@article {752, title = {Towards a metagenomics machine learning interpretable model for understanding the transition from adenoma to colorectal cancer.}, journal = {Sci Rep}, volume = {12}, year = {2022}, month = {2022 Jan 10}, pages = {450}, abstract = {

Gut microbiome is gaining interest because of its links with several diseases, including colorectal cancer (CRC), as well as the possibility of being used to obtain non-intrusive predictive disease biomarkers. Here we performed a meta-analysis of 1042 fecal metagenomic samples from seven publicly available studies. We used an interpretable machine learning approach based on functional profiles, instead of the conventional taxonomic profiles, to produce a highly accurate predictor of CRC with better precision than those of previous proposals. Moreover, this approach is also able to discriminate samples with adenoma, which makes this approach very promising for CRC prevention by detecting early stages in which intervention is easier and more effective. In addition, interpretable machine learning methods allow extracting features relevant for the classification, which reveals basic molecular mechanisms accounting for the changes undergone by the microbiome functional landscape in the transition from healthy gut to adenoma and CRC conditions. Functional profiles have demonstrated superior accuracy in predicting CRC and adenoma conditions than taxonomic profiles and additionally, in a context of explainable machine learning, provide useful hints on the molecular mechanisms operating in the microbiota behind these conditions.

}, issn = {2045-2322}, doi = {10.1038/s41598-021-04182-y}, author = {Casimiro-Soriguer, Carlos S and Loucera, Carlos and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {719, title = {Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.}, journal = {Mol Med}, volume = {27}, year = {2021}, month = {2021 05 24}, pages = {50}, abstract = {

OBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism.

METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways.

RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination.

CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

}, keywords = {Biodiversity, Computational Biology, Dysbiosis, Gastrointestinal Microbiome, Gout, Humans, Metagenome, metagenomics, Protein Interaction Mapping, Protein Interaction Maps, Uric Acid}, issn = {1528-3658}, doi = {10.1186/s10020-021-00311-5}, author = {M{\'e}ndez-Salazar, Eder Orlando and V{\'a}zquez-Mellado, Janitzia and Casimiro-Soriguer, Carlos S and Dopazo, Joaquin and Cubuk, Cankut and Zamudio-Cuevas, Yessica and Francisco-Balderas, Adriana and Mart{\'\i}nez-Flores, Karina and Fern{\'a}ndez-Torres, Javier and Lozada-P{\'e}rez, Carlos and Pineda, Carlos and S{\'a}nchez-Gonz{\'a}lez, Austreberto and Silveira, Luis H and Burguete-Garc{\'\i}a, Ana I and Orbe-Orihuela, Citlalli and Lagunas-Mart{\'\i}nez, Alfredo and Vazquez-Gomez, Alonso and L{\'o}pez-Reyes, Alberto and Palacios-Gonz{\'a}lez, Berenice and Mart{\'\i}nez-Nava, Gabriela Ang{\'e}lica} } @article {692, title = {Towards Improving Skin Cancer Diagnosis by Integrating Microarray and RNA-Seq Datasets.}, journal = {IEEE J Biomed Health Inform}, volume = {24}, year = {2020}, month = {2020 07}, pages = {2119-2130}, abstract = {

Many clinical studies have revealed the high biological similarities existing among different skin pathological states. These similarities create difficulties in the efficient diagnosis of skin cancer, and encourage to study and design new intelligent clinical decision support systems. In this sense, gene expression analysis can help find differentially expressed genes (DEGs) simultaneously discerning multiple skin pathological states in a single test. The integration of multiple heterogeneous transcriptomic datasets requires different pipeline stages to be properly designed: from suitable batch merging and efficient biomarker selection to automated classification assessment. This article presents a novel approach addressing all these technical issues, with the intention of providing new sights about skin cancer diagnosis. Although new future efforts will have to be made in the search for better biomarkers recognizing specific skin pathological states, our study found a panel of 8 highly relevant multiclass DEGs for discerning up to 10 skin pathological states: 2 healthy skin conditions a priori, 2 cataloged precancerous skin diseases and 6 cancerous skin states. Their power of diagnosis over new samples was widely tested by previously well-trained classification models. Robust performance metrics such as overall and mean multiclass F1-score outperformed recognition rates of 94\% and 80\%, respectively. Clinicians should give special attention to highlighted multiclass DEGs that have high gene expression changes present among them, and understand their biological relationship to different skin pathological states.

}, keywords = {Biomarkers, Tumor, Computational Biology, Diagnosis, Computer-Assisted, Gene Expression Profiling, Humans, Machine Learning, RNA-seq, Skin Neoplasms}, issn = {2168-2208}, doi = {10.1109/JBHI.2019.2953978}, author = {Galvez, Juan M and Castillo-Secilla, Daniel and Herrera, Luis J and Valenzuela, Olga and Caba, Octavio and Prados, Jose C and Ortuno, Francisco M and Rojas, Ignacio} } @article {710, title = {Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.}, journal = {Genes (Basel)}, volume = {12}, year = {2020}, month = {2020 12 31}, abstract = {

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients{\textquoteright} quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

}, keywords = {Animals, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Expression Regulation, Gene ontology, Humans, Metabolic Networks and Pathways, Mice, Mice, Nude, Microarray Analysis, Molecular Sequence Annotation, Principal Component Analysis, Signal Transduction, Skin, Skin Transplantation, Skin Ulcer, Streptozocin, Tissue Engineering, Transcriptome, Transplantation, Heterologous, Wound Healing}, issn = {2073-4425}, doi = {10.3390/genes12010047}, author = {Le{\'o}n, Carlos and Garcia-Garcia, Francisco and Llames, Sara and Garc{\'\i}a-P{\'e}rez, Eva and Carretero, Marta and Arriba, Mar{\'\i}a Del Carmen and Dopazo, Joaquin and Del Rio, Marcela and Escamez, Maria Jos{\'e} and Mart{\'\i}nez-Santamar{\'\i}a, Luc{\'\i}a} } @article {704, title = {Transparency and reproducibility in artificial intelligence.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {E14-E16}, keywords = {Algorithms, Artificial Intelligence, Reproducibility of Results}, issn = {1476-4687}, doi = {10.1038/s41586-020-2766-y}, author = {Haibe-Kains, Benjamin and Adam, George Alexandru and Hosny, Ahmed and Khodakarami, Farnoosh and Waldron, Levi and Wang, Bo and McIntosh, Chris and Goldenberg, Anna and Kundaje, Anshul and Greene, Casey S and Broderick, Tamara and Hoffman, Michael M and Leek, Jeffrey T and Korthauer, Keegan and Huber, Wolfgang and Brazma, Alvis and Pineau, Joelle and Tibshirani, Robert and Hastie, Trevor and Ioannidis, John P A and Quackenbush, John and Aerts, Hugo J W L} } @article {454, title = {The transcriptomics of an experimentally evolved plant-virus interaction.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 04 26}, pages = {24901}, abstract = {

Models of plant-virus interaction assume that the ability of a virus to infect a host genotype depends on the matching between virulence and resistance genes. Recently, we evolved tobacco etch potyvirus (TEV) lineages on different ecotypes of Arabidopsis thaliana, and found that some ecotypes selected for specialist viruses whereas others selected for generalists. Here we sought to evaluate the transcriptomic basis of such relationships. We have characterized the transcriptomic responses of five ecotypes infected with the ancestral and evolved viruses. Genes and functional categories differentially expressed by plants infected with local TEV isolates were identified, showing heterogeneous responses among ecotypes, although significant parallelism existed among lineages evolved in the same ecotype. Although genes involved in immune responses were altered upon infection, other functional groups were also pervasively over-represented, suggesting that plant resistance genes were not the only drivers of viral adaptation. Finally, the transcriptomic consequences of infection with the generalist and specialist lineages were compared. Whilst the generalist induced very similar perturbations in the transcriptomes of the different ecotypes, the perturbations induced by the specialist were divergent. Plant defense mechanisms were activated when the infecting virus was specialist but they were down-regulated when infecting with generalist.

}, keywords = {Arabidopsis, Ecotype, Gene Expression Profiling, Host-Pathogen Interactions, Potyvirus}, issn = {2045-2322}, doi = {10.1038/srep24901}, author = {Hillung, Julia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Cuevas, Jos{\'e} M and Elena, Santiago F} } @article {1111, title = {Therapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides.}, journal = {Molecular immunology}, volume = {64}, year = {2015}, month = {2015 Apr}, pages = {252-61}, abstract = {Two regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members.}, issn = {1872-9142}, doi = {10.1016/j.molimm.2014.12.002}, url = {http://www.sciencedirect.com/science/article/pii/S0161589014003356}, author = {Calzada, David and Aguerri, Miriam and Baos, Selene and Montaner, David and Mata, Manuel and Joaqu{\'\i}n Dopazo and Quiralte, Joaqu{\'\i}n and Florido, Fernando and Lahoz, Carlos and C{\'a}rdaba, Blanca} } @article {484, title = {Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Apr}, pages = {470-7}, abstract = {

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients{\textquoteright} clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

}, keywords = {Amino Acids, Branched-Chain, Developmental Disabilities, Fibroblasts, Humans, Male, Mutation, Missense, Nervous System Diseases, Pediatrics, Protein Kinases}, issn = {1098-1004}, doi = {10.1002/humu.22513}, author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Dopazo, Joaquin and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar and Alcaide, Patricia and Navarrete, Rosa and Sanz, Paloma and Font-Llitj{\'o}s, Mariona and Vilaseca, Ma Antonia and Ormaizabal, Aida and Pristoupilova, Anna and Agull{\'o}, Sergi Beltran} } @article {1041, title = {Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients.}, journal = {Human mutation}, volume = {35}, number = {4}, year = {2014}, month = {2014 Jan 21}, pages = {470-7}, abstract = {Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain keto-acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients{\textquoteright} clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. This article is protected by copyright. All rights reserved.}, issn = {1098-1004}, doi = {10.1002/humu.22513}, url = {http://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract}, author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Joaqu{\'\i}n Dopazo and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar} } @article {949, title = {Transcriptome profiling of the intoxication response of Tenebrio molitor larvae to Bacillus thuringiensis Cry3Aa protoxin.}, journal = {PloS one}, volume = {7}, year = {2012}, month = {2012}, pages = {e34624}, abstract = {Bacillus thuringiensis (Bt) crystal (Cry) proteins are effective against a select number of insect pests, but improvements are needed to increase efficacy and decrease time to mortality for coleopteran pests. To gain insight into the Bt intoxication process in Coleoptera, we performed RNA-Seq on cDNA generated from the guts of Tenebrio molitor larvae that consumed either a control diet or a diet containing Cry3Aa protoxin. Approximately 134,090 and 124,287 sequence reads from the control and Cry3Aa-treated groups were assembled into 1,318 and 1,140 contigs, respectively. Enrichment analyses indicated that functions associated with mitochondrial respiration, signalling, maintenance of cell structure, membrane integrity, protein recycling/synthesis, and glycosyl hydrolases were significantly increased in Cry3Aa-treated larvae, whereas functions associated with many metabolic processes were reduced, especially glycolysis, tricarboxylic acid cycle, and fatty acid synthesis. Microarray analysis was used to evaluate temporal changes in gene expression after 6, 12 or 24 h of Cry3Aa exposure. Overall, microarray analysis indicated that transcripts related to allergens, chitin-binding proteins, glycosyl hydrolases, and tubulins were induced, and those related to immunity and metabolism were repressed in Cry3Aa-intoxicated larvae. The 24 h microarray data validated most of the RNA-Seq data. Of the three intoxication intervals, larvae demonstrated more differential expression of transcripts after 12 h exposure to Cry3Aa. Gene expression examined by three different methods in control vs. Cry3Aa-treated larvae at the 24 h time point indicated that transcripts encoding proteins with chitin-binding domain 3 were the most differentially expressed in Cry3Aa-intoxicated larvae. Overall, the data suggest that T. molitor larvae mount a complex response to Cry3Aa during the initial 24 h of intoxication. Data from this study represent the largest genetic sequence dataset for T. molitor to date. Furthermore, the methods in this study are useful for comparative analyses in organisms lacking a sequenced genome.}, keywords = {Administration, Animals, Bacterial Proteins, Base Sequence, Biosynthetic Pathways, Complementary, DNA, Endotoxins, Energy Metabolism, Gene Expression Profiling, Hemolysin Proteins, Larva, Microarray Analysis, Molecular Sequence Data, Oral, Sequence Analysis, Tenebrio, Time Factors, Transcriptome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0034624}, author = {Oppert, Brenda and Dowd, Scot E and Bouffard, Pascal and Li, Lewyn and Ana Conesa and Lorenzen, Marc{\'e} D and Toutges, Michelle and Marshall, Jeremy and Huestis, Diana L and Fabrick, Jeff and Oppert, Cris and Jurat-Fuentes, Juan Luis} } @article {1028, title = {Transdifferentiation of MALME-3M and MCF-7 Cells toward Adipocyte-like Cells is Dependent on Clathrin-mediated Endocytosis.}, journal = {SpringerPlus}, volume = {1}, year = {2012}, month = {2012}, pages = {44}, abstract = {ABSTRACT: Enforced cell transdifferentiation of human cancer cells is a promising alternative to conventional chemotherapy. We previously identified albumin-associated lipid- and, more specifically, saturated fatty acid-induced transdifferentiation programs in human cancer cells (HCCLs). In this study, we further characterized the adipocyte-like cells, resulting from the transdifferentiation of human cancer cell lines MCF-7 and MALME-3M, and proposed a common mechanistic approach for these transdifferentiating programs. We showed the loss of pigmentation in MALME-3M cells treated with albumin-associated lipids, based on electron microscopic analysis, and the overexpression of perilipin 2 (PLIN2) by western blotting in MALME-3M and MCF-7 cells treated with unsaturated fatty acids. Comparing the gene expression profiles of naive melanoma MALME-3M cells and albumin-associated lipid-treated cells, based on RNA sequencing, we confirmed the transcriptional upregulation of some key adipogenic gene markers and also an alternative splicing of the adipogenic master regulator PPARG, that is probably related to the reported up regulated expression of the protein. Most importantly, these results also showed the upregulation of genes responsible for Clathrin (CLTC) and other adaptor-related proteins. An increase in CLTC expression in the transdifferentiated cells was confirmed by western blotting. Inactivation of CLTC by chlorpromazine (CHP), an inhibitor of CTLC mediated endocytosis (CME), and gene silencing by siRNAs, partially reversed the accumulation of neutral lipids observed in the transdifferentiated cells. These findings give a deeper insight into the phenotypic changes observed in HCCL to adipocyte-like transdifferentiation and point towards CME as a key pathway in distinct transdifferentiation programs. DISCLOSURES: Simon C and Aguilar-Gallardo C are co-inventors of the International Patent Application No. PCT/EP2011/004941 entitled "Methods for tumor treatment and adipogenesis differentiation".}, issn = {2193-1801}, doi = {10.1186/2193-1801-1-44}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725915/}, author = {Carcel-Trullols, Jaime and Aguilar-Gallardo, Crist{\'o}bal and Garc{\'\i}a-Alcalde, Fernando and Pardo-Cea, Miguel Angel and Dopazo, Joaquin and Ana Conesa and Simon, Carlos} } @article {21131981, title = {The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules.}, journal = {Nature structural \& molecular biology}, volume = {18}, year = {2011}, month = {2011 Jan}, pages = {107-14}, abstract = {

We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the \α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the \α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy.

}, author = {Ba{\`u}, Davide and Sanyal, Amartya and Lajoie, Bryan R and Capriotti, Emidio and Byron, Meg and Lawrence, Jeanne B and Dekker, Job and Marti-Renom, Marc A} } @article {18552980, title = {Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush}, journal = {Mol Vis}, volume = {14}, year = {2008}, note = {Agudo, Marta Perez-Marin, Maria Cruz Lonngren, Ulrika Sobrado, Paloma Conesa, Ana Canovas, Isabel Salinas-Navarro, Manuel Miralles-Imperial, Jaime Hallbook, Finn Vidal-Sanz, Manuel Research Support, Non-U.S. Gov{\textquoteright}t United States Molecular vision Mol Vis. 2008 Jun 3;14:1050-63.}, pages = {1050-63}, abstract = {PURPOSE: A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT). METHODS: RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naive and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.). RESULTS: Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naive and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling. CONCLUSIONS: This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.}, keywords = {Animals Cell Death Cluster Analysis Female *Gene Expression Profiling Gene Expression Regulation *Nerve Crush Optic Nerve/*metabolism/*pathology Optic Nerve Injuries/*genetics Rats Rats, Sprague-Dawley Reproducibility of Results Retina/*metabolism/*pathology Time Factors}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18552980}, author = {Agudo, M. and Perez-Marin, M. C. and Lonngren, U. and Sobrado, P. and A. Conesa and Canovas, I. and Salinas-Navarro, M. and Miralles-Imperial, J. and Hallbook, F. and Vidal-Sanz, M.} } @article {18848557, title = {Transcriptional profiling of mRNA expression in the mouse distal colon}, journal = {Gastroenterology}, volume = {135}, number = {6}, year = {2008}, note = {Hoogerwerf, Willemijntje A Sinha, Mala Conesa, Ana Luxon, Bruce A Shahinian, Vahakn B Cornelissen, Germaine Halberg, Franz Bostwick, Jonathon Timm, John Cassone, Vincent M R21 DK074477-01A1/DK/NIDDK NIH HHS/United States Comparative Study Research Support, N.I.H., Extramural United States Gastroenterology Gastroenterology. 2008 Dec;135(6):2019-29. Epub 2008 Sep 3.}, pages = {2019-29}, abstract = {BACKGROUND \& AIMS: Intestinal epithelial cells and the myenteric plexus of the mouse gastrointestinal tract contain a circadian clock-based intrinsic time-keeping system. Because disruption of the biological clock has been associated with increased susceptibility to colon cancer and gastrointestinal symptoms, we aimed to identify rhythmically expressed genes in the mouse distal colon. METHODS: Microarray analysis was used to identify genes that were rhythmically expressed over a 24-hour light/dark cycle. The transcripts were then classified according to expression pattern, function, and association with physiologic and pathophysiologic processes of the colon. RESULTS: A circadian gene expression pattern was detected in approximately 3.7\% of distal colonic genes. A large percentage of these genes were involved in cell signaling, differentiation, and proliferation and cell death. Of all the rhythmically expressed genes in the mouse colon, approximately 7\% (64/906) have been associated with colorectal cancer formation (eg, B-cell leukemia/lymphoma-2 [Bcl2]) and 1.8\% (18/906) with various colonic functions such as motility and secretion (eg, vasoactive intestinal polypeptide, cystic fibrosis transmembrane conductance regulator). CONCLUSIONS: A subset of genes in the murine colon follows a rhythmic expression pattern. These findings may have significant implications for colonic physiology and pathophysiology.}, keywords = {Animals Blotting, Genetic, Inbred C57BL Microarray Analysis Proteins/*genetics/metabolism RNA, Messenger/biosynthesis/*genetics Reverse Transcriptase Polymerase Chain Reaction *Transcription, Western Cell Proliferation Circadian Rhythm/*genetics Colon/cytology/*metabolism Male Mice Mice}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18848557}, author = {Hoogerwerf, W. A. and Sinha, M. and A. Conesa and Luxon, B. A. and Shahinian, V. B. and Cornelissen, G. and Halberg, F. and Bostwick, J. and Timm, J. and Cassone, V. M.} } @article {18539377, title = {Transcriptome analysis provides new insights into liver changes induced in the rat upon dietary administration of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole}, journal = {Food Chem Toxicol}, volume = {46}, number = {8}, year = {2008}, note = {Stierum, Rob Conesa, Ana Heijne, Wilbert Ommen, Ben van Junker, Karin Scott, Mary P Price, Roger J Meredith, Clive Lake, Brian G Groten, John Research Support, Non-U.S. Gov{\textquoteright}t England Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Food Chem Toxicol. 2008 Aug;46(8):2616-28. Epub 2008 Apr 25.}, pages = {2616-28}, abstract = {Transcriptomics was performed to gain insight into mechanisms of food additives butylated hydroxytoluene (BHT), curcumin (CC), propyl gallate (PG), and thiabendazole (TB), additives for which interactions in the liver can not be excluded. Additives were administered in diets for 28 days to Sprague-Dawley rats and cDNA microarray experiments were performed on hepatic RNA. BHT induced changes in the expression of 10 genes, including phase I (CYP2B1/2; CYP3A9; CYP2C6) and phase II metabolism (GST mu2). The CYP2B1/2 and GST expression findings were confirmed by real time RT-PCR, western blotting, and increased GST activity towards DCNB. CC altered the expression of 12 genes. Three out of these were related to peroxisomes (phytanoyl-CoA dioxygenase, enoyl-CoA hydratase; CYP4A3). Increased cyanide insensitive palmitoyl-CoA oxidation was observed, suggesting that CC is a weak peroxisome proliferator. TB changed the expression of 12 genes, including CYP1A2. In line, CYP1A2 protein expression was increased. The expression level of five genes, associated with p53 was found to change upon TB treatment, including p53 itself, GADD45alpha, DN-7, protein kinase C beta and serum albumin. These array experiments led to the novel finding that TB is capable of inducing p53 at the protein level, at least at the highest dose levels employed above the current NOAEL. The expression of eight genes changed upon PG administration. This study shows the value of gene expression profiling in food toxicology in terms of generating novel hypotheses on the mechanisms of action of food additives in relation to pathology.}, keywords = {Animals Aryl Hydrocarbon Hydroxylases/metabolism Body Weight/drug effects Butylated Hydroxytoluene/toxicity Curcumin/toxicity Cytochrome P-450 CYP1A2/metabolism Cytochrome P-450 CYP2B1/metabolism DNA, Complementary/biosynthesis/genetics Data Interpretation, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Steroid Hydroxylases/metabolism Thiabendazole/toxicity, Statistical *Diet Food Additives/*toxicity Gene Expression/drug effects *Gene Expression Profiling Glutathione Transferase/metabolism Liver/*drug effects Male Organ Size/drug effects Oxidation-Reduction Palmitoyl Coenzyme A/metabolism Propyl Gallate/toxi}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18539377}, author = {Stierum, R. and A. Conesa and Heijne, W. and Ommen, B. and Junker, K. and Scott, M. P. and Price, R. J. and Meredith, C. and Lake, B. G. and Groten, J.} } @article {17617431, title = {Transcriptional response of Citrus aurantifolia to infection by Citrus tristeza virus}, journal = {Virology}, volume = {367}, number = {2}, year = {2007}, note = {Gandia, Monica Conesa, Ana Ancillo, Gema Gadea, Jose Forment, Javier Pallas, Vicente Flores, Ricardo Duran-Vila, Nuria Moreno, Pedro Guerri, Jose Research Support, Non-U.S. Gov{\textquoteright}t United States Virology Virology. 2007 Oct 25;367(2):298-306. Epub 2007 Jul 9.}, pages = {298-306}, abstract = {Changes in gene expression of Mexican lime plants in response to infection with a severe (T305) or a mild (T385) isolate of Citrus tristeza virus (CTV) were analyzed using a cDNA microarray containing 12,672 probes to 6875 different citrus genes. Statistically significant (P<0.01) expression changes of 334 genes were detected in response to infection with isolate T305, whereas infection with T385 induced no significant change. Induced genes included 145 without significant similarity with known sequences and 189 that were classified in seven functional categories. Genes related with response to stress and defense were the main category and included 28\% of the genes induced. Selected transcription changes detected by microarray analysis were confirmed by quantitative real-time RT-PCR. Changes detected in the transcriptome upon infecting lime with T305 may be associated either with symptom expression, with a strain-specific defense mechanism, or with a general response to stress.}, keywords = {Citrus/*genetics/physiology/virology Closterovirus/genetics/*physiology Genes, Genetic, Plant Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction *Transcription}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17617431}, author = {Gandia, M. and A. Conesa and Ancillo, G. and J. Gadea and J. Forment and Pallas, V. and Flores, R. and Duran-Vila, N. and Moreno, P. and Guerri, J.} } @article {15843018, title = {Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I)}, journal = {J Mol Biol}, volume = {348}, number = {4}, year = {2005}, note = {Gabaldon, Toni Rainey, Daphne Huynen, Martijn A Research Support, Non-U.S. Gov{\textquoteright}t England Journal of molecular biology J Mol Biol. 2005 May 13;348(4):857-70.}, pages = {857-70}, abstract = {The increasing availability of sequenced genomes enables the reconstruction of the evolutionary history of large protein complexes. Here, we trace the evolution of NADH:ubiquinone oxidoreductase (Complex I), which has increased in size, by so-called supernumary subunits, from 14 subunits in the bacteria to 30 in the plants and algae, 37 in the fungi and 46 in the mammals. Using a combination of pair-wise and profile-based sequence comparisons at the levels of proteins and the DNA of the sequenced eukaryotic genomes, combined with phylogenetic analyses to establish orthology relationships, we were able to (1) trace the origin of six of the supernumerary subunits to the alpha-proteobacterial ancestor of the mitochondria, (2) detect previously unidentified homology relations between subunits from fungi and mammals, (3) detect previously unidentified subunits in the genomes of several species and (4) document several cases of gene duplications among supernumerary subunits in the eukaryotes. One of these, a duplication of N7BM (B17.2), is particularly interesting as it has been lost from genomes that have also lost Complex I proteins, making it a candidate for a Complex I interacting protein. A parsimonious reconstruction of eukaryotic Complex I evolution shows an initial increase in size that predates the separation of plants, fungi and metazoa, followed by a gradual adding and incidental losses of subunits in the various evolutionary lineages. This evolutionary scenario is in contrast to that for Complex I in the prokaryotes, for which the combination of several separate, and previously independently functioning modules into a single complex has been proposed.}, keywords = {Amino Acid Sequence Animals Computational Biology Electron Transport Complex I/*chemistry/*genetics/metabolism Eukaryotic Cells/*enzymology *Evolution, Molecular Humans Molecular Sequence Data Photosynthesis Phylogeny Plastids/enzymology Protein Binding Protein Subunits/chemistry/genetics/metabolism Sequence Alignment Structural Homology, Protein}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15843018}, author = {Gabald{\'o}n, T. and Rainey, D. and M. A. Huynen} } @article {12824331, title = {Tools for comparative protein structure modeling and analysis}, journal = {Nucleic Acids Res}, volume = {31}, number = {13}, year = {2003}, note = {Eswar, Narayanan John, Bino Mirkovic, Nebojsa Fiser, Andras Ilyin, Valentin A Pieper, Ursula Stuart, Ashley C Marti-Renom, Marc A Madhusudhan, M S Yerkovich, Bozidar Sali, Andrej P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM 54762/GM/NIGMS NIH HHS/United States R33 CA84699/CA/NCI NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Nucleic acids research Nucleic Acids Res. 2003 Jul 1;31(13):3375-80.}, pages = {3375-80}, abstract = {The following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution.}, keywords = {Amino Acid *Software *Structural Homology, Internet Models, Molecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology, Protein Systems Integration}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12824331}, author = {Eswar, N. and John, B. and Mirkovic, N. and Fiser, A. and Ilyin, V. A. and Pieper, U. and Stuart, A. C. and M. A. Marti-Renom and Madhusudhan, M. S. and Yerkovich, B. and Sali, A.} }