<?xml version="1.0" encoding="UTF-8"?><xmi:XMI xmlns:pos="http:///org/u_compare/shared/label/penn/pos.ecore" xmlns:grammatical="http:///org/u_compare/shared/label/penn/function/grammatical.ecore" xmlns:general="http:///org/u_compare/shared/label/penn/pos/general.ecore" xmlns:cas="http:///uima/cas.ecore" xmlns:stanford="http:///org/u_compare/shared/label/stanford.ecore" xmlns:semantic2="http:///uk/ac/nactem/semantic.ecore" xmlns:bioie="http:///org/u_compare/shared/label/penn/pos/bioie.ecore" xmlns:function="http:///org/u_compare/shared/label/penn/function.ecore" xmlns:tcas="http:///uima/tcas.ecore" xmlns:bio="http:///org/u_compare/shared/semantic/bio.ecore" xmlns:syntactic="http:///org/u_compare/shared/syntactic.ecore" xmlns:comparable="http:///org/u_compare/shared/comparable.ecore" xmlns:examples="http:///org/apache/uima/examples.ecore" xmlns:label="http:///org/u_compare/shared/label.ecore" xmlns:xmi="http://www.omg.org/XMI" xmlns:general2="http:///org/u_compare/shared/label/penn/bracket/general.ecore" xmlns:shared="http:///org/u_compare/shared.ecore" xmlns:fragment="http:///org/u_compare/shared/document/fragment.ecore" xmlns:document="http:///org/u_compare/shared/document.ecore" xmlns:bracket="http:///org/u_compare/shared/label/penn/bracket.ecore" xmlns:text="http:///org/u_compare/shared/label/penn/function/text.ecore" xmlns:structure="http:///org/u_compare/shared/document/structure.ecore" xmlns:text2="http:///org/u_compare/shared/document/text.ecore" xmlns:release="http:///org/u_compare/shared/label/penn/pos/release.ecore" xmlns:semantic="http:///org/u_compare/shared/semantic.ecore" xmlns:nontext="http:///org/u_compare/shared/document/nontext.ecore" xmlns:conll="http:///org/u_compare/shared/label/conll.ecore" xmlns:chemical="http:///org/u_compare/shared/semantic/chemical.ecore" xmlns:semantic3="http:///org/u_compare/shared/label/penn/function/semantic.ecore" xmlns:release2="http:///org/u_compare/shared/label/penn/bracket/release.ecore" xmlns:coindex="http:///org/u_compare/shared/label/penn/coindex.ecore" xmi:version="2.0"><cas:NULL xmi:id="0"/><cas:Sofa xmi:id="1" sofaNum="1" sofaID="_InitialView" mimeType="text" sofaString="The design of a new mutation model for active genes: expression of the Escherichia coli lac operon in mammalian cells. &#10;The design of a novel transgenic mouse model is described that should allow analysis of mutations at a single cell level in all tissues of a model animal. The model is based on the correct regulation of the Escherichia coli lac operon in mammalian cells. Induction of a mutation in the lacI gene will result in the loss of transcriptional repression of the lacZ gene in mutated cells. Expression of beta-galactosidase can subsequently be detected at the single cell level. The model was first tested in vitro using transfection of mouse LTK- cells. LacZ expression was very heterogeneous in most of the stable transfectants and seemed to be subject to epigenetic inactivation. One clone (IIB1) was isolated that stably expressed lacZ in more than 99% of its cells. Subsequent introduction of the lacI gene into IIB1 cells resulted in correct transcriptional repression of the lacZ gene that could be alleviated by IPTG, an allosteric inducer of lacI repression. However, in time the extent of beta-galactosidase induction gradually declined suggesting that the prolonged repressed transcriptional state triggers epigenetic inactivation. Variegated expression of the lacZ gene was not confined to cultured cells since several transgenic lines also did not express the lacZ transgene. This study shows that while the susceptibility of the lacZ gene to inactivation processes poses a fundamental problem, correct regulation of the expression of a reporter gene by the lacI repressor protein is feasible in mammalian cells when assayed at the single cell level. Thus, the model can in principle be used for the detection of mutagenic events at the lacI locus. Targeting of the lacZ gene to an endogenous housekeeping gene might prevent epigenetic inactivation. Alternatively, with the use of another reporter gene in the mutation detection system the proposed transgenic mouse model could be realized. "/><cas:FSArray xmi:id="314" elements="318 327"/><cas:FSArray xmi:id="321" elements="26"/><cas:FSArray xmi:id="330" elements="37"/><cas:FSArray xmi:id="336" elements="340 349"/><cas:FSArray xmi:id="343" elements="48"/><cas:FSArray xmi:id="352" elements="58"/><cas:FSArray xmi:id="358" elements="362 371"/><cas:FSArray xmi:id="365" elements="237"/><cas:FSArray xmi:id="374" elements="259"/><cas:FSArray xmi:id="380" elements="384 393"/><cas:FSArray xmi:id="387" elements="69"/><cas:FSArray xmi:id="396" elements="80"/><cas:FSArray xmi:id="402" elements="406 415"/><cas:FSArray xmi:id="409" elements="91"/><cas:FSArray xmi:id="418" elements="98"/><cas:FSArray xmi:id="424" elements="428 437"/><cas:FSArray xmi:id="431" elements="108"/><cas:FSArray xmi:id="440" elements="115"/><cas:FSArray xmi:id="446" elements="450 459"/><cas:FSArray xmi:id="453" elements="122"/><cas:FSArray xmi:id="462" elements="133"/><cas:FSArray xmi:id="468" elements="472 481"/><cas:FSArray xmi:id="475" elements="144"/><cas:FSArray xmi:id="484" elements="155"/><cas:FSArray xmi:id="493" elements="0 26 37 48 58 69 80 91 98 108 115 122 133 144 155 0 0 0 0 0 0 0 0"/><tcas:DocumentAnnotation xmi:id="8" sofa="1" begin="0" end="2018" language="x-unspecified"/><tcas:DocumentAnnotation xmi:id="21" sofa="1" begin="0" end="2018"/><examples:SourceDocumentInformation xmi:id="13" sofa="1" begin="0" end="2018" uri="/9360635.txt" offsetInSource="0" documentSize="2018" lastSegment="true"/><semantic:LinkedAnnotationSet xmi:id="318" linkingRelation="324" linkedAnnotations="321"/><semantic:LinkedAnnotationSet xmi:id="327" linkingRelation="333" linkedAnnotations="330"/><semantic:LinkedAnnotationSet xmi:id="340" linkingRelation="346" linkedAnnotations="343"/><semantic:LinkedAnnotationSet xmi:id="349" linkingRelation="355" linkedAnnotations="352"/><semantic:LinkedAnnotationSet xmi:id="362" linkingRelation="368" linkedAnnotations="365"/><semantic:LinkedAnnotationSet xmi:id="371" linkingRelation="377" linkedAnnotations="374"/><semantic:LinkedAnnotationSet xmi:id="384" linkingRelation="390" linkedAnnotations="387"/><semantic:LinkedAnnotationSet xmi:id="393" linkingRelation="399" linkedAnnotations="396"/><semantic:LinkedAnnotationSet xmi:id="406" linkingRelation="412" linkedAnnotations="409"/><semantic:LinkedAnnotationSet xmi:id="415" linkingRelation="421" linkedAnnotations="418"/><semantic:LinkedAnnotationSet xmi:id="428" linkingRelation="434" linkedAnnotations="431"/><semantic:LinkedAnnotationSet xmi:id="437" linkingRelation="443" linkedAnnotations="440"/><semantic:LinkedAnnotationSet xmi:id="450" linkingRelation="456" linkedAnnotations="453"/><semantic:LinkedAnnotationSet xmi:id="459" linkingRelation="465" linkedAnnotations="462"/><semantic:LinkedAnnotationSet xmi:id="472" linkingRelation="478" linkedAnnotations="475"/><semantic:LinkedAnnotationSet xmi:id="481" linkingRelation="487" linkedAnnotations="484"/><shared:ExternalReference xmi:id="34" namespace="GREC Concepts" ID="Operon"/><shared:ExternalReference xmi:id="45" namespace="GREC Concepts" ID="Cells"/><shared:ExternalReference xmi:id="55" namespace="GREC Concepts" ID="Mutation"/><shared:ExternalReference xmi:id="66" namespace="GREC Concepts" ID="Gene"/><shared:ExternalReference xmi:id="77" namespace="GREC Concepts" ID="Gene"/><shared:ExternalReference xmi:id="88" namespace="GREC Concepts" ID="Cells"/><shared:ExternalReference xmi:id="105" namespace="GREC Concepts" ID="Gene_Repression"/><shared:ExternalReference xmi:id="130" namespace="GREC Concepts" ID="Cells"/><shared:ExternalReference xmi:id="141" namespace="GREC Concepts" ID="Gene"/><shared:ExternalReference xmi:id="152" namespace="GREC Concepts" ID="Gene"/><shared:ExternalReference xmi:id="234" namespace="GREC" ID="Gene"/><shared:ExternalReference xmi:id="245" namespace="GREC" ID="Gene_Activation"/><shared:ExternalReference xmi:id="256" namespace="GREC" ID="GRE"/><shared:ExternalReference xmi:id="267" namespace="GREC" ID="Gene_Repression"/><shared:ExternalReference xmi:id="278" namespace="GREC" ID="GRE"/><shared:ExternalReference xmi:id="289" namespace="GREC" ID="GRE"/><shared:ExternalReference xmi:id="300" namespace="GREC" ID="GRE"/><shared:ExternalReference xmi:id="311" namespace="GREC" ID="GRE"/><shared:ExternalReference xmi:id="324" namespace="GREC Concepts" ID="Theme"/><shared:ExternalReference xmi:id="333" namespace="GREC Concepts" ID="Location"/><shared:ExternalReference xmi:id="346" namespace="GREC Concepts" ID="Theme"/><shared:ExternalReference xmi:id="355" namespace="GREC Concepts" ID="Location"/><shared:ExternalReference xmi:id="368" namespace="GREC Concepts" ID="Agent"/><shared:ExternalReference xmi:id="377" namespace="GREC Concepts" ID="Theme"/><shared:ExternalReference xmi:id="390" namespace="GREC Concepts" ID="Theme"/><shared:ExternalReference xmi:id="399" namespace="GREC Concepts" ID="Location"/><shared:ExternalReference xmi:id="412" namespace="GREC Concepts" ID="Theme"/><shared:ExternalReference xmi:id="421" namespace="GREC Concepts" ID="Descriptive-Theme"/><shared:ExternalReference xmi:id="434" namespace="GREC Concepts" ID="Agent"/><shared:ExternalReference xmi:id="443" namespace="GREC Concepts" ID="Theme"/><shared:ExternalReference xmi:id="456" namespace="GREC Concepts" ID="Agent"/><shared:ExternalReference xmi:id="465" namespace="GREC Concepts" ID="Theme"/><shared:ExternalReference xmi:id="478" namespace="GREC Concepts" ID="Agent"/><shared:ExternalReference xmi:id="487" namespace="GREC Concepts" ID="Theme"/><semantic:EventAnnotation xmi:id="226" sofa="1" begin="53" end="63" externalReference="234" linkedAnnotationSets="314"/><semantic:EventAnnotation xmi:id="237" sofa="1" begin="375" end="384" externalReference="245" linkedAnnotationSets="336"/><semantic:EventAnnotation xmi:id="248" sofa="1" begin="421" end="427" externalReference="256" linkedAnnotationSets="358"/><semantic:EventAnnotation xmi:id="259" sofa="1" begin="459" end="469" externalReference="267" linkedAnnotationSets="380"/><semantic:EventAnnotation xmi:id="270" sofa="1" begin="942" end="950" externalReference="278" linkedAnnotationSets="402"/><semantic:EventAnnotation xmi:id="281" sofa="1" begin="1223" end="1231" externalReference="289" linkedAnnotationSets="424"/><semantic:EventAnnotation xmi:id="292" sofa="1" begin="1375" end="1382" externalReference="300" linkedAnnotationSets="446"/><semantic:EventAnnotation xmi:id="303" sofa="1" begin="1844" end="1851" externalReference="311" linkedAnnotationSets="468"/><comparable:IDArray xmi:id="490" array="493" idType="t"/><semantic2:NucleicAcids xmi:id="26" sofa="1" begin="67" end="98" externalReference="34"/><semantic2:NucleicAcids xmi:id="58" sofa="1" begin="402" end="415" externalReference="66"/><semantic2:NucleicAcids xmi:id="69" sofa="1" begin="473" end="486" externalReference="77"/><semantic2:NucleicAcids xmi:id="133" sofa="1" begin="1383" end="1401" externalReference="141"/><semantic2:NucleicAcids xmi:id="144" sofa="1" begin="1789" end="1802" externalReference="152"/><semantic2:LivingSystems xmi:id="37" sofa="1" begin="102" end="117" externalReference="45"/><semantic2:LivingSystems xmi:id="80" sofa="1" begin="490" end="503" externalReference="88"/><semantic2:LivingSystems xmi:id="122" sofa="1" begin="1337" end="1361" externalReference="130"/><semantic2:Processes xmi:id="48" sofa="1" begin="388" end="398" externalReference="55"/><semantic2:Processes xmi:id="98" sofa="1" begin="954" end="988" externalReference="105"/><semantic2:EventArgumentSpan xmi:id="91" sofa="1" begin="896" end="908"/><semantic2:EventArgumentSpan xmi:id="108" sofa="1" begin="1201" end="1222"/><semantic2:EventArgumentSpan xmi:id="115" sofa="1" begin="1232" end="1255"/><semantic2:EventArgumentSpan xmi:id="155" sofa="1" begin="1852" end="1875"/><cas:View sofa="1" members="314 321 330 336 343 352 358 365 374 380 387 396 402 409 418 424 431 440 446 453 462 468 475 484 493 8 21 13 318 327 340 349 362 371 384 393 406 415 428 437 450 459 472 481 34 45 55 66 77 88 105 130 141 152 234 245 256 267 278 289 300 311 324 333 346 355 368 377 390 399 412 421 434 443 456 465 478 487 226 237 248 259 270 281 292 303 490 26 58 69 133 144 37 80 122 48 98 91 108 115 155"/></xmi:XMI>