<p>Integrative approaches are motivated by the desired improvement of<br />robustness, stability and accuracy. Clustering, the prevailing technique for<br />preliminary and exploratory analysis of experimental data, may benefit from<br />integration across multiple partitions. In this thesis we have proposed<br />integration methods based on non-negative matrix factorization that can fuse<br />clusterings stemming from different data sets, different data preprocessing<br />steps or different sub-samples of objects or features. Proposed methods are<br />evaluated from several points of view on typical machine learning data sets,<br />synthetics data, and above all, on data coming form bioinformatics realm,<br />which rise is fuelled by technological revolutions in molecular biology. For a<br />vast amounts of &#39;omics&#39; data that are nowadays available sophisticated<br />computational methods are necessary. We evaluated methods on problem<br />from cancer genomics, functional genomics and metagenomics.</p> / <p>Предмет истраживања докторске дисертације су алгоритми кластеровања,<br />односно груписања података, и могућности њиховог унапређења<br />интегративним приступом у циљу повећања поузданости, робустности на<br />присуство шума и екстремних вредности у подацима, омогућавања фузије<br />података. У дисертацији су предложене методе засноване на ненегативној<br />факторизацији матрице. Методе су успешно имплементиране и детаљно<br />анализиране на разноврсним подацима са UCI репозиторијума и<br />синтетичким подацима које се типично користе за евалуацију нових<br />алгоритама и поређење са већ постојећим методама. Већи део<br />дисертације посвећен је примени у домену биоинформатике која обилује<br />хетерогеним подацима и бројним изазовним задацима. Евалуација је<br />извршена на подацима из домена функционалне геномике, геномике рака и<br />метагеномике.</p> / <p>Predmet istraživanja doktorske disertacije su algoritmi klasterovanja,<br />odnosno grupisanja podataka, i mogućnosti njihovog unapređenja<br />integrativnim pristupom u cilju povećanja pouzdanosti, robustnosti na<br />prisustvo šuma i ekstremnih vrednosti u podacima, omogućavanja fuzije<br />podataka. U disertaciji su predložene metode zasnovane na nenegativnoj<br />faktorizaciji matrice. Metode su uspešno implementirane i detaljno<br />analizirane na raznovrsnim podacima sa UCI repozitorijuma i<br />sintetičkim podacima koje se tipično koriste za evaluaciju novih<br />algoritama i poređenje sa već postojećim metodama. Veći deo<br />disertacije posvećen je primeni u domenu bioinformatike koja obiluje<br />heterogenim podacima i brojnim izazovnim zadacima. Evaluacija je<br />izvršena na podacima iz domena funkcionalne genomike, genomike raka i<br />metagenomike.</p>

<p>Leydig-ove&nbsp; ćelije&nbsp; testisa&nbsp; su&nbsp; primarno&nbsp; mesto&nbsp; sinteze mu&scaron;kih polnih hormona. Ovi hormoni su neophodani za reproduktivno,&nbsp; ali&nbsp; i&nbsp; za&nbsp; op&scaron;te&nbsp; zdravlje&nbsp; budući&nbsp; da&nbsp; su<br />ozbiljni zdravstveni problemi često povezani sa njihovom smanjenom produkcijom.&nbsp; Insulin i insulinu sličan faktor rasta&nbsp; 1,&nbsp; IGF1&nbsp; <em>(engl.</em>&nbsp; insulin&nbsp; like&nbsp; growth&nbsp; factor&nbsp; 1),&nbsp; i<br />signalizacija koju pokreću preko svojih receptora&nbsp; (INSR i IGF1R),&nbsp; su&nbsp; jedan&nbsp; od&nbsp; ključnih&nbsp; faktora&nbsp; koji&nbsp; reguli&scaron;u specifični razvoj tkiva, pa i samih gonada. Ipak,&nbsp; uloga&nbsp; i<br />mehanizmi&nbsp; delovanja&nbsp; ovih&nbsp; receptora&nbsp; u&nbsp; steroidogenim tkivima nisu&nbsp; u potpunosti&nbsp; poznati.&nbsp; Stoga je&nbsp; istraživanje&nbsp; uokviru ove&nbsp; doktorske&nbsp; disertacije&nbsp; koncipirano sa ciljem da se,&nbsp; na&nbsp; modelu&nbsp; prepubertalnih&nbsp; (P21)&nbsp; i&nbsp; adultnih&nbsp; (P80) mužjaka mi&scaron;eva sa kondicionalnom delecijom<em> Insr </em>i <em>Igf1</em>r gena&nbsp; u&nbsp; steroidogenim&nbsp; ćelijama&nbsp; (Insr/Igf1r-DKO), defini&scaron;e uloga INSR i IGF1R u regulisanju diferencijacije i&nbsp; steroidogene&nbsp; funkcije&nbsp; Leydig-ovih&nbsp; ćelija.&nbsp; Pored&nbsp; toga, mužjaci&nbsp; i&nbsp; ženke&nbsp; P21&nbsp; mi&scaron;eva&nbsp; sa&nbsp; istom&nbsp; delecijom&nbsp; su kori&scaron;ćeni&nbsp; za&nbsp; praćenje&nbsp; ekspresije&nbsp; glavnih&nbsp; markera mitohondrijalne&nbsp; biogeneze&nbsp; i&nbsp; fuzije/arhitekture&nbsp; u&nbsp; Leydigovim&nbsp; ćelijama,&nbsp; ovarijumima&nbsp; i&nbsp;&nbsp; nadbubrežnim&nbsp; žlezdama. Rezultati&nbsp; su&nbsp; potvrdili&nbsp; da&nbsp; delecija&nbsp; Insr&nbsp; i&nbsp; Igf1r&nbsp; u<br />steroidogenim&nbsp; tkivima&nbsp; utiče&nbsp; na&nbsp; diferencijaciju&nbsp; i funkcionalne karakteristike Leydig-ovih ćelija P21 i P80 mi&scaron;eva,&nbsp; upućujući&nbsp; na&nbsp; pojavu&nbsp; tzv.&nbsp; &bdquo;feminizacije&ldquo;.&nbsp; Broj<br />Leydig-ovih&nbsp; ćelija&nbsp; izolovanih&nbsp; iz&nbsp; P21&nbsp; i&nbsp; P80&nbsp; Insr/Igf1rDKO&nbsp; mi&scaron;eva&nbsp; bio&nbsp; je&nbsp; smanjen,&nbsp; a&nbsp; morfologija&nbsp; i ultrastruktura&nbsp; ovih&nbsp; ćelija&nbsp; izmenjene&nbsp; kod&nbsp; P21&nbsp; Insr/Igf1rDKO&nbsp; mi&scaron;eva.&nbsp; Steroidogeni&nbsp; kapacitet&nbsp; i&nbsp; aktivnost,&nbsp; kao&nbsp; i ekspresija&nbsp; glavnih&nbsp; elemenata&nbsp; steroidogene&nbsp; ma&scaron;inerije <em>(Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1&nbsp; i&nbsp; 6, Hsd17b3,</em><br /><em>Sf</em>1)&nbsp; bili su&nbsp; smanjeni&nbsp; u Leydig-ovim ćelijama P21 i P80 <em>Insr/Igf1</em>r-DKO mi&scaron;eva,&nbsp; dok je ekspresija transkripcionih represora&nbsp; steroidogeneze&nbsp; (Arr19&nbsp; i&nbsp; Dax1)&nbsp; bila&nbsp; povećana specifično&nbsp; u&nbsp; istim&nbsp; ćelijama,&nbsp; ali&nbsp; ne&nbsp; i&nbsp; u&nbsp; ostatku&nbsp; testisa.<br />Transkripcioni&nbsp; profil&nbsp; markera&nbsp; mu&scaron;kog&nbsp; pola&nbsp; (<em>Sry,&nbsp; Sox9, Amh</em>)&nbsp; bio&nbsp; je&nbsp; izmenjen&nbsp; u Leydig-ovim ćelijama P21 i P80 <em>Insr/Igf1r</em>-DKO&nbsp; mi&scaron;eva.&nbsp; Transkripcija&nbsp; markera&nbsp; ženskog pola (<em>Rspo1, Wnt4</em>) u testisima,&nbsp; kao i ekspresija&nbsp; Cyp19a1 i&nbsp; produkcija estradiola (E2) u Leydig-ovim ćelijama,&nbsp; P21 i&nbsp; P80&nbsp;<em> Insr/Igf1r</em>-DKO&nbsp; mi&scaron;eva&nbsp; bile&nbsp; su&nbsp; povećane. Transkripcija&nbsp; markera&nbsp; mitohondrijalne&nbsp; biogenze (<em>Ppargc1a,&nbsp; Tfam</em>,&nbsp; <em>Mtnd1</em>)&nbsp; bila&nbsp; je&nbsp; smanjena&nbsp; u&nbsp; Leydigovim&nbsp; ćelijama&nbsp; P21&nbsp; <em>Insr/Igf1r</em>-DKO&nbsp; mi&scaron;eva,&nbsp; dok&nbsp; supromene&nbsp; ekspresije&nbsp; izostale&nbsp; u&nbsp; ovarijumima&nbsp; ženki&nbsp; istog&nbsp; genotipa.&nbsp; Isti&nbsp; markeri&nbsp; su&nbsp; bili&nbsp; povećani&nbsp; u&nbsp; nabdubrežnim&nbsp; žlezdama&nbsp; oba&nbsp; pola.&nbsp; Markeri&nbsp; mitohondrijalne fuzije/arhitekture&nbsp; (<em>Mfn1&nbsp; i&nbsp; Mfn2)</em>&nbsp; bili&nbsp; su&nbsp; povećani&nbsp; u Leydig-ovim ćelijama P21 <em>Insr/Igf1r</em>-DKO mi&scaron;eva, &scaron;to je&nbsp; praćeno&nbsp; i&nbsp; naru&scaron;enom&nbsp; mitohondrijalnom&nbsp; fazom steroidogeneze (produkcija progesterona), kao i brojem i&nbsp; morfologijom ovim organela.&nbsp; Ekspresija istih markera u ovarijumima&nbsp; bila&nbsp; je&nbsp; nepromenjena.&nbsp; Sumirano,&nbsp; rezultati ovog istraživanja&nbsp; su&nbsp; pokazali&nbsp; da su&nbsp; INSR i IGF1R&nbsp; važni za&nbsp; diferencijaciju&nbsp; i&nbsp; steroidogenu&nbsp; funkciju&nbsp; Leydig-ovih&nbsp; ćelija&nbsp; P21&nbsp; i&nbsp; P80&nbsp; mi&scaron;eva.&nbsp; Takođe,&nbsp; ovi&nbsp; receptori&nbsp; su&nbsp; važni regulatori&nbsp; markera&nbsp; mitohondrijalne&nbsp; biogeneze&nbsp; i fuzije/arhiteture u steroidogenim ćelijama mu&scaron;kih gonada&nbsp; P21 mi&scaron;eva, ali ne i u steroidogenim ćelijama ovarijuma.&nbsp;</p> / <p>Leydig cells of testes are the primary site of the male sex hormones&nbsp; synthesis.&nbsp; These&nbsp; hormones&nbsp; are&nbsp; indispensable for&nbsp; both&nbsp; reproductive&nbsp; and&nbsp; general&nbsp; health&nbsp; since&nbsp; serious health&nbsp; problems&nbsp; are&nbsp; often&nbsp; associated&nbsp; with&nbsp; their&nbsp; reduced production.&nbsp; Insulin&nbsp; and&nbsp; insulin-like&nbsp; growth&nbsp; factor&nbsp; 1, IGF1&nbsp; (insulin&nbsp; like&nbsp; growth&nbsp; factor&nbsp; 1),&nbsp; and&nbsp; signaling triggered through&nbsp; their receptors (INSR and IGF1R), are&nbsp; one of the key&nbsp; factors&nbsp; that regulate specific development of&nbsp; tissue&nbsp; including&nbsp; gonads.&nbsp; However,&nbsp; the&nbsp; role&nbsp; and mechanisms&nbsp; of&nbsp; these&nbsp; receptors&nbsp; action&nbsp; in&nbsp; steroidogenic tissues are not known enough. This study was designed to&nbsp; observe &nbsp; the role of INSR and IGF1R in regulating the differentiation and steroidogenic function of Leydig cells by using the model of prepubertal (P21) and adult (P80) male mice with the conditional deletion of the&nbsp; Insr&nbsp; and Igf1r&nbsp; genes&nbsp; in&nbsp; steroidogenic&nbsp; cells&nbsp; (<em>Insr/Igf1r-</em>DKO).&nbsp; In addition,&nbsp; male&nbsp; and&nbsp; female&nbsp; P21&nbsp; mice&nbsp; with&nbsp; the&nbsp; samedeletion were used to monitor the expression of the main markers&nbsp; of&nbsp; mitochondrial&nbsp; biogenesis&nbsp; and fusion/architecture&nbsp; in&nbsp; Leydig&nbsp; cells,&nbsp; ovaries&nbsp; and&nbsp; adrenal glands.&nbsp; The&nbsp; results&nbsp; confirmed&nbsp; that&nbsp; deletion&nbsp; of&nbsp;<em> Insr</em>&nbsp; and<em> Igf1r&nbsp;</em> in&nbsp; steroidogenic&nbsp; tissues&nbsp; influences&nbsp; differentiation and&nbsp; functional&nbsp; characteristics&nbsp; of&nbsp; Leydig&nbsp; cells&nbsp; isolated from&nbsp; P21&nbsp; and&nbsp; P80&nbsp; mice,&nbsp; suggesting&nbsp; an&nbsp; appearance&nbsp; of &quot;feminization&quot;.&nbsp; The&nbsp; number&nbsp; of&nbsp; Leydig&nbsp; cells&nbsp; isolated from&nbsp; both&nbsp; P21&nbsp; and&nbsp; P80&nbsp; <em>Insr/Igf1</em>r-DKO&nbsp; mice&nbsp; was reduced.&nbsp; Morphology&nbsp; and&nbsp; ultrastructure&nbsp; of&nbsp; Leydig&nbsp; cells were&nbsp; disturbed&nbsp; in&nbsp; P21&nbsp; <em>Insr/Igf1r-</em>DKO&nbsp; mice. Steroidogenic capacity and activity, as well as expression of the main elements of&nbsp; steroidogenic machinery (<em>Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1&nbsp; and&nbsp; 6, Hsd17b3, Sf1) </em>were&nbsp; decreased&nbsp; in&nbsp; Leydig&nbsp; cells&nbsp; from&nbsp; P21&nbsp; and&nbsp; P80 I<em>nsr/Igf1</em>r-DKO&nbsp; mice,&nbsp; while&nbsp; the&nbsp; expression&nbsp; of transcriptional&nbsp; repressors&nbsp; of&nbsp; steroidogenesis&nbsp; (<em>Arr19</em>&nbsp; and <em>Dax1) </em>was increased&nbsp; in the same cells, but not in the rest of&nbsp; the&nbsp; testes.&nbsp; Transcription&nbsp; profile&nbsp; of&nbsp; the&nbsp; male&nbsp; sex markers&nbsp; (<em>Sry,&nbsp; Sox9</em>,&nbsp; <em>Amh</em>)&nbsp; was&nbsp; altered&nbsp; in&nbsp; Leydig&nbsp; cells from&nbsp; P21&nbsp; and&nbsp; P80&nbsp; <em>Insr/Igf1</em>r-DKO&nbsp; mice.&nbsp; Transcription of the female sex markers (<em>Rspo1, Wnt4</em>) in the testes, as well&nbsp; as&nbsp; <em>Cyp19a1&nbsp; </em>expression&nbsp; and&nbsp; estradiol&nbsp; (E2) production in Leydig cells,&nbsp; from P21 and P80&nbsp; I<em>nsr/Igf1</em>rDKO&nbsp; mice&nbsp; were&nbsp; increased.&nbsp; Transcription&nbsp; of mitochondrial&nbsp; biogenesis&nbsp; markers&nbsp; (<em>Ppargc1a,&nbsp; Tfam, Mtnd1</em>)&nbsp; was&nbsp; declined&nbsp; in&nbsp; Leydig&nbsp; cells&nbsp; from&nbsp; P21<em> Insr/Igf1r-</em>DKO mice, while changes were absent in&nbsp; the ovaries of the same genotype.&nbsp; Transcription of the&nbsp; same markers&nbsp; was&nbsp; increased&nbsp; in&nbsp; the&nbsp; adrenal&nbsp; glands&nbsp; of&nbsp; both sexes.&nbsp; The&nbsp; mitochondrial&nbsp; fusion/architecture&nbsp; markers (<em>Mfn1</em>&nbsp; and&nbsp; <em>Mfn2</em>)&nbsp; were&nbsp; increased&nbsp; in&nbsp; Leydig&nbsp; cells&nbsp; from<em> Insr/Igf1r</em>-DKO&nbsp; mice&nbsp; and&nbsp; followed&nbsp; by&nbsp; disturbedmitochondrial&nbsp; phase&nbsp; of&nbsp; steroidogenesis&nbsp; (progesterone production), as well as&nbsp; decreased&nbsp; number and&nbsp; disturbed morphology&nbsp; of&nbsp; mitochondria.&nbsp;&nbsp; Expression&nbsp; of&nbsp; the&nbsp; same markers&nbsp; in&nbsp; the&nbsp; ovaries&nbsp; was&nbsp; unchanged.&nbsp; In&nbsp; summary, results&nbsp; of&nbsp; this&nbsp; study&nbsp; showed&nbsp; that&nbsp; INSR&nbsp; and&nbsp; IGF1R&nbsp; are important in differentiation and steroidogenic function of Leydig&nbsp; cells&nbsp; from&nbsp; P21&nbsp; and&nbsp; P80&nbsp; mice.&nbsp; Also,&nbsp; these receptors&nbsp; are&nbsp; important&nbsp; regulators&nbsp; of&nbsp; mitochondrial biogenesis&nbsp; and&nbsp;&nbsp; fusion/architecture&nbsp; markers&nbsp; in steroidogenic&nbsp; cells&nbsp; of&nbsp; P21&nbsp; male&nbsp; mice,&nbsp; but&nbsp; not&nbsp; in steroidogenic cells of ovaries.</p>