direction == True]\n",
    "pkn.head()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 59,
   "id": "1a040ca9-e406-4f04-82d6-aae294de7eff",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
       "<div>\n",
       "<style scoped>\n",
       "    .dataframe tbody tr th:only-of-type {\n",
       "        vertical-align: middle;\n",
       "    }\n",
       "\n",
       "    .dataframe tbody tr th {\n",
       "        vertical-align: top;\n",
       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>source_genesymbol</th>\n",
       "      <th>interaction</th>\n",
       "      <th>target_genesymbol</th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>0</th>\n",
       "      <td>PRKG1</td>\n",
       "      <td>-1</td>\n",
       "      <td>TRPC3</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>1</th>\n",
       "      <td>PRKG1</td>\n",
       "      <td>1</td>\n",
       "      <td>TRPC7</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>2</th>\n",
       "      <td>OS9</td>\n",
       "      <td>0</td>\n",
       "      <td>TRPV4</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>3</th>\n",
       "      <td>PTPN1</td>\n",
       "      <td>-1</td>\n",
       "      <td>TRPV6</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>4</th>\n",
       "      <td>RACK1</td>\n",
       "      <td>-1</td>\n",
       "      <td>TRPM6</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>...</th>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "      <td>...</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>61579</th>\n",
       "      <td>DTNBP1</td>\n",
       "      <td>1</td>\n",
       "      <td>WASF2</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>61580</th>\n",
       "      <td>CDK1</td>\n",
       "      <td>1</td>\n",
       "      <td>KMT5A</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>61581</th>\n",
       "      <td>PIM2</td>\n",
       "      <td>1</td>\n",
       "      <td>CDKN1A</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>61582</th>\n",
       "      <td>AKT1</td>\n",
       "      <td>1</td>\n",
       "      <td>WNK1</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>61583</th>\n",
       "      <td>PRKCA</td>\n",
       "      <td>1</td>\n",
       "      <td>CSPG4</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "<p>60903 rows × 3 columns</p>\n",
       "</div>"
      ],
      "text/plain": [
       "      source_genesymbol  interaction target_genesymbol\n",
       "0                 PRKG1           -1             TRPC3\n",
       "1                 PRKG1            1             TRPC7\n",
       "2                   OS9            0             TRPV4\n",
       "3                 PTPN1           -1             TRPV6\n",
       "4                 RACK1           -1             TRPM6\n",
       "...                 ...          ...               ...\n",
       "61579            DTNBP1            1             WASF2\n",
       "61580              CDK1            1             KMT5A\n",
       "61581              PIM2            1            CDKN1A\n",
       "61582              AKT1            1              WNK1\n",
       "61583             PRKCA            1             CSPG4\n",
       "\n",
       "[60903 rows x 3 columns]"
      ]
     },
     "execution_count": 59,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "pkn[\"interaction\"] = pkn[\"is_stimulation\"].astype(int) - pkn[\"is_inhibition\"].astype(\n",
    "    int\n",
    ")\n",
    "sel_pkn = pkn[[\"source_genesymbol\", \"interaction\", \"target_genesymbol\"]]\n",
    "sel_pkn"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 60,
   "id": "99849f5d-f449-40ae-94af-01d01bcd2240",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "(5436, 60020)"
      ]
     },
     "execution_count": 60,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We create the CORNETO graph by importing the edges and interaction\n",
    "G = cn.Graph.from_sif_tuples(\n",
    "    [(r[0], r[1], r[2]) for _, r in sel_pkn.iterrows() if r[1] != 0]\n",
    ")\n",
    "G.shape"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 61,
   "id": "634cac48-79f5-4812-a7bb-8ef37df7bcf9",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/html": [
       "<div>\n",
       "<style scoped>\n",
       "    .dataframe tbody tr th:only-of-type {\n",
       "        vertical-align: middle;\n",
       "    }\n",
       "\n",
       "    .dataframe tbody tr th {\n",
       "        vertical-align: top;\n",
       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>treatment.vs.control</th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>SRF</th>\n",
       "      <td>7.421123</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>MYOCD</th>\n",
       "      <td>7.372481</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>SMAD3</th>\n",
       "      <td>7.190940</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>BTG2</th>\n",
       "      <td>6.206934</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>TCF21</th>\n",
       "      <td>6.183177</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>...</th>\n",
       "      <td>...</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>SPI1</th>\n",
       "      <td>-5.427345</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>NR4A3</th>\n",
       "      <td>-5.749818</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>HIF3A</th>\n",
       "      <td>-5.882730</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>NR1H4</th>\n",
       "      <td>-6.081834</td>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>IRF1</th>\n",
       "      <td>-9.395861</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "<p>84 rows × 1 columns</p>\n",
       "</div>"
      ],
      "text/plain": [
       "       treatment.vs.control\n",
       "SRF                7.421123\n",
       "MYOCD              7.372481\n",
       "SMAD3              7.190940\n",
       "BTG2               6.206934\n",
       "TCF21              6.183177\n",
       "...                     ...\n",
       "SPI1              -5.427345\n",
       "NR4A3             -5.749818\n",
       "HIF3A             -5.882730\n",
       "NR1H4             -6.081834\n",
       "IRF1              -9.395861\n",
       "\n",
       "[84 rows x 1 columns]"
      ]
     },
     "execution_count": 61,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# As measurements, we take the estimated TFs, we will filter out TFs with p-val > 0.001\n",
    "significant_tfs = (\n",
    "    tf_acts[tf_pvals <= 0.001]\n",
    "    .T.dropna()\n",
    "    .sort_values(by=\"treatment.vs.control\", ascending=False)\n",
    ")\n",
    "significant_tfs"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 62,
   "id": "83c01323-be92-456e-bb46-c79d5147f40a",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "{'SRF': 7.4211225509643555,\n",
       " 'MYOCD': 7.372481346130371,\n",
       " 'SMAD3': 7.190939903259277,\n",
       " 'BTG2': 6.206934452056885,\n",
       " 'SMAD2': 5.634183883666992,\n",
       " 'JUNB': 5.632753849029541,\n",
       " 'HMGA2': 4.937854766845703,\n",
       " 'POU3F1': 4.921204090118408,\n",
       " 'RORA': 4.765202045440674,\n",
       " 'SMAD4': 4.588079452514648,\n",
       " 'MEF2A': 4.287934303283691,\n",
       " 'FOSL1': 3.938856363296509,\n",
       " 'SOX4': 3.9252400398254395,\n",
       " 'NCOA1': 3.8250725269317627,\n",
       " 'SFPQ': 3.7440223693847656,\n",
       " 'FOSB': 3.7315196990966797,\n",
       " 'SP7': 3.6977312564849854,\n",
       " 'HBP1': 3.6794629096984863,\n",
       " 'CREB3': 3.632990837097168,\n",
       " 'ASXL1': 3.574924945831299,\n",
       " 'MEIS2': 3.4930355548858643,\n",
       " 'TAL1': 3.354771852493286,\n",
       " 'HOXC8': 3.347809314727783,\n",
       " 'DLX5': 3.3378002643585205,\n",
       " 'DLX2': -3.2941677570343018,\n",
       " 'CDX2': -3.2988994121551514,\n",
       " 'MAFA': -3.310776472091675,\n",
       " 'STAT5A': -3.430389165878296,\n",
       " 'RXRB': -3.4593443870544434,\n",
       " 'MSX2': -3.5386831760406494,\n",
       " 'SMAD6': -3.5516138076782227,\n",
       " 'CEBPA': -3.59158992767334,\n",
       " 'PLAGL1': -3.6208605766296387,\n",
       " 'RELA': -3.63592267036438,\n",
       " 'TP53': -3.6599860191345215,\n",
       " 'NKX2-1': -3.6630992889404297,\n",
       " 'NFKB1': -3.842646598815918,\n",
       " 'CEBPB': -3.861898422241211,\n",
       " 'WWTR1': -3.9853055477142334,\n",
       " 'SMAD5': -4.020087242126465,\n",
       " 'VHL': -4.030272483825684,\n",
       " 'CIITA': -4.151106834411621,\n",
       " 'NFKBIB': -4.1750593185424805,\n",
       " 'REL': -4.184780120849609,\n",
       " 'PITX3': -4.216534614562988,\n",
       " 'PITX1': -4.358892440795898,\n",
       " 'MECP2': -4.400153160095215,\n",
       " 'TGIF1': -4.501400470733643,\n",
       " 'MECOM': -4.5638203620910645,\n",
       " 'IRF3': -4.733184814453125,\n",
       " 'RELB': -4.848578453063965,\n",
       " 'NFE2L2': -4.937533378601074,\n",
       " 'STAT1': -5.215514659881592,\n",
       " 'HOXC6': -5.283187389373779,\n",
       " 'IRF2': -5.291377544403076,\n",
       " 'KLF11': -5.293704509735107,\n",
       " 'SMAD7': -5.3725266456604,\n",
       " 'SPI1': -5.427344799041748,\n",
       " 'NR4A3': -5.749818325042725,\n",
       " 'HIF3A': -5.882729530334473,\n",
       " 'NR1H4': -6.081834316253662,\n",
       " 'IRF1': -9.39586067199707}"
      ]
     },
     "execution_count": 62,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We keep only the ones in the PKN graph\n",
    "measurements = significant_tfs.loc[significant_tfs.index.intersection(G.V)].to_dict()[\n",
    "    \"treatment.vs.control\"\n",
    "]\n",
    "measurements"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 64,
   "id": "8f644411-e8c8-4072-b62e-230adea6eb08",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "{'CDH6': 0,\n",
       " 'CRLF1': 0,\n",
       " 'FZD8': 0,\n",
       " 'CDH2': 0,\n",
       " 'INHBA': 0,\n",
       " 'VDR': 0,\n",
       " 'IGF1': 0,\n",
       " 'EFNB2': 0,\n",
       " 'ITGB3': 0,\n",
       " 'TGFB1': 0,\n",
       " 'IL21R': 0,\n",
       " 'EGF': 0,\n",
       " 'ITGA11': 0}"
      ]
     },
     "execution_count": 64,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We will infer the direction, so for the inputs, we use a value of 0 (=unknown direction)\n",
    "inputs = {k: 0 for k in df_top_receptors.index.intersection(G.V).values}\n",
    "inputs"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 65,
   "id": "7f5b695a-e965-4e3d-8f7c-55efda9b2eb1",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "(958, 3279)"
      ]
     },
     "execution_count": 65,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We prune the network from inputs (receptors) to TFs to improve the performance.\n",
    "# The pruning step removes only parts of the network that cannot be reached from the pre-selected receptors\n",
    "from corneto.methods.carnival import preprocess_graph\n",
    "\n",
    "Gp, inputs_p, measurements_p = preprocess_graph(G, inputs, measurements)\n",
    "Gp.shape"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 66,
   "id": "cab88e0f-333a-463a-942a-86aefea03be4",
   "metadata": {},
   "outputs": [],
   "source": [
    "vertices = Gp.V"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 75,
   "id": "a94e21f6-14a8-4f01-804a-73b88eda11ba",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "{'vertex_inhibited': Variable((958,), vertex_inhibited, boolean=True),\n",
       " 'edge_activating': Variable((3279,), edge_activating, boolean=True),\n",
       " 'edge_inhibiting': Variable((3279,), edge_inhibiting, boolean=True),\n",
       " 'vertex_activated': Variable((958,), vertex_activated, boolean=True),\n",
       " 'vertex_position': Variable((958,), vertex_position),\n",
       " 'vertex_values': Expression(AFFINE, UNKNOWN, (958,)),\n",
       " 'edge_values': Expression(AFFINE, UNKNOWN, (3279,))}"
      ]
     },
     "execution_count": 75,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "from corneto.methods.carnival import milp_carnival\n",
    "\n",
    "# We create a CARNIVAL problem\n",
    "P = milp_carnival(Gp, inputs_p, measurements_p, beta_weight=0.2)\n",
    "\n",
    "# The CARNIVAL problem contains useful variables that we will estimate from the data\n",
    "P.expr"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 76,
   "id": "3b32b7e6-e5d1-458d-9b52-cc5eb44323c7",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
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       "<!-- TRIP11&#45;&gt;THRA -->\n",
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       "<title>SMAD6&#45;&gt;MAP3K7</title>\n",
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       "<!-- SMAD7 -->\n",
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       "<title>SMAD7</title>\n",
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       "<text text-anchor=\"middle\" x=\"450\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">SMAD7</text>\n",
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       "<!-- EP300&#45;&gt;SMAD7 -->\n",
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       "<title>EP300&#45;&gt;SMAD7</title>\n",
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       "<title>MAPK14</title>\n",
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       "<!-- MEF2A -->\n",
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       "<title>MEF2A</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"693\" cy=\"-450\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"693\" y=\"-444.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">MEF2A</text>\n",
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       "<g id=\"edge16\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;MEF2A</title>\n",
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       "<!-- JUNB -->\n",
       "<g id=\"node29\" class=\"node\">\n",
       "<title>JUNB</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"747\" cy=\"-450\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"747\" y=\"-444.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">JUNB</text>\n",
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       "<!-- MAPK14&#45;&gt;JUNB -->\n",
       "<g id=\"edge17\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;JUNB</title>\n",
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       "<!-- DLX5 -->\n",
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       "<title>DLX5</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"801\" cy=\"-450\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"801\" y=\"-444.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">DLX5</text>\n",
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       "<!-- MAPK14&#45;&gt;DLX5 -->\n",
       "<g id=\"edge57\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;DLX5</title>\n",
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       "<!-- SMAD3 -->\n",
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       "<title>SMAD3</title>\n",
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       "<!-- MAPK14&#45;&gt;SMAD3 -->\n",
       "<g id=\"edge66\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;SMAD3</title>\n",
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       "<!-- GSK3B -->\n",
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       "<title>GSK3B</title>\n",
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       "<!-- MAPK14&#45;&gt;GSK3B -->\n",
       "<g id=\"edge33\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;GSK3B</title>\n",
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       "<!-- SP7 -->\n",
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       "<title>SP7</title>\n",
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       "<!-- MAPK14&#45;&gt;SP7 -->\n",
       "<g id=\"edge37\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;SP7</title>\n",
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       "<!-- CDX2 -->\n",
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       "<title>CDX2</title>\n",
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       "<!-- MAPK14&#45;&gt;CDX2 -->\n",
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       "<title>MAPK14&#45;&gt;CDX2</title>\n",
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       "<!-- HBP1 -->\n",
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       "<title>HBP1</title>\n",
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       "<title>MAPK14&#45;&gt;HBP1</title>\n",
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       "<!-- PITX1 -->\n",
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       "<!-- EGR1&#45;&gt;PITX1 -->\n",
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       "<title>EGR1&#45;&gt;PITX1</title>\n",
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       "<!-- VHL&#45;&gt;TP53 -->\n",
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       "<title>VHL&#45;&gt;TP53</title>\n",
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       "<!-- ASXL1 -->\n",
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       "<title>IGF1</title>\n",
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       "<title>SPI1&#45;&gt;TAL1</title>\n",
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       "<!-- NKX2&#45;1 -->\n",
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       "<!-- GSK3B&#45;&gt;MYOCD -->\n",
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       "<title>GSK3B&#45;&gt;NFKB1</title>\n",
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       "<!-- CIITA -->\n",
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       "<!-- GSK3B&#45;&gt;CIITA -->\n",
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       "<!-- GSK3B&#45;&gt;CEBPA -->\n",
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       "<title>GSK3B&#45;&gt;CEBPA</title>\n",
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       "<!-- SMAD4 -->\n",
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       "<!-- SMAD2&#45;&gt;SMAD4 -->\n",
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       "<!-- CDON&#45;&gt;MAPK14 -->\n",
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       "<title>CDON&#45;&gt;MAPK14</title>\n",
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       "<title>CDK1&#45;&gt;HMGA2</title>\n",
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     },
     "execution_count": 76,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We first run CARNIVAL using all selected receptors.\n",
    "# We find the value for the variables using the solver GUROBI\n",
    "# (needs to be installed with a valid license, academic licenses are free)\n",
    "# TimeLimit and Seed are GUROBI specific parameters\n",
    "P.solve(solver=\"GUROBI\", Seed=seed)\n",
    "\n",
    "# We extract the selected edges\n",
    "G_sol = Gp.edge_subgraph(np.flatnonzero(P.expr.edge_values.value))\n",
    "\n",
    "# We plot generating custom drawing attributes\n",
    "values = P.expr.vertex_values.value\n",
    "vertex_values = {v: values[i] for i, v in enumerate(Gp.V)}\n",
    "vertex_sol_values = [vertex_values[v] for v in G_sol.V]\n",
    "G_sol.plot(\n",
    "    custom_vertex_attr=cn.pl.create_graphviz_vertex_attributes(\n",
    "        G_sol.V, vertex_sol_values\n",
    "    )\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 77,
   "id": "f37de568-afd8-4c83-a4d0-9d36ed258afa",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "10.373496770858765\n",
      "88.0\n"
     ]
    }
   ],
   "source": [
    "# Print the values of the objectives:\n",
    "# - First objective is error (non-fited TFs).\n",
    "# - Second objective is number of interactions\n",
    "for o in P.objectives:\n",
    "    print(o.value)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 78,
   "id": "89140b57-43da-4150-b71f-25956ccad4dd",
   "metadata": {},
   "outputs": [],
   "source": [
    "# The CARNIVAL problem can be manipulated for hypothesis exploration.\n",
    "# For example, we will say that only 1 of the provided receptors has to be selected, at most.\n",
    "P = milp_carnival(Gp, inputs_p, measurements_p, beta_weight=0.2)\n",
    "idx_receptors = [vertices.index(k) for k in inputs_p.keys()]\n",
    "protein_selected = P.expr.vertex_activated + P.expr.vertex_inhibited\n",
    "P += sum(protein_selected[idx_receptors]) == 1\n",
    "P.solve(solver=\"GUROBI\", TimeLimit=max_time, Seed=seed);"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 79,
   "id": "538e1d57-3c9f-4513-a89f-0138454ce23e",
   "metadata": {},
   "outputs": [
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      "Warning: node 'NFKB1', graph '%3' size too small for label\n",
      "Warning: node 'PDPK1', graph '%3' size too small for label\n",
      "Warning: node 'PPP2CA', graph '%3' size too small for label\n",
      "Warning: node 'TRAF2', graph '%3' size too small for label\n",
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      "Warning: node 'SMAD6', graph '%3' size too small for label\n",
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      "Warning: node 'GSK3B', graph '%3' size too small for label\n",
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      "Warning: node 'ASXL1', graph '%3' size too small for label\n",
      "Warning: node 'MSX2', graph '%3' size too small for label\n",
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      "Warning: node 'NFE2L2', graph '%3' size too small for label\n",
      "Warning: node 'TICAM1', graph '%3' size too small for label\n",
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      "Warning: node 'FBXW7', graph '%3' size too small for label\n",
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      "Warning: node 'MUC1', graph '%3' size too small for label\n",
      "Warning: node 'NCOA1', graph '%3' size too small for label\n",
      "Warning: node 'ASXL1', graph '%3' size too small for label\n",
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      "Warning: node 'STAT1', graph '%3' size too small for label\n",
      "Warning: node 'NKX2-1', graph '%3' size too small for label\n",
      "Warning: node 'PITX1', graph '%3' size too small for label\n",
      "Warning: node 'CDON', graph '%3' size too small for label\n",
      "Warning: node 'CHEK2', graph '%3' size too small for label\n",
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      "Warning: node 'MECP2', graph '%3' size too small for label\n",
      "Warning: node 'MAFA', graph '%3' size too small for label\n",
      "Warning: node 'APC_AXIN1_GSK3B', graph '%3' size too small for label\n",
      "Warning: node 'CSNK1D', graph '%3' size too small for label\n",
      "Warning: node 'HIF3A', graph '%3' size too small for label\n",
      "Warning: node 'MAP3K7', graph '%3' size too small for label\n",
      "Warning: node 'NFKBIB', graph '%3' size too small for label\n",
      "Warning: node 'MAPK3', graph '%3' size too small for label\n",
      "Warning: node 'CEBPA', graph '%3' size too small for label\n",
      "Warning: node 'CUL1_RBX1_SKP1', graph '%3' size too small for label\n",
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      "Warning: node 'CEBPB', graph '%3' size too small for label\n",
      "Warning: node 'STAT5A', graph '%3' size too small for label\n",
      "Warning: node 'SMAD5', graph '%3' size too small for label\n",
      "Warning: node 'RARB', graph '%3' size too small for label\n",
      "Warning: node 'RXRB', graph '%3' size too small for label\n",
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       "<!-- MAPK14&#45;&gt;KHSRP -->\n",
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       "<title>MAPK14&#45;&gt;CDX2</title>\n",
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       "<title>ABL1&#45;&gt;HIPK2</title>\n",
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       "<title>REL</title>\n",
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       "<!-- MAPK3&#45;&gt;NCOA1 -->\n",
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       "<!-- CDH2&#45;&gt;CDON -->\n",
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       "<title>RARB&#45;&gt;RXRB</title>\n",
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      "text/plain": [
       "<graphviz.graphs.Digraph at 0x1dd185fcd50>"
      ]
     },
     "execution_count": 79,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# We extract the edges that have some signal (edge_values != 0)\n",
    "# We select the sub-graph from the processed PKN\n",
    "G_sol = Gp.edge_subgraph(np.flatnonzero(P.expr.edge_values.value))\n",
    "\n",
    "# We plot generating custom drawing attributes\n",
    "values = P.expr.vertex_values.value\n",
    "vertex_values = {v: values[i] for i, v in enumerate(Gp.V)}\n",
    "vertex_sol_values = [vertex_values[v] for v in G_sol.V]\n",
    "G_sol.plot(\n",
    "    custom_vertex_attr=cn.pl.create_graphviz_vertex_attributes(\n",
    "        G_sol.V, vertex_sol_values\n",
    "    )\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 80,
   "id": "7c0cba49-68d4-4c30-99f9-684c4f346979",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "10.373496770858765\n",
      "88.0\n"
     ]
    }
   ],
   "source": [
    "# Print the values of the objectives:\n",
    "# - First objective is error (non-fited TFs).\n",
    "# - Second objective is number of interactions\n",
    "for o in P.objectives:\n",
    "    print(o.value)"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "1a182f07-2ca6-4d4e-9e78-f9d655444750",
   "metadata": {},
   "source": [
    "## Adding more knowledge\n",
    "\n",
    "We can add more prior knowledge to the CARNIVAL problem. For example, we are going to penalise genes that are lowly abundant, according to the average basal gene expression levels. "
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 101,
   "id": "f38f62f5-ff99-4c4c-8281-b6dc4856ba58",
   "metadata": {},
   "outputs": [
    {
     "data": {
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       "      <th>baseMean</th>\n",
       "      <th>log2FoldChange</th>\n",
       "      <th>lfcSE</th>\n",
       "      <th>stat</th>\n",
       "      <th>pvalue</th>\n",
       "      <th>padj</th>\n",
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       "      <th>GeneName</th>\n",
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       "      <th>NLGN3</th>\n",
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       "                 baseMean  log2FoldChange     lfcSE      stat    pvalue  \\\n",
       "GeneName                                                                  \n",
       "TRIM17          53.443434       -0.689125  0.300338 -2.294499  0.021762   \n",
       "NLGN3           32.581601       -0.895798  0.390573 -2.293545  0.021817   \n",
       "RP11-1109F11.3  11.672715       -1.587070  0.692036 -2.293336  0.021829   \n",
       "RP11-661A12.5   15.285895       -1.297808  0.566496 -2.290938  0.021967   \n",
       "RP11-77K12.7    25.489581       -0.991542  0.432922 -2.290350  0.022001   \n",
       "...                   ...             ...       ...       ...       ...   \n",
       "GDPD1           74.892252        0.000326  0.262746  0.001241  0.999010   \n",
       "RP11-452K12.7   49.986985       -0.000259  0.302890 -0.000855  0.999317   \n",
       "MIR6859-1       10.114621        0.000625  0.657581  0.000950  0.999242   \n",
       "RP11-463C8.4    48.479410       -0.000280  0.305891 -0.000916  0.999269   \n",
       "AIF1L           11.870434       -0.000351  0.619997 -0.000566  0.999549   \n",
       "\n",
       "                    padj  \n",
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       "TRIM17          0.050210  \n",
       "NLGN3           0.050307  \n",
       "RP11-1109F11.3  0.050323  \n",
       "RP11-661A12.5   0.050602  \n",
       "RP11-77K12.7    0.050661  \n",
       "...                  ...  \n",
       "GDPD1           0.999415  \n",
       "RP11-452K12.7   0.999520  \n",
       "MIR6859-1       0.999520  \n",
       "RP11-463C8.4    0.999520  \n",
       "AIF1L           0.999599  \n",
       "\n",
       "[3750 rows x 6 columns]"
      ]
     },
     "execution_count": 101,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "df_lowly_abundant_genes = results_df[\n",
    "    (results_df.baseMean <= results_df.baseMean.quantile(0.25))\n",
    "    & (results_df.padj >= 0.05)\n",
    "]\n",
    "df_lowly_abundant_genes.sort_values(by=\"padj\")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 103,
   "id": "fd4b32f4-aa01-488f-b6b8-52d50882a3b1",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "({'CARD11',\n",
       "  'DCC',\n",
       "  'DLX2',\n",
       "  'ERBB3',\n",
       "  'FERMT3',\n",
       "  'GHR',\n",
       "  'HOXC8',\n",
       "  'INPP5D',\n",
       "  'ITGB4',\n",
       "  'MAF',\n",
       "  'MSX1',\n",
       "  'NOXO1',\n",
       "  'PARD6A',\n",
       "  'PLEKHG6',\n",
       "  'PSTPIP1',\n",
       "  'PTPN22',\n",
       "  'RPS6KA5',\n",
       "  'TEC',\n",
       "  'TIAM1'},\n",
       " 19)"
      ]
     },
     "execution_count": 103,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "lowly_abundant_genes = set(Gp.V).intersection(df_lowly_abundant_genes.index.tolist())\n",
    "lowly_abundant_genes, len(lowly_abundant_genes)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 104,
   "id": "201455a9-04be-4558-98ff-377721cc413b",
   "metadata": {},
   "outputs": [
    {
     "data": {
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       "       0.  ])"
      ]
     },
     "execution_count": 104,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# Now we will add a penalty to avoid selecting lowly expressed genes\n",
    "vertices = Gp.V\n",
    "penalties = np.zeros(Gp.num_vertices)\n",
    "penalties[[vertices.index(v) for v in lowly_abundant_genes.intersection(vertices)]] = (\n",
    "    0.01\n",
    ")\n",
    "penalties"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 105,
   "id": "25208669-b019-4ec8-afe8-4d1cda41cd14",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "C:\\Users\\pablo\\miniconda3\\envs\\corneto-dev-mini\\Lib\\site-packages\\cvxpy\\problems\\problem.py:158: UserWarning: Objective contains too many subexpressions. Consider vectorizing your CVXPY code to speed up compilation.\n",
      "  warnings.warn(\"Objective contains too many subexpressions. \"\n"
     ]
    }
   ],
   "source": [
    "# Create the carnival problem\n",
    "P = milp_carnival(Gp, inputs_p, measurements_p, beta_weight=0.2)\n",
    "\n",
    "# We penalize the inclusion of lowly expressed genes:\n",
    "# protein_selected is just the sum of the binary variables vertex activated and vertex inhibited, defined in carnival.\n",
    "# these variables are mutually exclusive, so the sum is at most 1, meaning that the vertex was selected, either activated (+1) or inhibited (-1)\n",
    "protein_selected = P.expr.vertex_activated + P.expr.vertex_inhibited\n",
    "\n",
    "# We multiply the vector variable of selected proteins and the penalties to\n",
    "# sum the total cost: sum (v1 * penalty1 + v2 * penalty2, + v3 ...) and we add this as an objective\n",
    "penalty_vertices = protein_selected @ penalties\n",
    "P.add_objectives(penalty_vertices)\n",
    "\n",
    "# Select only 1 receptor\n",
    "protein_selected = P.expr.vertex_activated + P.expr.vertex_inhibited\n",
    "# P += sum(protein_selected[idx_receptors]) == 1\n",
    "\n",
    "P.solve(solver=\"GUROBI\", Seed=seed, TimeLimit=max_time);"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 106,
   "id": "a4c0f22c-748e-457e-9223-8c83f5829897",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
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      "Warning: node 'PRKCA', graph '%3' size too small for label\n",
      "Warning: node 'HIPK2', graph '%3' size too small for label\n",
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      "Warning: node 'SMAD4', graph '%3' size too small for label\n",
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       "<!-- PPP2CA&#45;&gt;RB1 -->\n",
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       "<!-- EP300&#45;&gt;SMAD7 -->\n",
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       "<title>EP300&#45;&gt;SMAD7</title>\n",
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       "<title>JUNB</title>\n",
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       "<title>MAPK14&#45;&gt;JUNB</title>\n",
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       "<title>MAPK14&#45;&gt;SMAD3</title>\n",
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       "<title>MAPK14&#45;&gt;CDX2</title>\n",
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       "<title>MAPK14&#45;&gt;HBP1</title>\n",
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       "<title>JUN</title>\n",
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       "<!-- RELA&#45;&gt;JUN -->\n",
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       "<title>RELA&#45;&gt;JUN</title>\n",
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       "<title>SMAD3&#45;&gt;CEBPB</title>\n",
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       "<!-- ASXL1 -->\n",
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       "<!-- IGF1&#45;&gt;APC_AXIN1_GSK3B -->\n",
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       "<!-- DLX5&#45;&gt;MSX2 -->\n",
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       "<title>DLX5&#45;&gt;MSX2</title>\n",
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       "<!-- TICAM1&#45;&gt;TBK1 -->\n",
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       "<title>TICAM1&#45;&gt;TBK1</title>\n",
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       "<!-- JUN&#45;&gt;SPI1 -->\n",
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       "<title>CIITA</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"803\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"803\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CIITA</text>\n",
       "</g>\n",
       "<!-- GSK3B&#45;&gt;CIITA -->\n",
       "<g id=\"edge55\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;CIITA</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M572.89,-366.24C576.69,-363.89 580.88,-361.62 585,-360 665.41,-328.43 695.59,-355.57 776,-324 776.77,-323.7 777.55,-323.37 778.32,-323.02\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"779.63,-326.3 786.78,-318.48 776.31,-320.13 779.63,-326.3\"/>\n",
       "</g>\n",
       "<!-- CEBPA -->\n",
       "<g id=\"node80\" class=\"node\">\n",
       "<title>CEBPA</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"857\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"857\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CEBPA</text>\n",
       "</g>\n",
       "<!-- GSK3B&#45;&gt;CEBPA -->\n",
       "<g id=\"edge87\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;CEBPA</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M572.56,-366.3C576.44,-363.88 580.74,-361.57 585,-360 688.24,-321.86 726.76,-362.14 830,-324 830.8,-323.7 831.6,-323.38 832.4,-323.04\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"833.92,-326.2 841.1,-318.41 830.63,-320.02 833.92,-326.2\"/>\n",
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       "<!-- VHL -->\n",
       "<g id=\"node54\" class=\"node\">\n",
       "<title>VHL</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"207\" cy=\"-450\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"207\" y=\"-444.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">VHL</text>\n",
       "</g>\n",
       "<!-- CHEK2&#45;&gt;VHL -->\n",
       "<g id=\"edge34\" class=\"edge\">\n",
       "<title>CHEK2&#45;&gt;VHL</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M207,-503.34C207,-496.34 207,-488.12 207,-480.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"210.5,-480.42 207,-470.42 203.5,-480.42 210.5,-480.42\"/>\n",
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       "<!-- CDH6 -->\n",
       "<g id=\"node56\" class=\"node\">\n",
       "<title>CDH6</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"699\" cy=\"-810\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"699\" y=\"-804.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CDH6</text>\n",
       "</g>\n",
       "<!-- CTNNB1 -->\n",
       "<g id=\"node57\" class=\"node\">\n",
       "<title>CTNNB1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"699\" cy=\"-738\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"699\" y=\"-732.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CTNNB1</text>\n",
       "</g>\n",
       "<!-- CDH6&#45;&gt;CTNNB1 -->\n",
       "<g id=\"edge36\" class=\"edge\">\n",
       "<title>CDH6&#45;&gt;CTNNB1</title>\n",
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       "<polygon fill=\"black\" stroke=\"black\" points=\"702.5,-768.42 699,-758.42 695.5,-768.42 702.5,-768.42\"/>\n",
       "</g>\n",
       "<!-- KLF4 -->\n",
       "<g id=\"node75\" class=\"node\">\n",
       "<title>KLF4</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"699\" cy=\"-666\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"699\" y=\"-660.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">KLF4</text>\n",
       "</g>\n",
       "<!-- CTNNB1&#45;&gt;KLF4 -->\n",
       "<g id=\"edge67\" class=\"edge\">\n",
       "<title>CTNNB1&#45;&gt;KLF4</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M699,-719.34C699,-712.34 699,-704.12 699,-696.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"702.5,-696.42 699,-686.42 695.5,-696.42 702.5,-696.42\"/>\n",
       "</g>\n",
       "<!-- CDK1 -->\n",
       "<g id=\"node58\" class=\"node\">\n",
       "<title>CDK1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"781\" cy=\"-666\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"781\" y=\"-660.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CDK1</text>\n",
       "</g>\n",
       "<!-- HMGA2 -->\n",
       "<g id=\"node59\" class=\"node\">\n",
       "<title>HMGA2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"754\" cy=\"-594\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"754\" y=\"-588.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">HMGA2</text>\n",
       "</g>\n",
       "<!-- CDK1&#45;&gt;HMGA2 -->\n",
       "<g id=\"edge38\" class=\"edge\">\n",
       "<title>CDK1&#45;&gt;HMGA2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M774.6,-648.41C770.87,-638.73 766.12,-626.43 762.13,-616.08\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"756.05,-614.2 765.38,-610.6 766.1,-612.47 756.77,-616.07 756.05,-614.2\"/>\n",
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       "</g>\n",
       "<!-- HMGA1 -->\n",
       "<g id=\"node81\" class=\"node\">\n",
       "<title>HMGA1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"808\" cy=\"-594\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"808\" y=\"-588.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">HMGA1</text>\n",
       "</g>\n",
       "<!-- CDK1&#45;&gt;HMGA1 -->\n",
       "<g id=\"edge68\" class=\"edge\">\n",
       "<title>CDK1&#45;&gt;HMGA1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M787.4,-648.41C791.13,-638.73 795.88,-626.43 799.87,-616.08\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"796.62,-610.6 805.95,-614.2 805.23,-616.07 795.9,-612.47 796.62,-610.6\"/>\n",
       "<polyline fill=\"none\" stroke=\"black\" points=\"801.65,-611.47 799.85,-616.13\"/>\n",
       "</g>\n",
       "<!-- PTPRR&#45;&gt;MAPK14 -->\n",
       "<g id=\"edge62\" class=\"edge\">\n",
       "<title>PTPRR&#45;&gt;MAPK14</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M438.05,-510.67C456.13,-498.26 486.47,-477.44 506.11,-463.96\"/>\n",
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       "</g>\n",
       "<!-- WWTR1 -->\n",
       "<g id=\"node77\" class=\"node\">\n",
       "<title>WWTR1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"563\" cy=\"-594\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"563\" y=\"-588.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">WWTR1</text>\n",
       "</g>\n",
       "<!-- CSNK1D&#45;&gt;WWTR1 -->\n",
       "<g id=\"edge60\" class=\"edge\">\n",
       "<title>CSNK1D&#45;&gt;WWTR1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M563,-647.34C563,-638.37 563,-627.37 563,-617.77\"/>\n",
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       "</g>\n",
       "<!-- HIF3A -->\n",
       "<g id=\"node68\" class=\"node\">\n",
       "<title>HIF3A</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"153\" cy=\"-378\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"153\" y=\"-372.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">HIF3A</text>\n",
       "</g>\n",
       "<!-- PRKN&#45;&gt;HIF3A -->\n",
       "<g id=\"edge51\" class=\"edge\">\n",
       "<title>PRKN&#45;&gt;HIF3A</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M153,-431.34C153,-422.37 153,-411.37 153,-401.77\"/>\n",
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       "<polyline fill=\"none\" stroke=\"black\" points=\"153,-396.9 153,-401.9\"/>\n",
       "</g>\n",
       "<!-- IL21R -->\n",
       "<g id=\"node69\" class=\"node\">\n",
       "<title>IL21R</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"644\" cy=\"-810\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"644\" y=\"-804.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">IL21R</text>\n",
       "</g>\n",
       "<!-- JAK1 -->\n",
       "<g id=\"node70\" class=\"node\">\n",
       "<title>JAK1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"644\" cy=\"-738\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"644\" y=\"-732.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">JAK1</text>\n",
       "</g>\n",
       "<!-- IL21R&#45;&gt;JAK1 -->\n",
       "<g id=\"edge52\" class=\"edge\">\n",
       "<title>IL21R&#45;&gt;JAK1</title>\n",
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       "<polygon fill=\"black\" stroke=\"black\" points=\"647.5,-768.42 644,-758.42 640.5,-768.42 647.5,-768.42\"/>\n",
       "</g>\n",
       "<!-- JAK1&#45;&gt;STAT1 -->\n",
       "<g id=\"edge86\" class=\"edge\">\n",
       "<title>JAK1&#45;&gt;STAT1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M644,-719.34C644,-712.34 644,-704.12 644,-696.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"647.5,-696.42 644,-686.42 640.5,-696.42 647.5,-696.42\"/>\n",
       "</g>\n",
       "<!-- NFKBIB -->\n",
       "<g id=\"node72\" class=\"node\">\n",
       "<title>NFKBIB</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"18\" cy=\"-162\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"18\" y=\"-156.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">NFKBIB</text>\n",
       "</g>\n",
       "<!-- MAP3K7&#45;&gt;NFKBIB -->\n",
       "<g id=\"edge53\" class=\"edge\">\n",
       "<title>MAP3K7&#45;&gt;NFKBIB</title>\n",
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       "</g>\n",
       "<!-- CUL1_RBX1_SKP1&#45;&gt;SMURF1 -->\n",
       "<g id=\"edge66\" class=\"edge\">\n",
       "<title>CUL1_RBX1_SKP1&#45;&gt;SMURF1</title>\n",
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       "</g>\n",
       "<!-- MEIS2 -->\n",
       "<g id=\"node76\" class=\"node\">\n",
       "<title>MEIS2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"699\" cy=\"-594\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"699\" y=\"-588.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">MEIS2</text>\n",
       "</g>\n",
       "<!-- KLF4&#45;&gt;MEIS2 -->\n",
       "<g id=\"edge59\" class=\"edge\">\n",
       "<title>KLF4&#45;&gt;MEIS2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M699,-647.34C699,-640.34 699,-632.12 699,-624.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"702.5,-624.42 699,-614.42 695.5,-624.42 702.5,-624.42\"/>\n",
       "</g>\n",
       "<!-- INHBA -->\n",
       "<g id=\"node78\" class=\"node\">\n",
       "<title>INHBA</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"507\" cy=\"-810\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"507\" y=\"-804.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">INHBA</text>\n",
       "</g>\n",
       "<!-- ACVR2B -->\n",
       "<g id=\"node79\" class=\"node\">\n",
       "<title>ACVR2B</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"507\" cy=\"-738\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"507\" y=\"-732.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">ACVR2B</text>\n",
       "</g>\n",
       "<!-- INHBA&#45;&gt;ACVR2B -->\n",
       "<g id=\"edge61\" class=\"edge\">\n",
       "<title>INHBA&#45;&gt;ACVR2B</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M507,-791.34C507,-784.34 507,-776.12 507,-768.28\"/>\n",
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       "<!-- ACVR2B&#45;&gt;SMAD2 -->\n",
       "<g id=\"edge63\" class=\"edge\">\n",
       "<title>ACVR2B&#45;&gt;SMAD2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M507,-719.34C507,-712.34 507,-704.12 507,-696.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"510.5,-696.42 507,-686.42 503.5,-696.42 510.5,-696.42\"/>\n",
       "</g>\n",
       "<!-- CEBPA&#45;&gt;USF1 -->\n",
       "<g id=\"edge64\" class=\"edge\">\n",
       "<title>CEBPA&#45;&gt;USF1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M857,-287.34C857,-280.34 857,-272.12 857,-264.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"860.5,-264.42 857,-254.42 853.5,-264.42 860.5,-264.42\"/>\n",
       "</g>\n",
       "<!-- POU3F1 -->\n",
       "<g id=\"node86\" class=\"node\">\n",
       "<title>POU3F1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"808\" cy=\"-522\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"808\" y=\"-516.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">POU3F1</text>\n",
       "</g>\n",
       "<!-- HMGA1&#45;&gt;POU3F1 -->\n",
       "<g id=\"edge71\" class=\"edge\">\n",
       "<title>HMGA1&#45;&gt;POU3F1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M808,-575.34C808,-568.34 808,-560.12 808,-552.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"811.5,-552.42 808,-542.42 804.5,-552.42 811.5,-552.42\"/>\n",
       "</g>\n",
       "<!-- EGF -->\n",
       "<g id=\"node82\" class=\"node\">\n",
       "<title>EGF</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"781\" cy=\"-810\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"781\" y=\"-804.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">EGF</text>\n",
       "</g>\n",
       "<!-- ERBB2 -->\n",
       "<g id=\"node83\" class=\"node\">\n",
       "<title>ERBB2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"781\" cy=\"-738\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"781\" y=\"-732.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">ERBB2</text>\n",
       "</g>\n",
       "<!-- EGF&#45;&gt;ERBB2 -->\n",
       "<g id=\"edge69\" class=\"edge\">\n",
       "<title>EGF&#45;&gt;ERBB2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M781,-791.34C781,-784.34 781,-776.12 781,-768.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"784.5,-768.42 781,-758.42 777.5,-768.42 784.5,-768.42\"/>\n",
       "</g>\n",
       "<!-- ERBB2&#45;&gt;CDK1 -->\n",
       "<g id=\"edge77\" class=\"edge\">\n",
       "<title>ERBB2&#45;&gt;CDK1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M781,-719.34C781,-710.37 781,-699.37 781,-689.77\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"776,-685.9 786,-685.9 786,-687.9 776,-687.9 776,-685.9\"/>\n",
       "<polyline fill=\"none\" stroke=\"black\" points=\"781,-684.9 781,-689.9\"/>\n",
       "</g>\n",
       "<!-- MAPK3 -->\n",
       "<g id=\"node85\" class=\"node\">\n",
       "<title>MAPK3</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"263\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"263\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">MAPK3</text>\n",
       "</g>\n",
       "<!-- PPP1CA&#45;&gt;MAPK3 -->\n",
       "<g id=\"edge70\" class=\"edge\">\n",
       "<title>PPP1CA&#45;&gt;MAPK3</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M268.98,-359.34C267.94,-350.23 266.66,-339.03 265.55,-329.33\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"260.14,-325.98 270.07,-324.84 270.3,-326.83 260.36,-327.96 260.14,-325.98\"/>\n",
       "<polyline fill=\"none\" stroke=\"black\" points=\"264.99,-324.42 265.56,-329.38\"/>\n",
       "</g>\n",
       "<!-- MAPK3&#45;&gt;NCOA1 -->\n",
       "<g id=\"edge80\" class=\"edge\">\n",
       "<title>MAPK3&#45;&gt;NCOA1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M263,-287.34C263,-280.34 263,-272.12 263,-264.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"266.5,-264.42 263,-254.42 259.5,-264.42 266.5,-264.42\"/>\n",
       "</g>\n",
       "<!-- RXRB -->\n",
       "<g id=\"node92\" class=\"node\">\n",
       "<title>RXRB</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"209\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"209\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">RXRB</text>\n",
       "</g>\n",
       "<!-- RARB&#45;&gt;RXRB -->\n",
       "<g id=\"edge83\" class=\"edge\">\n",
       "<title>RARB&#45;&gt;RXRB</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M209.75,-359.34C209.65,-352.34 209.53,-344.12 209.42,-336.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"212.92,-336.36 209.28,-326.42 205.92,-336.46 212.92,-336.36\"/>\n",
       "</g>\n",
       "</g>\n",
       "</svg>\n"
      ],
      "text/plain": [
       "<graphviz.graphs.Digraph at 0x1dd19109610>"
      ]
     },
     "execution_count": 106,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "G_sol = Gp.edge_subgraph(np.flatnonzero(P.expr.edge_values.value))\n",
    "values = P.expr.vertex_values.value\n",
    "vertex_values = {v: values[i] for i, v in enumerate(Gp.V)}\n",
    "vertex_sol_values = [vertex_values[v] for v in G_sol.V]\n",
    "G_sol.plot(\n",
    "    custom_vertex_attr=cn.pl.create_graphviz_vertex_attributes(\n",
    "        G_sol.V, vertex_sol_values\n",
    "    )\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 107,
   "id": "897bd341-948d-4026-a17a-b0b6b6796f4d",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "10.373496770858765\n",
      "88.0\n",
      "0.0\n"
     ]
    }
   ],
   "source": [
    "# Print the values of the objectives:\n",
    "for o in P.objectives:\n",
    "    print(o.value)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 108,
   "id": "16795952-fb4a-4490-b418-6439fbf5ae5d",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "(949, 3261)"
      ]
     },
     "execution_count": 108,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# Now we are going to force that only TGFB1 (active)\n",
    "Gp, inputs_p, measurements_p = preprocess_graph(G, {\"TGFB1\": 1}, measurements)\n",
    "Gp.shape"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 109,
   "id": "56fab499-da46-4387-8b53-04f2a050d7b1",
   "metadata": {},
   "outputs": [],
   "source": [
    "P = milp_carnival(Gp, inputs_p, measurements_p, beta_weight=0.2)\n",
    "P.solve(solver=\"GUROBI\", Seed=seed, TimeLimit=max_time);"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 110,
   "id": "73530ad5-a8b8-41fb-b8ba-087c8ecb592a",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "10.373496770858765\n",
      "90.0\n"
     ]
    }
   ],
   "source": [
    "# Same error but +2 edges were included to explain the TFs\n",
    "for o in P.objectives:\n",
    "    print(o.value)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 111,
   "id": "170e8316-5307-48de-8ba5-5a69091ac237",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Warning: node 'CDKN1A', graph '%3' size too small for label\n",
      "Warning: node 'TRIP11', graph '%3' size too small for label\n",
      "Warning: node 'THRA', graph '%3' size too small for label\n",
      "Warning: node 'HIPK2', graph '%3' size too small for label\n",
      "Warning: node 'MAPK1', graph '%3' size too small for label\n",
      "Warning: node 'PHLPP1', graph '%3' size too small for label\n",
      "Warning: node 'PRKCA', graph '%3' size too small for label\n",
      "Warning: node 'MYOCD', graph '%3' size too small for label\n",
      "Warning: node 'NFKB2', graph '%3' size too small for label\n",
      "Warning: node 'RORA', graph '%3' size too small for label\n",
      "Warning: node 'PPP2CA', graph '%3' size too small for label\n",
      "Warning: node 'TRAF2', graph '%3' size too small for label\n",
      "Warning: node 'SMURF1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD6', graph '%3' size too small for label\n",
      "Warning: node 'DUSP16', graph '%3' size too small for label\n",
      "Warning: node 'MAPK14', graph '%3' size too small for label\n",
      "Warning: node 'FOSL1', graph '%3' size too small for label\n",
      "Warning: node 'MEF2A', graph '%3' size too small for label\n",
      "Warning: node 'GSK3B', graph '%3' size too small for label\n",
      "Warning: node 'MUC1', graph '%3' size too small for label\n",
      "Warning: node 'NCOA1', graph '%3' size too small for label\n",
      "Warning: node 'ASXL1', graph '%3' size too small for label\n",
      "Warning: node 'MSX2', graph '%3' size too small for label\n",
      "Warning: node 'SMAD3', graph '%3' size too small for label\n",
      "Warning: node 'SMAD4', graph '%3' size too small for label\n",
      "Warning: node 'NFE2L2', graph '%3' size too small for label\n",
      "Warning: node 'STAT1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD7', graph '%3' size too small for label\n",
      "Warning: node 'TICAM1', graph '%3' size too small for label\n",
      "Warning: node 'AURKA', graph '%3' size too small for label\n",
      "Warning: node 'LATS2', graph '%3' size too small for label\n",
      "Warning: node 'NKX2-1', graph '%3' size too small for label\n",
      "Warning: node 'PITX1', graph '%3' size too small for label\n",
      "Warning: node 'CHEK2', graph '%3' size too small for label\n",
      "Warning: node 'HMGA2', graph '%3' size too small for label\n",
      "Warning: node 'STAT5A', graph '%3' size too small for label\n",
      "Warning: node 'MECP2', graph '%3' size too small for label\n",
      "Warning: node 'NFKB1', graph '%3' size too small for label\n",
      "Warning: node 'MAFA', graph '%3' size too small for label\n",
      "Warning: node 'HIF3A', graph '%3' size too small for label\n",
      "Warning: node 'MAP3K7', graph '%3' size too small for label\n",
      "Warning: node 'NFKBIB', graph '%3' size too small for label\n",
      "Warning: node 'KHSRP', graph '%3' size too small for label\n",
      "Warning: node 'CEBPB', graph '%3' size too small for label\n",
      "Warning: node 'MAPK3', graph '%3' size too small for label\n",
      "Warning: node 'FBXW7', graph '%3' size too small for label\n",
      "Warning: node 'CUL1_RBX1_SKP1', graph '%3' size too small for label\n",
      "Warning: node 'PIK3CA_PIK3R1', graph '%3' size too small for label\n",
      "Warning: node 'TGFB1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD2', graph '%3' size too small for label\n",
      "Warning: node 'PPP1CA', graph '%3' size too small for label\n",
      "Warning: node 'MEIS2', graph '%3' size too small for label\n",
      "Warning: node 'CEBPA', graph '%3' size too small for label\n",
      "Warning: node 'RARG', graph '%3' size too small for label\n",
      "Warning: node 'RXRB', graph '%3' size too small for label\n",
      "Warning: node 'HMGA1', graph '%3' size too small for label\n",
      "Warning: node 'POU3F1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD5', graph '%3' size too small for label\n",
      "Warning: node 'WWTR1', graph '%3' size too small for label\n",
      "Warning: node 'NR1H4', graph '%3' size too small for label\n",
      "Warning: node 'CDKN1A', graph '%3' size too small for label\n",
      "Warning: node 'TRIP11', graph '%3' size too small for label\n",
      "Warning: node 'THRA', graph '%3' size too small for label\n",
      "Warning: node 'HIPK2', graph '%3' size too small for label\n",
      "Warning: node 'MAPK1', graph '%3' size too small for label\n",
      "Warning: node 'PHLPP1', graph '%3' size too small for label\n",
      "Warning: node 'PRKCA', graph '%3' size too small for label\n",
      "Warning: node 'MYOCD', graph '%3' size too small for label\n",
      "Warning: node 'NFKB2', graph '%3' size too small for label\n",
      "Warning: node 'RORA', graph '%3' size too small for label\n",
      "Warning: node 'PPP2CA', graph '%3' size too small for label\n",
      "Warning: node 'TRAF2', graph '%3' size too small for label\n",
      "Warning: node 'SMURF1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD6', graph '%3' size too small for label\n",
      "Warning: node 'DUSP16', graph '%3' size too small for label\n",
      "Warning: node 'MAPK14', graph '%3' size too small for label\n",
      "Warning: node 'FOSL1', graph '%3' size too small for label\n",
      "Warning: node 'MEF2A', graph '%3' size too small for label\n",
      "Warning: node 'GSK3B', graph '%3' size too small for label\n",
      "Warning: node 'MUC1', graph '%3' size too small for label\n",
      "Warning: node 'NCOA1', graph '%3' size too small for label\n",
      "Warning: node 'ASXL1', graph '%3' size too small for label\n",
      "Warning: node 'MSX2', graph '%3' size too small for label\n",
      "Warning: node 'SMAD3', graph '%3' size too small for label\n",
      "Warning: node 'SMAD4', graph '%3' size too small for label\n",
      "Warning: node 'NFE2L2', graph '%3' size too small for label\n",
      "Warning: node 'STAT1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD7', graph '%3' size too small for label\n",
      "Warning: node 'TICAM1', graph '%3' size too small for label\n",
      "Warning: node 'AURKA', graph '%3' size too small for label\n",
      "Warning: node 'LATS2', graph '%3' size too small for label\n",
      "Warning: node 'NKX2-1', graph '%3' size too small for label\n",
      "Warning: node 'PITX1', graph '%3' size too small for label\n",
      "Warning: node 'CHEK2', graph '%3' size too small for label\n",
      "Warning: node 'HMGA2', graph '%3' size too small for label\n",
      "Warning: node 'STAT5A', graph '%3' size too small for label\n",
      "Warning: node 'MECP2', graph '%3' size too small for label\n",
      "Warning: node 'NFKB1', graph '%3' size too small for label\n",
      "Warning: node 'MAFA', graph '%3' size too small for label\n",
      "Warning: node 'HIF3A', graph '%3' size too small for label\n",
      "Warning: node 'MAP3K7', graph '%3' size too small for label\n",
      "Warning: node 'NFKBIB', graph '%3' size too small for label\n",
      "Warning: node 'KHSRP', graph '%3' size too small for label\n",
      "Warning: node 'CEBPB', graph '%3' size too small for label\n",
      "Warning: node 'MAPK3', graph '%3' size too small for label\n",
      "Warning: node 'FBXW7', graph '%3' size too small for label\n",
      "Warning: node 'CUL1_RBX1_SKP1', graph '%3' size too small for label\n",
      "Warning: node 'PIK3CA_PIK3R1', graph '%3' size too small for label\n",
      "Warning: node 'TGFB1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD2', graph '%3' size too small for label\n",
      "Warning: node 'PPP1CA', graph '%3' size too small for label\n",
      "Warning: node 'MEIS2', graph '%3' size too small for label\n",
      "Warning: node 'CEBPA', graph '%3' size too small for label\n",
      "Warning: node 'RARG', graph '%3' size too small for label\n",
      "Warning: node 'RXRB', graph '%3' size too small for label\n",
      "Warning: node 'HMGA1', graph '%3' size too small for label\n",
      "Warning: node 'POU3F1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD5', graph '%3' size too small for label\n",
      "Warning: node 'WWTR1', graph '%3' size too small for label\n",
      "Warning: node 'NR1H4', graph '%3' size too small for label\n"
     ]
    },
    {
     "data": {
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       "<!-- CDKN1A -->\n",
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       "<title>CDKN1A</title>\n",
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       "<text text-anchor=\"middle\" x=\"234\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CDKN1A</text>\n",
       "</g>\n",
       "<!-- CDK1 -->\n",
       "<g id=\"node2\" class=\"node\">\n",
       "<title>CDK1</title>\n",
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       "<text text-anchor=\"middle\" x=\"72\" y=\"-228.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CDK1</text>\n",
       "</g>\n",
       "<!-- CDKN1A&#45;&gt;CDK1 -->\n",
       "<g id=\"edge1\" class=\"edge\">\n",
       "<title>CDKN1A&#45;&gt;CDK1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M218.94,-294.63C215.14,-292.27 211.01,-289.89 207,-288 161.26,-266.36 144.74,-273.64 99,-252 96.37,-250.76 93.69,-249.31 91.08,-247.79\"/>\n",
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       "<!-- ABL1&#45;&gt;PRKN -->\n",
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       "<title>ABL1&#45;&gt;PRKN</title>\n",
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       "<!-- CEBPB -->\n",
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       "<!-- ABL1&#45;&gt;CEBPB -->\n",
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       "<title>HMGA1</title>\n",
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       "<!-- HIPK2&#45;&gt;HMGA1 -->\n",
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       "<!-- MAPK1 -->\n",
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       "<title>MAPK1</title>\n",
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       "</g>\n",
       "<!-- JUN -->\n",
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       "<!-- MAPK14 -->\n",
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       "<!-- DUSP16&#45;&gt;MAPK14 -->\n",
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       "<title>DUSP16&#45;&gt;MAPK14</title>\n",
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       "<!-- MAPK14&#45;&gt;CDKN1A -->\n",
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       "<title>MAPK14&#45;&gt;CDKN1A</title>\n",
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       "<title>JUNB</title>\n",
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       "<!-- MAPK14&#45;&gt;JUNB -->\n",
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       "<title>MAPK14&#45;&gt;JUNB</title>\n",
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       "<!-- MEF2A -->\n",
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       "<title>MEF2A</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"342\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"342\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">MEF2A</text>\n",
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       "<!-- MAPK14&#45;&gt;MEF2A -->\n",
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       "<title>MAPK14&#45;&gt;MEF2A</title>\n",
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       "<!-- GSK3B -->\n",
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       "<title>GSK3B</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"396\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"396\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">GSK3B</text>\n",
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       "<!-- MAPK14&#45;&gt;GSK3B -->\n",
       "<g id=\"edge35\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;GSK3B</title>\n",
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       "<!-- DLX5 -->\n",
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       "<title>DLX5</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"450\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"450\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">DLX5</text>\n",
       "</g>\n",
       "<!-- MAPK14&#45;&gt;DLX5 -->\n",
       "<g id=\"edge59\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;DLX5</title>\n",
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       "<!-- SMAD3 -->\n",
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       "<title>SMAD3</title>\n",
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       "<text text-anchor=\"middle\" x=\"504\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">SMAD3</text>\n",
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       "<!-- MAPK14&#45;&gt;SMAD3 -->\n",
       "<g id=\"edge71\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;SMAD3</title>\n",
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       "<!-- SP7 -->\n",
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       "<title>SP7</title>\n",
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       "<text text-anchor=\"middle\" x=\"558\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">SP7</text>\n",
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       "<!-- MAPK14&#45;&gt;SP7 -->\n",
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       "<title>MAPK14&#45;&gt;SP7</title>\n",
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       "<!-- CDX2 -->\n",
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       "<title>CDX2</title>\n",
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       "<!-- MAPK14&#45;&gt;CDX2 -->\n",
       "<g id=\"edge80\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;CDX2</title>\n",
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       "<!-- HBP1 -->\n",
       "<g id=\"node88\" class=\"node\">\n",
       "<title>HBP1</title>\n",
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       "<text text-anchor=\"middle\" x=\"666\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">HBP1</text>\n",
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       "<!-- MAPK14&#45;&gt;HBP1 -->\n",
       "<g id=\"edge83\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;HBP1</title>\n",
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       "<!-- USF1 -->\n",
       "<g id=\"node26\" class=\"node\">\n",
       "<title>USF1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"504\" cy=\"-162\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"504\" y=\"-156.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">USF1</text>\n",
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       "<!-- FOSL1 -->\n",
       "<g id=\"node27\" class=\"node\">\n",
       "<title>FOSL1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"504\" cy=\"-90\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"504\" y=\"-84.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">FOSL1</text>\n",
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       "<!-- USF1&#45;&gt;FOSL1 -->\n",
       "<g id=\"edge15\" class=\"edge\">\n",
       "<title>USF1&#45;&gt;FOSL1</title>\n",
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       "<!-- RELA -->\n",
       "<g id=\"node30\" class=\"node\">\n",
       "<title>RELA</title>\n",
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       "<!-- EGR1 -->\n",
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       "<title>EGR1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"234\" cy=\"-162\" rx=\"18\" ry=\"18\"/>\n",
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       "<!-- RELA&#45;&gt;EGR1 -->\n",
       "<g id=\"edge18\" class=\"edge\">\n",
       "<title>RELA&#45;&gt;EGR1</title>\n",
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       "<!-- PITX1 -->\n",
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       "<title>PITX1</title>\n",
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       "<!-- EGR1&#45;&gt;PITX1 -->\n",
       "<g id=\"edge33\" class=\"edge\">\n",
       "<title>EGR1&#45;&gt;PITX1</title>\n",
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       "<!-- GSK3B&#45;&gt;PHLPP1 -->\n",
       "<g id=\"edge46\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;PHLPP1</title>\n",
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       "<!-- GSK3B&#45;&gt;MYOCD -->\n",
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       "<title>GSK3B&#45;&gt;MYOCD</title>\n",
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       "<!-- GSK3B&#45;&gt;RELA -->\n",
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       "<title>GSK3B&#45;&gt;RELA</title>\n",
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       "<title>MUC1</title>\n",
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       "<!-- GSK3B&#45;&gt;MUC1 -->\n",
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       "<title>GSK3B&#45;&gt;MUC1</title>\n",
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       "<!-- SFPQ -->\n",
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       "<!-- GSK3B&#45;&gt;SFPQ -->\n",
       "<g id=\"edge32\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;SFPQ</title>\n",
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       "<!-- NFKB1 -->\n",
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       "<!-- GSK3B&#45;&gt;NFKB1 -->\n",
       "<g id=\"edge47\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;NFKB1</title>\n",
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       "<!-- GSK3B&#45;&gt;CIITA -->\n",
       "<g id=\"edge60\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;CIITA</title>\n",
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       "<title>GSK3B&#45;&gt;CEBPA</title>\n",
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       "<title>MUC1&#45;&gt;KLF4</title>\n",
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       "<title>NCOA1</title>\n",
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       "<title>NCOA1&#45;&gt;ASXL1</title>\n",
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       "<title>DLX5&#45;&gt;MSX2</title>\n",
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       "<title>FBXW7&#45;&gt;CUL1_RBX1_SKP1</title>\n",
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       "</g>\n",
       "<!-- CUL1_RBX1_SKP1&#45;&gt;SMURF1 -->\n",
       "<g id=\"edge69\" class=\"edge\">\n",
       "<title>CUL1_RBX1_SKP1&#45;&gt;SMURF1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1152,-359.34C1152,-350.37 1152,-339.37 1152,-329.77\"/>\n",
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       "</g>\n",
       "<!-- PIK3CA_PIK3R1 -->\n",
       "<g id=\"node75\" class=\"node\">\n",
       "<title>PIK3CA_PIK3R1</title>\n",
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       "</g>\n",
       "<!-- PIK3CA_PIK3R1&#45;&gt;AKT1 -->\n",
       "<g id=\"edge62\" class=\"edge\">\n",
       "<title>PIK3CA_PIK3R1&#45;&gt;AKT1</title>\n",
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       "<g id=\"node76\" class=\"node\">\n",
       "<title>TGFB1</title>\n",
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       "</g>\n",
       "<!-- TGFB1&#45;&gt;PIK3CA_PIK3R1 -->\n",
       "<g id=\"edge63\" class=\"edge\">\n",
       "<title>TGFB1&#45;&gt;PIK3CA_PIK3R1</title>\n",
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       "<g id=\"node80\" class=\"node\">\n",
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       "<text text-anchor=\"middle\" x=\"288\" y=\"-84.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">MEIS2</text>\n",
       "</g>\n",
       "<!-- KLF4&#45;&gt;MEIS2 -->\n",
       "<g id=\"edge67\" class=\"edge\">\n",
       "<title>KLF4&#45;&gt;MEIS2</title>\n",
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       "</g>\n",
       "<!-- PPP1CA&#45;&gt;AURKA -->\n",
       "<g id=\"edge66\" class=\"edge\">\n",
       "<title>PPP1CA&#45;&gt;AURKA</title>\n",
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       "</g>\n",
       "<!-- PPP1CA&#45;&gt;MAPK3 -->\n",
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       "<title>PPP1CA&#45;&gt;MAPK3</title>\n",
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       "</g>\n",
       "<!-- CEBPA&#45;&gt;USF1 -->\n",
       "<g id=\"edge68\" class=\"edge\">\n",
       "<title>CEBPA&#45;&gt;USF1</title>\n",
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       "</g>\n",
       "<!-- RARG&#45;&gt;RXRB -->\n",
       "<g id=\"edge70\" class=\"edge\">\n",
       "<title>RARG&#45;&gt;RXRB</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M720,-287.34C720,-280.34 720,-272.12 720,-264.28\"/>\n",
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       "<g id=\"node85\" class=\"node\">\n",
       "<title>POU3F1</title>\n",
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       "</g>\n",
       "<!-- HMGA1&#45;&gt;POU3F1 -->\n",
       "<g id=\"edge74\" class=\"edge\">\n",
       "<title>HMGA1&#45;&gt;POU3F1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M936,-287.34C936,-280.34 936,-272.12 936,-264.28\"/>\n",
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      ],
      "text/plain": [
       "<graphviz.graphs.Digraph at 0x1dd29a2fbd0>"
      ]
     },
     "execution_count": 111,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "G_sol = Gp.edge_subgraph(np.flatnonzero(P.expr.edge_values.value))\n",
    "values = P.expr.vertex_values.value\n",
    "vertex_values = {v: values[i] for i, v in enumerate(Gp.V)}\n",
    "vertex_sol_values = [vertex_values[v] for v in G_sol.V]\n",
    "G_sol.plot(\n",
    "    custom_vertex_attr=cn.pl.create_graphviz_vertex_attributes(\n",
    "        G_sol.V, vertex_sol_values\n",
    "    )\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 112,
   "id": "6380c9af-ef90-4bb7-8337-9b6981d5c5ea",
   "metadata": {},
   "outputs": [],
   "source": [
    "# Biasing the networks towards activatory interactions\n",
    "\n",
    "# Create the carnival problem with Beta = 0 (to not equally penalise all interactions)\n",
    "# Gp, inputs_p, measurements_p = preprocess_graph(G, {\"TGFB1\": 0}, measurements)\n",
    "Gp, inputs_p, measurements_p = preprocess_graph(G, inputs, measurements)\n",
    "P = milp_carnival(Gp, inputs_p, measurements_p, beta_weight=0)\n",
    "\n",
    "# Bias towards activations, by penalizing only inhibitions\n",
    "P.add_objectives(P.expr.edge_inhibiting.sum(), weights=0.2)\n",
    "\n",
    "# Much smaller penalty for activations, since we only want to penalise them\n",
    "# slightly to avoid having spurious interactions. However, inhibitions are\n",
    "# penalised 20x more than activations (weight 0.2 vs 0.01)\n",
    "P.add_objectives(P.expr.edge_activating.sum(), weights=0.01)\n",
    "\n",
    "P.solve(solver=\"GUROBI\", TimeLimit=max_time, Seed=seed);"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 113,
   "id": "b0e07155-d54f-4e4a-8ba3-a4384aef0d8a",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Warning: node 'FBXW7', graph '%3' size too small for label\n",
      "Warning: node 'MAPK1', graph '%3' size too small for label\n",
      "Warning: node 'PPP2R5C', graph '%3' size too small for label\n",
      "Warning: node 'HIPK2', graph '%3' size too small for label\n",
      "Warning: node 'PTPN7', graph '%3' size too small for label\n",
      "Warning: node 'NFKB2', graph '%3' size too small for label\n",
      "Warning: node 'TRIP11', graph '%3' size too small for label\n",
      "Warning: node 'THRA', graph '%3' size too small for label\n",
      "Warning: node 'PHLPP1', graph '%3' size too small for label\n",
      "Warning: node 'PRKCA', graph '%3' size too small for label\n",
      "Warning: node 'MYOCD', graph '%3' size too small for label\n",
      "Warning: node 'MAP2K1', graph '%3' size too small for label\n",
      "Warning: node 'RORA', graph '%3' size too small for label\n",
      "Warning: node 'SMAD2', graph '%3' size too small for label\n",
      "Warning: node 'MEF2A', graph '%3' size too small for label\n",
      "Warning: node 'PPP2CA', graph '%3' size too small for label\n",
      "Warning: node 'TRAF2', graph '%3' size too small for label\n",
      "Warning: node 'SMURF1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD6', graph '%3' size too small for label\n",
      "Warning: node 'PRKCQ', graph '%3' size too small for label\n",
      "Warning: node 'MAPK3', graph '%3' size too small for label\n",
      "Warning: node 'MAPK14', graph '%3' size too small for label\n",
      "Warning: node 'SMAD3', graph '%3' size too small for label\n",
      "Warning: node 'SMAD4', graph '%3' size too small for label\n",
      "Warning: node 'NCOA1', graph '%3' size too small for label\n",
      "Warning: node 'ASXL1', graph '%3' size too small for label\n",
      "Warning: node 'MSX2', graph '%3' size too small for label\n",
      "Warning: node 'NFE2L2', graph '%3' size too small for label\n",
      "Warning: node 'TICAM1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD7', graph '%3' size too small for label\n",
      "Warning: node 'STAT1', graph '%3' size too small for label\n",
      "Warning: node 'NKX2-1', graph '%3' size too small for label\n",
      "Warning: node 'GSK3B', graph '%3' size too small for label\n",
      "Warning: node 'FOSL1', graph '%3' size too small for label\n",
      "Warning: node 'PITX1', graph '%3' size too small for label\n",
      "Warning: node 'CDON', graph '%3' size too small for label\n",
      "Warning: node 'CHEK2', graph '%3' size too small for label\n",
      "Warning: node 'CTNNB1', graph '%3' size too small for label\n",
      "Warning: node 'LATS2', graph '%3' size too small for label\n",
      "Warning: node 'HMGA2', graph '%3' size too small for label\n",
      "Warning: node 'STAT5A', graph '%3' size too small for label\n",
      "Warning: node 'MECP2', graph '%3' size too small for label\n",
      "Warning: node 'NFKB1', graph '%3' size too small for label\n",
      "Warning: node 'MAFA', graph '%3' size too small for label\n",
      "Warning: node 'STAT6', graph '%3' size too small for label\n",
      "Warning: node 'HIF3A', graph '%3' size too small for label\n",
      "Warning: node 'MAP3K7', graph '%3' size too small for label\n",
      "Warning: node 'NFKBIB', graph '%3' size too small for label\n",
      "Warning: node 'CEBPB', graph '%3' size too small for label\n",
      "Warning: node 'CUL1_RBX1_SKP1', graph '%3' size too small for label\n",
      "Warning: node 'MEIS2', graph '%3' size too small for label\n",
      "Warning: node 'INHBA', graph '%3' size too small for label\n",
      "Warning: node 'ACVR2B', graph '%3' size too small for label\n",
      "Warning: node 'GATA2', graph '%3' size too small for label\n",
      "Warning: node 'HMGA1', graph '%3' size too small for label\n",
      "Warning: node 'ERBB2', graph '%3' size too small for label\n",
      "Warning: node 'POU3F1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD5', graph '%3' size too small for label\n",
      "Warning: node 'RARB', graph '%3' size too small for label\n",
      "Warning: node 'RXRB', graph '%3' size too small for label\n",
      "Warning: node 'WWTR1', graph '%3' size too small for label\n",
      "Warning: node 'CEBPA', graph '%3' size too small for label\n",
      "Warning: node 'NR1H4', graph '%3' size too small for label\n",
      "Warning: node 'FBXW7', graph '%3' size too small for label\n",
      "Warning: node 'MAPK1', graph '%3' size too small for label\n",
      "Warning: node 'PPP2R5C', graph '%3' size too small for label\n",
      "Warning: node 'HIPK2', graph '%3' size too small for label\n",
      "Warning: node 'PTPN7', graph '%3' size too small for label\n",
      "Warning: node 'NFKB2', graph '%3' size too small for label\n",
      "Warning: node 'TRIP11', graph '%3' size too small for label\n",
      "Warning: node 'THRA', graph '%3' size too small for label\n",
      "Warning: node 'PHLPP1', graph '%3' size too small for label\n",
      "Warning: node 'PRKCA', graph '%3' size too small for label\n",
      "Warning: node 'MYOCD', graph '%3' size too small for label\n",
      "Warning: node 'MAP2K1', graph '%3' size too small for label\n",
      "Warning: node 'RORA', graph '%3' size too small for label\n",
      "Warning: node 'SMAD2', graph '%3' size too small for label\n",
      "Warning: node 'MEF2A', graph '%3' size too small for label\n",
      "Warning: node 'PPP2CA', graph '%3' size too small for label\n",
      "Warning: node 'TRAF2', graph '%3' size too small for label\n",
      "Warning: node 'SMURF1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD6', graph '%3' size too small for label\n",
      "Warning: node 'PRKCQ', graph '%3' size too small for label\n",
      "Warning: node 'MAPK3', graph '%3' size too small for label\n",
      "Warning: node 'MAPK14', graph '%3' size too small for label\n",
      "Warning: node 'SMAD3', graph '%3' size too small for label\n",
      "Warning: node 'SMAD4', graph '%3' size too small for label\n",
      "Warning: node 'NCOA1', graph '%3' size too small for label\n",
      "Warning: node 'ASXL1', graph '%3' size too small for label\n",
      "Warning: node 'MSX2', graph '%3' size too small for label\n",
      "Warning: node 'NFE2L2', graph '%3' size too small for label\n",
      "Warning: node 'TICAM1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD7', graph '%3' size too small for label\n",
      "Warning: node 'STAT1', graph '%3' size too small for label\n",
      "Warning: node 'NKX2-1', graph '%3' size too small for label\n",
      "Warning: node 'GSK3B', graph '%3' size too small for label\n",
      "Warning: node 'FOSL1', graph '%3' size too small for label\n",
      "Warning: node 'PITX1', graph '%3' size too small for label\n",
      "Warning: node 'CDON', graph '%3' size too small for label\n",
      "Warning: node 'CHEK2', graph '%3' size too small for label\n",
      "Warning: node 'CTNNB1', graph '%3' size too small for label\n",
      "Warning: node 'LATS2', graph '%3' size too small for label\n",
      "Warning: node 'HMGA2', graph '%3' size too small for label\n",
      "Warning: node 'STAT5A', graph '%3' size too small for label\n",
      "Warning: node 'MECP2', graph '%3' size too small for label\n",
      "Warning: node 'NFKB1', graph '%3' size too small for label\n",
      "Warning: node 'MAFA', graph '%3' size too small for label\n",
      "Warning: node 'STAT6', graph '%3' size too small for label\n",
      "Warning: node 'HIF3A', graph '%3' size too small for label\n",
      "Warning: node 'MAP3K7', graph '%3' size too small for label\n",
      "Warning: node 'NFKBIB', graph '%3' size too small for label\n",
      "Warning: node 'CEBPB', graph '%3' size too small for label\n",
      "Warning: node 'CUL1_RBX1_SKP1', graph '%3' size too small for label\n",
      "Warning: node 'MEIS2', graph '%3' size too small for label\n",
      "Warning: node 'INHBA', graph '%3' size too small for label\n",
      "Warning: node 'ACVR2B', graph '%3' size too small for label\n",
      "Warning: node 'GATA2', graph '%3' size too small for label\n",
      "Warning: node 'HMGA1', graph '%3' size too small for label\n",
      "Warning: node 'ERBB2', graph '%3' size too small for label\n",
      "Warning: node 'POU3F1', graph '%3' size too small for label\n",
      "Warning: node 'SMAD5', graph '%3' size too small for label\n",
      "Warning: node 'RARB', graph '%3' size too small for label\n",
      "Warning: node 'RXRB', graph '%3' size too small for label\n",
      "Warning: node 'WWTR1', graph '%3' size too small for label\n",
      "Warning: node 'CEBPA', graph '%3' size too small for label\n",
      "Warning: node 'NR1H4', graph '%3' size too small for label\n"
     ]
    },
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       "<!-- ABL1&#45;&gt;HIPK2 -->\n",
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       "<title>ABL1&#45;&gt;HIPK2</title>\n",
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       "<title>ABL1&#45;&gt;PRKN</title>\n",
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       "<!-- CDK1 -->\n",
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       "<title>MAP2K1</title>\n",
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       "<!-- HMGA2 -->\n",
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       "<!-- MAPK3 -->\n",
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       "<title>MAPK3</title>\n",
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       "<title>MAP2K1&#45;&gt;MAPK3</title>\n",
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       "<title>SMAD2</title>\n",
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       "<!-- MEF2A -->\n",
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       "<title>MEF2A</title>\n",
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       "<!-- SMAD2&#45;&gt;MEF2A -->\n",
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       "<title>SMAD2&#45;&gt;MEF2A</title>\n",
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       "<title>TBK1</title>\n",
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       "<!-- REL -->\n",
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       "<title>REL</title>\n",
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       "<!-- TBK1&#45;&gt;REL -->\n",
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       "<title>TBK1&#45;&gt;REL</title>\n",
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       "<title>PPP2CA&#45;&gt;ATM</title>\n",
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       "<!-- PPP2CA&#45;&gt;RB1 -->\n",
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       "<title>PPP2CA&#45;&gt;RB1</title>\n",
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       "<!-- PPP2CA&#45;&gt;TRAF2 -->\n",
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       "<title>PPP2CA&#45;&gt;TRAF2</title>\n",
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       "<!-- RELA -->\n",
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       "<!-- PPP2CA&#45;&gt;RELA -->\n",
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       "<title>PPP2CA&#45;&gt;RELA</title>\n",
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       "<!-- IRF3 -->\n",
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       "<!-- TICAM1 -->\n",
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       "<title>TRAF2&#45;&gt;TICAM1</title>\n",
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       "<!-- SMURF1&#45;&gt;SMAD6 -->\n",
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       "<title>SMURF1&#45;&gt;SMAD5</title>\n",
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       "<!-- LCK -->\n",
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       "<!-- LCK&#45;&gt;PRKCQ -->\n",
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       "<title>LCK&#45;&gt;PRKCQ</title>\n",
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       "<title>PRKCQ&#45;&gt;FOSL1</title>\n",
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       "<title>MAPK14&#45;&gt;DLX5</title>\n",
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       "<title>GSK3B</title>\n",
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       "<text text-anchor=\"middle\" x=\"989\" y=\"-876.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">GSK3B</text>\n",
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       "<!-- MAPK14&#45;&gt;GSK3B -->\n",
       "<g id=\"edge36\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;GSK3B</title>\n",
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       "<!-- SP7 -->\n",
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       "<title>SP7</title>\n",
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       "<text text-anchor=\"middle\" x=\"1043\" y=\"-876.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">SP7</text>\n",
       "</g>\n",
       "<!-- MAPK14&#45;&gt;SP7 -->\n",
       "<g id=\"edge40\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;SP7</title>\n",
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       "<!-- GATA2 -->\n",
       "<g id=\"node81\" class=\"node\">\n",
       "<title>GATA2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1097\" cy=\"-882\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1097\" y=\"-876.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">GATA2</text>\n",
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       "<!-- MAPK14&#45;&gt;GATA2 -->\n",
       "<g id=\"edge72\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;GATA2</title>\n",
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       "<!-- CDX2 -->\n",
       "<g id=\"node88\" class=\"node\">\n",
       "<title>CDX2</title>\n",
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       "<!-- MAPK14&#45;&gt;CDX2 -->\n",
       "<g id=\"edge80\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;CDX2</title>\n",
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       "<!-- HBP1 -->\n",
       "<g id=\"node90\" class=\"node\">\n",
       "<title>HBP1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1205\" cy=\"-882\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1205\" y=\"-876.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">HBP1</text>\n",
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       "<!-- MAPK14&#45;&gt;HBP1 -->\n",
       "<g id=\"edge83\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;HBP1</title>\n",
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       "<!-- LATS2 -->\n",
       "<g id=\"node60\" class=\"node\">\n",
       "<title>LATS2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"868\" cy=\"-666\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"868\" y=\"-660.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">LATS2</text>\n",
       "</g>\n",
       "<!-- STK4&#45;&gt;LATS2 -->\n",
       "<g id=\"edge43\" class=\"edge\">\n",
       "<title>STK4&#45;&gt;LATS2</title>\n",
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       "<!-- EGR1 -->\n",
       "<g id=\"node37\" class=\"node\">\n",
       "<title>EGR1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"423\" cy=\"-378\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"423\" y=\"-372.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">EGR1</text>\n",
       "</g>\n",
       "<!-- RELA&#45;&gt;EGR1 -->\n",
       "<g id=\"edge23\" class=\"edge\">\n",
       "<title>RELA&#45;&gt;EGR1</title>\n",
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       "<!-- PITX1 -->\n",
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       "<title>PITX1</title>\n",
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       "<!-- EGR1&#45;&gt;PITX1 -->\n",
       "<g id=\"edge37\" class=\"edge\">\n",
       "<title>EGR1&#45;&gt;PITX1</title>\n",
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       "<!-- VHL -->\n",
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       "<title>VHL</title>\n",
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       "<text text-anchor=\"middle\" x=\"261\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">VHL</text>\n",
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       "<!-- VHL&#45;&gt;TP53 -->\n",
       "<g id=\"edge24\" class=\"edge\">\n",
       "<title>VHL&#45;&gt;TP53</title>\n",
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       "<!-- SMAD4 -->\n",
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       "<title>SMAD4</title>\n",
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       "<text text-anchor=\"middle\" x=\"1313\" y=\"-876.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">SMAD4</text>\n",
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       "<!-- SMAD3&#45;&gt;SMAD4 -->\n",
       "<g id=\"edge25\" class=\"edge\">\n",
       "<title>SMAD3&#45;&gt;SMAD4</title>\n",
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       "<!-- NKX2&#45;1 -->\n",
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       "<title>NKX2&#45;1</title>\n",
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       "<text text-anchor=\"middle\" x=\"1367\" y=\"-876.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">NKX2&#45;1</text>\n",
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       "<!-- SMAD3&#45;&gt;NKX2&#45;1 -->\n",
       "<g id=\"edge33\" class=\"edge\">\n",
       "<title>SMAD3&#45;&gt;NKX2&#45;1</title>\n",
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       "<!-- ASXL1 -->\n",
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       "<title>ASXL1</title>\n",
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       "<!-- NCOA1&#45;&gt;ASXL1 -->\n",
       "<g id=\"edge26\" class=\"edge\">\n",
       "<title>NCOA1&#45;&gt;ASXL1</title>\n",
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       "<!-- DLX5&#45;&gt;MSX2 -->\n",
       "<g id=\"edge27\" class=\"edge\">\n",
       "<title>DLX5&#45;&gt;MSX2</title>\n",
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       "<!-- TICAM1&#45;&gt;TBK1 -->\n",
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       "<title>TICAM1&#45;&gt;TBK1</title>\n",
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       "<!-- STAT1 -->\n",
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       "<title>STAT1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"760\" cy=\"-450\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"760\" y=\"-444.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">STAT1</text>\n",
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       "<!-- IRF2 -->\n",
       "<g id=\"node49\" class=\"node\">\n",
       "<title>IRF2</title>\n",
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       "<!-- STAT1&#45;&gt;IRF2 -->\n",
       "<g id=\"edge32\" class=\"edge\">\n",
       "<title>STAT1&#45;&gt;IRF2</title>\n",
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       "<!-- GSK3B&#45;&gt;PHLPP1 -->\n",
       "<g id=\"edge49\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;PHLPP1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M973.81,-870.9C970.01,-868.53 965.91,-866.09 962,-864 927.24,-845.46 915.76,-846.54 881,-828 878.43,-826.63 875.79,-825.11 873.2,-823.55\"/>\n",
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       "<!-- GSK3B&#45;&gt;MYOCD -->\n",
       "<g id=\"edge42\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;MYOCD</title>\n",
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       "<!-- SFPQ -->\n",
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       "<title>SFPQ</title>\n",
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       "<!-- GSK3B&#45;&gt;SFPQ -->\n",
       "<g id=\"edge34\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;SFPQ</title>\n",
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       "<!-- NFKB1 -->\n",
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       "<title>NFKB1</title>\n",
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       "<!-- GSK3B&#45;&gt;NFKB1 -->\n",
       "<g id=\"edge50\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;NFKB1</title>\n",
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       "<!-- GSK3B&#45;&gt;CIITA -->\n",
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       "<title>GSK3B&#45;&gt;CIITA</title>\n",
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       "<title>GSK3B&#45;&gt;CEBPA</title>\n",
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       "<title>CDON&#45;&gt;MAPK14</title>\n",
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       "<title>CTNNB1</title>\n",
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       "<text text-anchor=\"middle\" x=\"1421\" y=\"-1020.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CTNNB1</text>\n",
       "</g>\n",
       "<!-- CDH6&#45;&gt;CTNNB1 -->\n",
       "<g id=\"edge41\" class=\"edge\">\n",
       "<title>CDH6&#45;&gt;CTNNB1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1421,-1079.34C1421,-1072.34 1421,-1064.12 1421,-1056.28\"/>\n",
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       "<!-- KLF4 -->\n",
       "<g id=\"node77\" class=\"node\">\n",
       "<title>KLF4</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1421\" cy=\"-954\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1421\" y=\"-948.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">KLF4</text>\n",
       "</g>\n",
       "<!-- CTNNB1&#45;&gt;KLF4 -->\n",
       "<g id=\"edge70\" class=\"edge\">\n",
       "<title>CTNNB1&#45;&gt;KLF4</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1421,-1007.34C1421,-1000.34 1421,-992.12 1421,-984.28\"/>\n",
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       "</g>\n",
       "<!-- WWTR1 -->\n",
       "<g id=\"node94\" class=\"node\">\n",
       "<title>WWTR1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"868\" cy=\"-594\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"868\" y=\"-588.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">WWTR1</text>\n",
       "</g>\n",
       "<!-- LATS2&#45;&gt;WWTR1 -->\n",
       "<g id=\"edge89\" class=\"edge\">\n",
       "<title>LATS2&#45;&gt;WWTR1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M868,-647.34C868,-638.37 868,-627.37 868,-617.77\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"863,-613.9 873,-613.9 873,-615.9 863,-615.9 863,-613.9\"/>\n",
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       "</g>\n",
       "<!-- STAT6 -->\n",
       "<g id=\"node66\" class=\"node\">\n",
       "<title>STAT6</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"760\" cy=\"-522\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"760\" y=\"-516.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">STAT6</text>\n",
       "</g>\n",
       "<!-- STAT6&#45;&gt;STAT1 -->\n",
       "<g id=\"edge52\" class=\"edge\">\n",
       "<title>STAT6&#45;&gt;STAT1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M760,-503.34C760,-494.37 760,-483.37 760,-473.77\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"755,-469.9 765,-469.9 765,-471.9 755,-471.9 755,-469.9\"/>\n",
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       "</g>\n",
       "<!-- JAK2 -->\n",
       "<g id=\"node68\" class=\"node\">\n",
       "<title>JAK2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"760\" cy=\"-594\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"760\" y=\"-588.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">JAK2</text>\n",
       "</g>\n",
       "<!-- KIT&#45;&gt;JAK2 -->\n",
       "<g id=\"edge53\" class=\"edge\">\n",
       "<title>KIT&#45;&gt;JAK2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M760,-647.34C760,-640.34 760,-632.12 760,-624.28\"/>\n",
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       "</g>\n",
       "<!-- JAK2&#45;&gt;STAT6 -->\n",
       "<g id=\"edge69\" class=\"edge\">\n",
       "<title>JAK2&#45;&gt;STAT6</title>\n",
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       "</g>\n",
       "<!-- HIF3A -->\n",
       "<g id=\"node71\" class=\"node\">\n",
       "<title>HIF3A</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"153\" cy=\"-234\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"153\" y=\"-228.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">HIF3A</text>\n",
       "</g>\n",
       "<!-- PRKN&#45;&gt;HIF3A -->\n",
       "<g id=\"edge56\" class=\"edge\">\n",
       "<title>PRKN&#45;&gt;HIF3A</title>\n",
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       "</g>\n",
       "<!-- NFKBIB -->\n",
       "<g id=\"node73\" class=\"node\">\n",
       "<title>NFKBIB</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"18\" cy=\"-18\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"18\" y=\"-12.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">NFKBIB</text>\n",
       "</g>\n",
       "<!-- MAP3K7&#45;&gt;NFKBIB -->\n",
       "<g id=\"edge57\" class=\"edge\">\n",
       "<title>MAP3K7&#45;&gt;NFKBIB</title>\n",
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       "</g>\n",
       "<!-- CUL1_RBX1_SKP1&#45;&gt;SMURF1 -->\n",
       "<g id=\"edge68\" class=\"edge\">\n",
       "<title>CUL1_RBX1_SKP1&#45;&gt;SMURF1</title>\n",
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       "</g>\n",
       "<!-- MEIS2 -->\n",
       "<g id=\"node78\" class=\"node\">\n",
       "<title>MEIS2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1421\" cy=\"-882\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1421\" y=\"-876.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">MEIS2</text>\n",
       "</g>\n",
       "<!-- KLF4&#45;&gt;MEIS2 -->\n",
       "<g id=\"edge63\" class=\"edge\">\n",
       "<title>KLF4&#45;&gt;MEIS2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1421,-935.34C1421,-928.34 1421,-920.12 1421,-912.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"1424.5,-912.42 1421,-902.42 1417.5,-912.42 1424.5,-912.42\"/>\n",
       "</g>\n",
       "<!-- INHBA -->\n",
       "<g id=\"node79\" class=\"node\">\n",
       "<title>INHBA</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1286\" cy=\"-1098\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1286\" y=\"-1092.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">INHBA</text>\n",
       "</g>\n",
       "<!-- ACVR2B -->\n",
       "<g id=\"node80\" class=\"node\">\n",
       "<title>ACVR2B</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1286\" cy=\"-1026\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1286\" y=\"-1020.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">ACVR2B</text>\n",
       "</g>\n",
       "<!-- INHBA&#45;&gt;ACVR2B -->\n",
       "<g id=\"edge64\" class=\"edge\">\n",
       "<title>INHBA&#45;&gt;ACVR2B</title>\n",
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       "<!-- ACVR2B&#45;&gt;SMAD2 -->\n",
       "<g id=\"edge65\" class=\"edge\">\n",
       "<title>ACVR2B&#45;&gt;SMAD2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1279.6,-1008.41C1276.58,-1000.57 1272.88,-990.99 1269.47,-982.13\"/>\n",
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       "<!-- ACVR2B&#45;&gt;SMAD3 -->\n",
       "<g id=\"edge90\" class=\"edge\">\n",
       "<title>ACVR2B&#45;&gt;SMAD3</title>\n",
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       "<!-- SPI1 -->\n",
       "<g id=\"node82\" class=\"node\">\n",
       "<title>SPI1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"1178\" cy=\"-810\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1178\" y=\"-804.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">SPI1</text>\n",
       "</g>\n",
       "<!-- GATA2&#45;&gt;SPI1 -->\n",
       "<g id=\"edge66\" class=\"edge\">\n",
       "<title>GATA2&#45;&gt;SPI1</title>\n",
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       "<!-- TAL1 -->\n",
       "<g id=\"node93\" class=\"node\">\n",
       "<title>TAL1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1178\" cy=\"-738\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1178\" y=\"-732.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">TAL1</text>\n",
       "</g>\n",
       "<!-- SPI1&#45;&gt;TAL1 -->\n",
       "<g id=\"edge87\" class=\"edge\">\n",
       "<title>SPI1&#45;&gt;TAL1</title>\n",
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       "</g>\n",
       "<!-- POU3F1 -->\n",
       "<g id=\"node87\" class=\"node\">\n",
       "<title>POU3F1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"706\" cy=\"-810\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"706\" y=\"-804.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">POU3F1</text>\n",
       "</g>\n",
       "<!-- HMGA1&#45;&gt;POU3F1 -->\n",
       "<g id=\"edge75\" class=\"edge\">\n",
       "<title>HMGA1&#45;&gt;POU3F1</title>\n",
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       "<!-- CDH2 -->\n",
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       "<title>CDH2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1043\" cy=\"-1098\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1043\" y=\"-1092.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CDH2</text>\n",
       "</g>\n",
       "<!-- CDH2&#45;&gt;CDON -->\n",
       "<g id=\"edge73\" class=\"edge\">\n",
       "<title>CDH2&#45;&gt;CDON</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1043,-1079.34C1043,-1072.34 1043,-1064.12 1043,-1056.28\"/>\n",
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       "<g id=\"node85\" class=\"node\">\n",
       "<title>EGF</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"652\" cy=\"-1098\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"652\" y=\"-1092.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">EGF</text>\n",
       "</g>\n",
       "<!-- ERBB2 -->\n",
       "<g id=\"node86\" class=\"node\">\n",
       "<title>ERBB2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"652\" cy=\"-1026\" rx=\"18\" ry=\"18\"/>\n",
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       "</g>\n",
       "<!-- EGF&#45;&gt;ERBB2 -->\n",
       "<g id=\"edge74\" class=\"edge\">\n",
       "<title>EGF&#45;&gt;ERBB2</title>\n",
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       "<!-- ERBB2&#45;&gt;CDK1 -->\n",
       "<g id=\"edge79\" class=\"edge\">\n",
       "<title>ERBB2&#45;&gt;CDK1</title>\n",
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       "</g>\n",
       "<!-- RXRB -->\n",
       "<g id=\"node92\" class=\"node\">\n",
       "<title>RXRB</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"315\" cy=\"-162\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"315\" y=\"-156.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">RXRB</text>\n",
       "</g>\n",
       "<!-- RARB&#45;&gt;RXRB -->\n",
       "<g id=\"edge86\" class=\"edge\">\n",
       "<title>RARB&#45;&gt;RXRB</title>\n",
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       "</g>\n",
       "</g>\n",
       "</svg>\n"
      ],
      "text/plain": [
       "<graphviz.graphs.Digraph at 0x1dd19619050>"
      ]
     },
     "execution_count": 113,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "G_sol = Gp.edge_subgraph(np.flatnonzero(P.expr.edge_values.value))\n",
    "values = P.expr.vertex_values.value\n",
    "vertex_values = {v: values[i] for i, v in enumerate(Gp.V)}\n",
    "vertex_sol_values = [vertex_values[v] for v in G_sol.V]\n",
    "G_sol.plot(\n",
    "    custom_vertex_attr=cn.pl.create_graphviz_vertex_attributes(\n",
    "        G_sol.V, vertex_sol_values\n",
    "    )\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 114,
   "id": "50f2269f-5cc0-4572-be18-46887726d191",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "10.373496770858765\n",
      "48.0\n",
      "44.0\n"
     ]
    }
   ],
   "source": [
    "# 48 inhibitory interactions and 44 activations\n",
    "for o in P.objectives:\n",
    "    print(o.value)"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "3249fa12-4cda-4b79-9964-21137acb480e",
   "metadata": {},
   "source": [
    "We have explored different approaches and assumptions to recover a signalling network from TF activities and a list of potential receptors. Although changes in gene expression for signalling proteins are not always predictive of signalling cascades—hence the use of CARNIVAL as a footprint-based method to bridge the gaps between receptors and TFs—we can introduce a slight bias in the network towards signalling proteins whose gene expression has changed significantly after treatment. These changes, while indirect, may still provide valuable cues. In a manner similar to how we penalised low-abundance genes, we will now prioritize the inclusion of upregulated genes."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 139,
   "id": "aca3c182-9eba-4e7b-bb69-e9b55cd332c3",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "Index(['ABL1', 'AHR', 'AIRE', 'AP1', 'APEX1', 'AR', 'ARID1A', 'ARID3A',\n",
       "       'ARID3B', 'ARID4A',\n",
       "       ...\n",
       "       'ZNF362', 'ZNF382', 'ZNF384', 'ZNF395', 'ZNF436', 'ZNF699', 'ZNF76',\n",
       "       'ZNF804A', 'ZNF91', 'ZXDC'],\n",
       "      dtype='object', length=655)"
      ]
     },
     "execution_count": 139,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "tf_acts.columns"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 140,
   "id": "4ec4d220-c63d-466a-a524-967b09fc19f5",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "NUAK1      -40.581591\n",
       "CDH6       -39.007075\n",
       "FZD8       -37.421427\n",
       "CDH2       -34.291273\n",
       "STK38L     -30.552887\n",
       "              ...    \n",
       "IL6R        21.833188\n",
       "MAP3K5      21.883284\n",
       "CASP1       23.060970\n",
       "IL1R1       24.058471\n",
       "TNFRSF1B    25.812839\n",
       "Name: stat, Length: 627, dtype: float64"
      ]
     },
     "execution_count": 140,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# Since the problem minimises error, we change sign. Upregulated genes get negative score\n",
    "# so if they are selected, the error decreases. The opposite for downregulated genes\n",
    "df_gene_scores = -results_df.loc[\n",
    "    results_df.index.intersection(Gp.V).difference(tf_acts.columns)\n",
    "].stat\n",
    "dict_scores = df_gene_scores.to_dict()\n",
    "\n",
    "df_gene_scores.sort_values()"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 141,
   "id": "796cf5b1-25d4-4807-9679-e9bf04a4b475",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "3045.9775260752576"
      ]
     },
     "execution_count": 141,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "# Now we will add a penalty to avoid selecting lowly expressed genes\n",
    "vertices = Gp.V\n",
    "scores = np.array([dict_scores.get(v, 0) for v in vertices])\n",
    "np.sum(np.abs(scores))"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 142,
   "id": "90eb8df5-a39d-4ebc-a508-6e75d90617bb",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "C:\\Users\\pablo\\miniconda3\\envs\\corneto-dev-mini\\Lib\\site-packages\\cvxpy\\problems\\problem.py:158: UserWarning: Objective contains too many subexpressions. Consider vectorizing your CVXPY code to speed up compilation.\n",
      "  warnings.warn(\"Objective contains too many subexpressions. \"\n"
     ]
    }
   ],
   "source": [
    "# Create the carnival problem\n",
    "P = milp_carnival(Gp, inputs_p, measurements_p, beta_weight=0.2)\n",
    "vertex_selected = P.expr.vertex_activated + P.expr.vertex_inhibited\n",
    "total_score = vertex_selected @ scores\n",
    "P.add_objectives(total_score, weights=1e-3)\n",
    "P.solve(solver=\"GUROBI\", Seed=seed, TimeLimit=max_time);"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 143,
   "id": "bd7dcb88-bc2b-4131-b102-25dfd7d31921",
   "metadata": {},
   "outputs": [
    {
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       "<title>ABL1&#45;&gt;JAK2</title>\n",
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       "<!-- HIPK2&#45;&gt;MECP2 -->\n",
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       "<title>HIPK2&#45;&gt;MECP2</title>\n",
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       "<title>MAPK1</title>\n",
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       "<!-- JUN -->\n",
       "<g id=\"node8\" class=\"node\">\n",
       "<title>JUN</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"524\" cy=\"-378\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"524\" y=\"-372.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">JUN</text>\n",
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       "<!-- MAPK1&#45;&gt;JUN -->\n",
       "<g id=\"edge4\" class=\"edge\">\n",
       "<title>MAPK1&#45;&gt;JUN</title>\n",
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       "<text text-anchor=\"middle\" x=\"578\" y=\"-372.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">RORA</text>\n",
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       "<!-- MAPK1&#45;&gt;RORA -->\n",
       "<g id=\"edge12\" class=\"edge\">\n",
       "<title>MAPK1&#45;&gt;RORA</title>\n",
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       "<!-- STAT5A -->\n",
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       "<title>STAT5A</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"632\" cy=\"-378\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"632\" y=\"-372.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">STAT5A</text>\n",
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       "<!-- MAPK1&#45;&gt;STAT5A -->\n",
       "<g id=\"edge46\" class=\"edge\">\n",
       "<title>MAPK1&#45;&gt;STAT5A</title>\n",
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       "<title>MAFA</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"686\" cy=\"-378\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"686\" y=\"-372.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">MAFA</text>\n",
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       "<!-- MAPK1&#45;&gt;MAFA -->\n",
       "<g id=\"edge51\" class=\"edge\">\n",
       "<title>MAPK1&#45;&gt;MAFA</title>\n",
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       "<!-- SPI1 -->\n",
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       "<title>JUN&#45;&gt;SPI1</title>\n",
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       "<!-- NFKB2 -->\n",
       "<g id=\"node9\" class=\"node\">\n",
       "<title>NFKB2</title>\n",
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       "<text text-anchor=\"middle\" x=\"821\" y=\"-156.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">NFKB2</text>\n",
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       "<!-- RELB -->\n",
       "<g id=\"node10\" class=\"node\">\n",
       "<title>RELB</title>\n",
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       "<!-- NFKB2&#45;&gt;RELB -->\n",
       "<g id=\"edge5\" class=\"edge\">\n",
       "<title>NFKB2&#45;&gt;RELB</title>\n",
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       "<title>TRIP11</title>\n",
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       "<!-- THRA -->\n",
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       "<!-- TRIP11&#45;&gt;THRA -->\n",
       "<g id=\"edge6\" class=\"edge\">\n",
       "<title>TRIP11&#45;&gt;THRA</title>\n",
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       "<!-- THRA&#45;&gt;RARG -->\n",
       "<g id=\"edge84\" class=\"edge\">\n",
       "<title>THRA&#45;&gt;RARG</title>\n",
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       "<!-- PHLPP1 -->\n",
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       "<title>PHLPP1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1118\" cy=\"-378\" rx=\"18\" ry=\"18\"/>\n",
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       "<!-- PRKCA -->\n",
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       "<title>PRKCA</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"1064\" cy=\"-306\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1064\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">PRKCA</text>\n",
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       "<!-- PHLPP1&#45;&gt;PRKCA -->\n",
       "<g id=\"edge7\" class=\"edge\">\n",
       "<title>PHLPP1&#45;&gt;PRKCA</title>\n",
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       "<!-- STK4 -->\n",
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       "<title>STK4</title>\n",
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       "<text text-anchor=\"middle\" x=\"1118\" y=\"-300.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">STK4</text>\n",
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       "<!-- PHLPP1&#45;&gt;STK4 -->\n",
       "<g id=\"edge20\" class=\"edge\">\n",
       "<title>PHLPP1&#45;&gt;STK4</title>\n",
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       "<!-- PRKCA&#45;&gt;NFE2L2 -->\n",
       "<g id=\"edge28\" class=\"edge\">\n",
       "<title>PRKCA&#45;&gt;NFE2L2</title>\n",
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       "<!-- NR1H4 -->\n",
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       "<!-- PRKCA&#45;&gt;NR1H4 -->\n",
       "<g id=\"edge88\" class=\"edge\">\n",
       "<title>PRKCA&#45;&gt;NR1H4</title>\n",
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       "<!-- MYOCD -->\n",
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       "<!-- MYOCD&#45;&gt;SRF -->\n",
       "<g id=\"edge8\" class=\"edge\">\n",
       "<title>MYOCD&#45;&gt;SRF</title>\n",
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       "<title>TP53&#45;&gt;NFKB2</title>\n",
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       "<title>TBK1&#45;&gt;REL</title>\n",
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       "<title>TBK1&#45;&gt;IRF3</title>\n",
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       "<!-- USF1 -->\n",
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       "<!-- FOSL1 -->\n",
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       "<!-- MAPK14 -->\n",
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       "<title>MAPK14</title>\n",
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       "<!-- MEF2A -->\n",
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       "<!-- MAPK14&#45;&gt;MEF2A -->\n",
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       "<!-- JUNB -->\n",
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       "<!-- MAPK14&#45;&gt;JUNB -->\n",
       "<g id=\"edge19\" class=\"edge\">\n",
       "<title>MAPK14&#45;&gt;JUNB</title>\n",
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       "<!-- MAPK14&#45;&gt;SMAD3 -->\n",
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       "<title>MAPK14&#45;&gt;SMAD3</title>\n",
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       "<title>MAPK14&#45;&gt;GSK3B</title>\n",
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       "<!-- DLX5 -->\n",
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       "<title>MAPK14&#45;&gt;DLX5</title>\n",
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       "<!-- SP7 -->\n",
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       "<title>MAPK14&#45;&gt;SP7</title>\n",
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       "<title>MAPK14&#45;&gt;CDX2</title>\n",
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       "<title>MAPK14&#45;&gt;HBP1</title>\n",
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       "<!-- MUC1 -->\n",
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       "<!-- SFPQ -->\n",
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       "<!-- GSK3B&#45;&gt;SFPQ -->\n",
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       "<!-- NFKB1 -->\n",
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       "<!-- GSK3B&#45;&gt;NFKB1 -->\n",
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       "<title>GSK3B&#45;&gt;NFKB1</title>\n",
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       "<!-- CIITA -->\n",
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       "<title>CIITA</title>\n",
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       "<!-- GSK3B&#45;&gt;CIITA -->\n",
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       "<title>GSK3B&#45;&gt;CIITA</title>\n",
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       "<!-- CEBPA -->\n",
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       "<title>CEBPA</title>\n",
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       "<!-- GSK3B&#45;&gt;CEBPA -->\n",
       "<g id=\"edge87\" class=\"edge\">\n",
       "<title>GSK3B&#45;&gt;CEBPA</title>\n",
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       "<!-- MUC1&#45;&gt;KLF4 -->\n",
       "<g id=\"edge62\" class=\"edge\">\n",
       "<title>MUC1&#45;&gt;KLF4</title>\n",
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       "<!-- NCOA1&#45;&gt;ASXL1 -->\n",
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       "<title>NCOA1&#45;&gt;ASXL1</title>\n",
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       "<!-- DLX5&#45;&gt;MSX2 -->\n",
       "<g id=\"edge26\" class=\"edge\">\n",
       "<title>DLX5&#45;&gt;MSX2</title>\n",
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       "<!-- EP300&#45;&gt;RELA -->\n",
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       "<title>EP300&#45;&gt;RELA</title>\n",
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       "<!-- EP300&#45;&gt;SMAD7 -->\n",
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       "<title>EP300&#45;&gt;SMAD7</title>\n",
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       "<!-- TICAM1&#45;&gt;TBK1 -->\n",
       "<g id=\"edge30\" class=\"edge\">\n",
       "<title>TICAM1&#45;&gt;TBK1</title>\n",
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       "<!-- SPI1&#45;&gt;TAL1 -->\n",
       "<g id=\"edge85\" class=\"edge\">\n",
       "<title>SPI1&#45;&gt;TAL1</title>\n",
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       "<!-- STAT1 -->\n",
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       "<!-- STAT1&#45;&gt;IRF2 -->\n",
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       "<title>STAT1&#45;&gt;IRF2</title>\n",
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       "<title>TGFB1</title>\n",
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       "<!-- PPP2R2A -->\n",
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       "<!-- TGFB1&#45;&gt;PPP2R2A -->\n",
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       "<title>TGFB1&#45;&gt;PPP2R2A</title>\n",
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       "<!-- PPP2R2A&#45;&gt;PPP2CA -->\n",
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       "<title>CDON</title>\n",
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       "<title>CDON&#45;&gt;MAPK14</title>\n",
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       "<!-- CHEK2&#45;&gt;VHL -->\n",
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       "<title>CHEK2&#45;&gt;VHL</title>\n",
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       "<title>PRKN&#45;&gt;HIF3A</title>\n",
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       "<title>JAK2&#45;&gt;STAT1</title>\n",
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       "<title>INHBA&#45;&gt;ACVR2B</title>\n",
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       "<polygon fill=\"black\" stroke=\"black\" points=\"1310.5,-624.42 1307,-614.42 1303.5,-624.42 1310.5,-624.42\"/>\n",
       "</g>\n",
       "<!-- SMAD2 -->\n",
       "<g id=\"node78\" class=\"node\">\n",
       "<title>SMAD2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1307\" cy=\"-522\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1307\" y=\"-516.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">SMAD2</text>\n",
       "</g>\n",
       "<!-- ACVR2B&#45;&gt;SMAD2 -->\n",
       "<g id=\"edge65\" class=\"edge\">\n",
       "<title>ACVR2B&#45;&gt;SMAD2</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1307,-575.34C1307,-568.34 1307,-560.12 1307,-552.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"1310.5,-552.42 1307,-542.42 1303.5,-552.42 1310.5,-552.42\"/>\n",
       "</g>\n",
       "<!-- RXRB -->\n",
       "<g id=\"node80\" class=\"node\">\n",
       "<title>RXRB</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"153\" cy=\"-18\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"153\" y=\"-12.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">RXRB</text>\n",
       "</g>\n",
       "<!-- RARG&#45;&gt;RXRB -->\n",
       "<g id=\"edge66\" class=\"edge\">\n",
       "<title>RARG&#45;&gt;RXRB</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M153,-71.34C153,-64.34 153,-56.12 153,-48.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"156.5,-48.42 153,-38.42 149.5,-48.42 156.5,-48.42\"/>\n",
       "</g>\n",
       "<!-- CEBPA&#45;&gt;USF1 -->\n",
       "<g id=\"edge67\" class=\"edge\">\n",
       "<title>CEBPA&#45;&gt;USF1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1442,-359.34C1442,-352.34 1442,-344.12 1442,-336.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"1445.5,-336.42 1442,-326.42 1438.5,-336.42 1445.5,-336.42\"/>\n",
       "</g>\n",
       "<!-- POU3F1 -->\n",
       "<g id=\"node85\" class=\"node\">\n",
       "<title>POU3F1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"983\" cy=\"-162\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"983\" y=\"-156.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">POU3F1</text>\n",
       "</g>\n",
       "<!-- HMGA1&#45;&gt;POU3F1 -->\n",
       "<g id=\"edge73\" class=\"edge\">\n",
       "<title>HMGA1&#45;&gt;POU3F1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M983,-215.34C983,-208.34 983,-200.12 983,-192.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"986.5,-192.42 983,-182.42 979.5,-192.42 986.5,-192.42\"/>\n",
       "</g>\n",
       "<!-- CDH2 -->\n",
       "<g id=\"node83\" class=\"node\">\n",
       "<title>CDH2</title>\n",
       "<ellipse fill=\"none\" stroke=\"#8b1a1a\" stroke-width=\"2\" cx=\"1253\" cy=\"-666\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1253\" y=\"-660.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">CDH2</text>\n",
       "</g>\n",
       "<!-- CDH2&#45;&gt;CDON -->\n",
       "<g id=\"edge71\" class=\"edge\">\n",
       "<title>CDH2&#45;&gt;CDON</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1253,-647.34C1253,-640.34 1253,-632.12 1253,-624.28\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"1256.5,-624.42 1253,-614.42 1249.5,-624.42 1256.5,-624.42\"/>\n",
       "</g>\n",
       "<!-- WWTR1 -->\n",
       "<g id=\"node86\" class=\"node\">\n",
       "<title>WWTR1</title>\n",
       "<ellipse fill=\"none\" stroke=\"#104e8b\" stroke-width=\"2\" cx=\"1145\" cy=\"-162\" rx=\"18\" ry=\"18\"/>\n",
       "<text text-anchor=\"middle\" x=\"1145\" y=\"-156.95\" font-family=\"Times New Roman,serif\" font-size=\"14.00\">WWTR1</text>\n",
       "</g>\n",
       "<!-- LATS1&#45;&gt;WWTR1 -->\n",
       "<g id=\"edge78\" class=\"edge\">\n",
       "<title>LATS1&#45;&gt;WWTR1</title>\n",
       "<path fill=\"none\" stroke=\"black\" d=\"M1145,-215.34C1145,-206.37 1145,-195.37 1145,-185.77\"/>\n",
       "<polygon fill=\"black\" stroke=\"black\" points=\"1140,-181.9 1150,-181.9 1150,-183.9 1140,-183.9 1140,-181.9\"/>\n",
       "<polyline fill=\"none\" stroke=\"black\" points=\"1145,-180.9 1145,-185.9\"/>\n",
       "</g>\n",
       "</g>\n",
       "</svg>\n"
      ],
      "text/plain": [
       "<graphviz.graphs.Digraph at 0x1dd311f4a50>"
      ]
     },
     "execution_count": 143,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "G_sol = Gp.edge_subgraph(np.flatnonzero(P.expr.edge_values.value))\n",
    "values = P.expr.vertex_values.value\n",
    "vertex_values = {v: values[i] for i, v in enumerate(Gp.V)}\n",
    "vertex_sol_values = [vertex_values[v] for v in G_sol.V]\n",
    "G_sol.plot(\n",
    "    custom_vertex_attr=cn.pl.create_graphviz_vertex_attributes(\n",
    "        G_sol.V, vertex_sol_values\n",
    "    )\n",
    ")"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 144,
   "id": "aa10a36a-de26-467a-9cdd-2b4392b504c8",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "10.373496770858765\n",
      "88.0\n",
      "-245.81810302737185\n"
     ]
    }
   ],
   "source": [
    "for o in P.objectives:\n",
    "    print(o.value)"
   ]
  }
 ],
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