A Kinetic-Model-Based Approach to Identify Malfunctioning Components in Signal Transduction Pathways from Artificial Clinical Data

<div>The patterns shown in <svg height="10.446pt" id="M105" style="vertical-align:-0.2130003pt" version="1.1" viewbox="-0.0498162 -10.233 109.158 10.446" width="109.158pt" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><g transform="matrix(.013,0,0,-0.013,0,0)"><path d="M416 501L399 642C356 655 314 665 271 665C140 665 63 582 63 486C63 372 163 325 229 290C304 250 359 217 359 142C359 70 316 25 240 25C138 25 94 125 78 186L44 178C52 123 64 45 72 21C81 16 96 8 121 0S179 -15 220 -15C353 -15 445 68 445 176C445 289 350 335 270 375C191 414 143 449 143 520C143 572 177 627 253 627C340 627 366 556 382 495L416 501Z" id="g58-81"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="484" vert-adv-y="484"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,6.175,0)"><path d="M601 496C596 555 591 627 591 675H567C551 656 544 650 516 650H120C91 650 79 651 64 675H41C38 619 34 555 29 492H63C75 537 83 566 96 582C110 604 128 612 207 612H272V126C272 46 264 38 170 33V0H464V33C368 38 359 48 359 126V612H430C502 612 520 605 535 582C547 566 556 541 567 492L601 496Z" id="g58-82"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="628" vert-adv-y="628"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,13.386,0)"><path d="M682 0V33C615 38 603 49 571 134C507 305 441 494 378 665L343 655L136 136C101 48 86 41 22 33V0H246V33C170 41 161 50 183 112C196 152 209 192 224 232H441C461 176 478 126 493 87C504 49 499 41 433 33V0H682ZM425 279H242C273 363 303 448 335 533H337L425 279Z" id="g58-63"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="703" vert-adv-y="703"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,21.651,0)"><path d="M601 496C596 555 591 627 591 675H567C551 656 544 650 516 650H120C91 650 79 651 64 675H41C38 619 34 555 29 492H63C75 537 83 566 96 582C110 604 128 612 207 612H272V126C272 46 264 38 170 33V0H464V33C368 38 359 48 359 126V612H430C502 612 520 605 535 582C547 566 556 541 567 492L601 496Z" id="g58-82"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="628" vert-adv-y="628"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,29.815,0)"><path d="M290 377C321 398 342 415 358 430C378 450 389 473 389 502C389 578 329 635 238 635H237C184 635 137 610 109 578L64 515L88 493C112 529 154 573 208 573S303 542 303 482C303 409 233 370 141 341L149 308C165 313 190 319 215 319C272 319 341 283 341 193C342 98 292 43 222 43C163 43 122 72 96 94C88 101 79 100 70 94C61 87 47 73 46 60C44 47 48 37 62 23C76 10 118 -12 165 -12C238 -12 430 62 430 223C430 297 379 359 290 375V377Z" id="g50-52"></path><glyph.data ascent="3443" descent="-2856" horiz-adv-x="487" vert-adv-y="487"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,36.146,0)"><path d="M731 650H485V618C556 614 580 601 585 558C588 530 592 485 592 390V153H589L173 650H22V618C69 614 92 606 112 582C131 558 132 555 132 483V266C132 175 129 128 125 96C120 49 95 36 36 33V0H281V33C212 36 188 50 183 98C180 129 177 175 177 266V510H179L603 -9H638V390C638 483 640 530 644 561C649 602 674 615 731 618V650Z" id="g58-76"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="754" vert-adv-y="754"></glyph.data></g><g transform="matrix(.0091,0,0,-0.0091,45.948,-5.872)"><path d="M486 158C486 177 478 202 466 220C413 228 386 236 336 262C386 288 413 297 466 304C478 323 486 347 485 366C470 376 444 381 422 380C389 338 368 319 321 288C323 345 329 372 349 422C339 442 322 461 305 470C289 461 271 442 262 422C281 372 287 345 290 288C243 319 222 338 189 380C167 381 142 376 125 366C125 347 133 322 145 304C198 296 225 288 275 262C225 236 198 227 145 220C133 201 125 177 126 158C141 148 167 143 189 144C222 186 243 205 290 236C288 179 282 152 262 102C272 82 289 63 306 54C322 63 340 82 350 102C330 152 324 179 321 236C368 205 390 186 422 144C444 143 470 148 486 158Z" id="g50-43"></path><glyph.data ascent="3443" descent="-2856" horiz-adv-x="611" vert-adv-y="611"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,52.027,0)"><path d="M300 253H71L57 198H286L300 253Z" id="g190-46"></path><glyph.data ascent="989" descent="-360" horiz-adv-x="356" vert-adv-y="356"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,56.672,0)"><path d="M416 501L399 642C356 655 314 665 271 665C140 665 63 582 63 486C63 372 163 325 229 290C304 250 359 217 359 142C359 70 316 25 240 25C138 25 94 125 78 186L44 178C52 123 64 45 72 21C81 16 96 8 121 0S179 -15 220 -15C353 -15 445 68 445 176C445 289 350 335 270 375C191 414 143 449 143 520C143 572 177 627 253 627C340 627 366 556 382 495L416 501Z" id="g58-81"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="484" vert-adv-y="484"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,62.847,0)"><path d="M601 496C596 555 591 627 591 675H567C551 656 544 650 516 650H120C91 650 79 651 64 675H41C38 619 34 555 29 492H63C75 537 83 566 96 582C110 604 128 612 207 612H272V126C272 46 264 38 170 33V0H464V33C368 38 359 48 359 126V612H430C502 612 520 605 535 582C547 566 556 541 567 492L601 496Z" id="g58-82"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="628" vert-adv-y="628"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,70.058,0)"><path d="M682 0V33C615 38 603 49 571 134C507 305 441 494 378 665L343 655L136 136C101 48 86 41 22 33V0H246V33C170 41 161 50 183 112C196 152 209 192 224 232H441C461 176 478 126 493 87C504 49 499 41 433 33V0H682ZM425 279H242C273 363 303 448 335 533H337L425 279Z" id="g58-63"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="703" vert-adv-y="703"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,78.323,0)"><path d="M601 496C596 555 591 627 591 675H567C551 656 544 650 516 650H120C91 650 79 651 64 675H41C38 619 34 555 29 492H63C75 537 83 566 96 582C110 604 128 612 207 612H272V126C272 46 264 38 170 33V0H464V33C368 38 359 48 359 126V612H430C502 612 520 605 535 582C547 566 556 541 567 492L601 496Z" id="g58-82"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="628" vert-adv-y="628"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,86.487,0)"><path d="M290 377C321 398 342 415 358 430C378 450 389 473 389 502C389 578 329 635 238 635H237C184 635 137 610 109 578L64 515L88 493C112 529 154 573 208 573S303 542 303 482C303 409 233 370 141 341L149 308C165 313 190 319 215 319C272 319 341 283 341 193C342 98 292 43 222 43C163 43 122 72 96 94C88 101 79 100 70 94C61 87 47 73 46 60C44 47 48 37 62 23C76 10 118 -12 165 -12C238 -12 430 62 430 223C430 297 379 359 290 375V377Z" id="g50-52"></path><glyph.data ascent="3443" descent="-2856" horiz-adv-x="487" vert-adv-y="487"></glyph.data></g><g transform="matrix(.013,0,0,-0.013,92.818,0)"><path d="M731 650H485V618C556 614 580 601 585 558C588 530 592 485 592 390V153H589L173 650H22V618C69 614 92 606 112 582C131 558 132 555 132 483V266C132 175 129 128 125 96C120 49 95 36 36 33V0H281V33C212 36 188 50 183 98C180 129 177 175 177 266V510H179L603 -9H638V390C638 483 640 530 644 561C649 602 674 615 731 618V650Z" id="g58-76"></path><glyph.data ascent="1007" descent="-369" horiz-adv-x="754" vert-adv-y="754"></glyph.data></g><g transform="matrix(.0091,0,0,-0.0091,102.62,-5.872)"><path d="M486 158C486 177 478 202 466 220C413 228 386 236 336 262C386 288 413 297 466 304C478 323 486 347 485 366C470 376 444 381 422 380C389 338 368 319 321 288C323 345 329 372 349 422C339 442 322 461 305 470C289 461 271 442 262 422C281 372 287 345 290 288C243 319 222 338 189 380C167 381 142 376 125 366C125 347 133 322 145 304C198 296 225 288 275 262C225 236 198 227 145 220C133 201 125 177 126 158C141 148 167 143 189 144C222 186 243 205 290 236C288 179 282 152 262 102C272 82 289 63 306 54C322 63 340 82 350 102C330 152 324 179 321 236C368 205 390 186 422 144C444 143 470 148 486 158Z" id="g50-43"></path><glyph.data ascent="3443" descent="-2856" horiz-adv-x="611" vert-adv-y="611"></glyph.data></g></svg> and SOCS3 problems upon the down/upregulation of single reactions/preexisting proteins: (a) upregulation of each reaction rate constant by 1000 times, (b) downregulation of each reaction rate constant by 0.001 times, (c) upregulation of each preexisting molecule by 100 times, and (d) downregulation of each preexisting molecule by 0.01 times. The red curves represent representative abnormal patterns studied in this work, while the green curves are obtained for the normal condition.</div>

BioMed Research International

fig4

Figure 4

Figure 4: A Kinetic-Model-Based Approach to Identify Malfunctioning Components in Signal Transduction Pathways from Artificial Clinical Data 