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Lehner, Ben

Rik G H Lindeboom, Fran Supek, Ben Lehner
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs...
October 2016: Nature Genetics
Rob Jelier, Angela Kruger, Jim Swoger, Timo Zimmermann, Ben Lehner
Embryonic development must proceed despite both internal molecular fluctuations and external perturbations. However, mechanisms that provide robustness to mechanical perturbation remain largely uncharacterized. Here, we use light-sheet microscopy, comprehensive single-cell tracking, and targeted cell ablation to study the response of Caenorhabditis elegans embryos to external compression. Compression changes the relative positions of many cells and causes severe distortions of the embryonic axes. A large-scale movement of cells then corrects this distortion...
August 2016: Cell Systems
Athmanya K Eshwar, Ben D Tall, Jayanthi Gangiredla, Gopal R Gopinath, Isha R Patel, Stephan C F Neuhauss, Roger Stephan, Angelika Lehner
Bacteria belonging to the genus Cronobacter have been recognized as causative agents of life-threatening systemic infections primarily in premature, low-birth weight and immune-compromised neonates. Apparently not all Cronobacter species are linked to infantile infections and it has been proposed that virulence varies among strains. Whole genome comparisons and in silico analysis have proven to be powerful tools in elucidating potential virulence determinants, the presence/absence of which may explain the differential virulence behaviour of strains...
2016: PloS One
Ara Cho, Jung Eun Shim, Eiru Kim, Fran Supek, Ben Lehner, Insuk Lee
A major challenge for distinguishing cancer-causing driver mutations from inconsequential passenger mutations is the long-tail of infrequently mutated genes in cancer genomes. Here, we present and evaluate a method for prioritizing cancer genes accounting not only for mutations in individual genes but also in their neighbors in functional networks, MUFFINN (MUtations For Functional Impact on Network Neighbors). This pathway-centric method shows high sensitivity compared with gene-centric analyses of mutation data...
2016: Genome Biology
Benedetta Bolognesi, Nieves Lorenzo Gotor, Riddhiman Dhar, Davide Cirillo, Marta Baldrighi, Gian Gaetano Tartaglia, Ben Lehner
Multiple human diseases are associated with a liquid-to-solid phase transition resulting in the formation of amyloid fibers or protein aggregates. Here, we present an alternative mechanism for cellular toxicity based on a concentration-dependent liquid-liquid demixing. Analyzing proteins that are toxic when their concentration is increased in yeast reveals that they share physicochemical properties with proteins that participate in physiological liquid-liquid demixing in the cell. Increasing the concentration of one of these proteins indeed results in the formation of cytoplasmic foci with liquid properties...
June 28, 2016: Cell Reports
Philippe Julien, Belén Miñana, Pablo Baeza-Centurion, Juan Valcárcel, Ben Lehner
The properties of genotype-phenotype landscapes are crucial for understanding evolution but are not characterized for most traits. Here, we present a >95% complete local landscape for a defined molecular function-the alternative splicing of a human exon (FAS/CD95 exon 6, involved in the control of apoptosis). The landscape provides important mechanistic insights, revealing that regulatory information is dispersed throughout nearly every nucleotide in an exon, that the exon is more robust to the effects of mutations than its immediate neighbours in genotype space, and that high mutation sensitivity (evolvability) will drive the rapid divergence of alternative splicing between species unless it is constrained by selection...
May 10, 2016: Nature Communications
Adam Klosin, Ben Lehner
Development never starts from a blank slate of DNA. Therefore, in principle, plenty beyond DNA could transmit phenotypic information from one generation to the next. However, the extent to which epigenetic information is actually transmitted between generations and whether this information is modulated by the environment are questions that have only recently started to be investigated at the molecular level. Here we review molecular work on inter-generation epigenetic effects in animals and highlight some principles of epigenetic transmission...
February 2016: Current Opinion in Genetics & Development
Mirko Francesconi, Ben Lehner
Genome-wide gene expression profiling is a fast, cheap and standardised analysis that provides a high dimensional measurement of the state of a biological sample. In this review we describe computational methods that can be applied to identify and interpret sources of variance in gene expression in whole organisms, organs, tissues or single cells. This allows the identification of constituent cell types and states in complex mixtures, the reconstruction of temporal trajectories of development, differentiation and progression, and the reconstruction of spatial patterning...
October 2015: Molecular BioSystems
David van Dijk, Riddhiman Dhar, Alsu M Missarova, Lorena Espinar, William R Blevins, Ben Lehner, Lucas B Carey
Isogenic cells show a large degree of variability in growth rate, even when cultured in the same environment. Such cell-to-cell variability in growth can alter sensitivity to antibiotics, chemotherapy and environmental stress. To characterize transcriptional differences associated with this variability, we have developed a method--FitFlow--that enables the sorting of subpopulations by growth rate. The slow-growing subpopulation shows a transcriptional stress response, but, more surprisingly, these cells have reduced RNA polymerase fidelity and exhibit a DNA damage response...
August 13, 2015: Nature Communications
Solip Park, Ben Lehner
Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co-occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer...
July 2015: Molecular Systems Biology
Aaron M New, Ben Lehner
No abstract text is available yet for this article.
July 16, 2015: Nature
Ben Davies Tall, Jayanthi Gangiredla, Gopal R Gopinath, Qiongqiong Yan, Hannah R Chase, Boram Lee, Seongeun Hwang, Larisa Trach, Eunbi Park, YeonJoo Yoo, TaeJung Chung, Scott A Jackson, Isha R Patel, Venugopal Sathyamoorthy, Monica Pava-Ripoll, Michael L Kotewicz, Laurenda Carter, Carol Iversen, Franco Pagotto, Roger Stephan, Angelika Lehner, Séamus Fanning, Christopher J Grim
Cronobacter species cause infections in all age groups; however neonates are at highest risk and remain the most susceptible age group for life-threatening invasive disease. The genus contains seven species:Cronobacter sakazakii, Cronobacter malonaticus, Cronobacter turicensis, Cronobacter muytjensii, Cronobacter dublinensis, Cronobacter universalis, and Cronobacter condimenti. Despite an abundance of published genomes of these species, genomics-based epidemiology of the genus is not well established. The gene content of a diverse group of 126 unique Cronobacter and taxonomically related isolates was determined using a pan genomic-based DNA microarray as a genotyping tool and as a means to identify outbreak isolates for food safety, environmental, and clinical surveillance purposes...
2015: Frontiers in Pediatrics
Kiana Toufighi, Jae-Seong Yang, Nuno Miguel Luis, Salvador Aznar Benitah, Ben Lehner, Luis Serrano, Christina Kiel
The molecular details underlying the time-dependent assembly of protein complexes in cellular networks, such as those that occur during differentiation, are largely unexplored. Focusing on the calcium-induced differentiation of primary human keratinocytes as a model system for a major cellular reorganization process, we look at the expression of genes whose products are involved in manually-annotated protein complexes. Clustering analyses revealed only moderate co-expression of functionally related proteins during differentiation...
May 2015: PLoS Computational Biology
S E Bouyoucef, V Uusitalo, V Kamperidis, M A De Graaf, T Maaniitty, I Stenstrom, A Broersen, A J Scholte, A Saraste, J J Bax, J Knuuti, T Furuhashi, M Moroi, T Awaya, H Masai, M Minakawa, T Kunimasa, H Fukuda, K Sugi, A Berezin, A Kremzer, O F Clerc, B Kaufmann, M Possner, R Liga, J Vontobel, F Mikulicic, C Graeni, D C Benz, P A Kaufmann, R B Buechel, Mjv Ferreira, M J Cunha, A Albuquerque, D Ramos, G Costa, J Lima, M Pego, A Peix, L Cisneros, L O Cabrera, K Padron, L Rodriguez, F Heres, R Carrillo, E Mena, Y Fernandez, E D Huizing, J D Van Dijk, J A Van Dalen, J R Timmer, J P Ottervanger, C H Slump, P L Jager, S Venuraju, A Jeevarethinam, A Yerramasu, S Atwal, V S Mehta, A Lahiri, A Arjonilla Lopez, M J Calero Rueda, G Gallardo, J Fernandez-Cuadrado, D Hernandez Aceituno, J Sanchez Hernandez, H Yoshida, A Mizukami, A Matsumura, O Smettei, R Abazid, S Sayed, A Mlynarska, R Mlynarski, K Golba, M Sosnowski, S Winther, M Svensson, H S Jorgensen, K Bouchelouche, L C Gormsen, N R Holm, H E Botker, P R Ivarsen, M Bottcher, C M Cortes, E N Aramayo G, M Daicz, J F Casuscelli, E D Alaguibe, A Neira Sepulveda, M Cerda, G E Ganum, M Embon, J Vigne, B Enilorac, A Lebasnier, L Valancogne, D Peyronnet, A Manrique, D Agostini, D Menendez, S Rajpal, C Kocherla, M Acharya, P Reddy, I Sazonova, Yun Ilushenkova, R E Batalov, Y V Rogovskaya, Y B Lishmanov, S V Popov, N V Varlamova, S Prado Diaz, C Jimenez Rubio, D Gemma, E Refoyo Salicio, S C Valbuena Lopez, M Moreno Yanguela, M Torres, M Fernandez-Velilla, J L Lopez-Sendon, G Guzman Martinez, A Puente, S Rosales, C Martinez, M Cabada, G M Melendez, R Ferreira, A Gonzaga, J Santos, S Vijayan, Smg Smith, M Smith, R Muthusamy, Y Takeishi, M Oikawa, J L Goral, J Napoli, O R Montana, A C Damico, M C Quiroz, A E Damico, P J Forcada, J M Schmidberg, N E Zucchiatti, D B Olivieri, A Jeevarethinam, S Venuraju, A Dumo, S Ruano, R Rakhit, J Davar, D Nair, M Cohen, D Darko, A Lahiri, S Yokota, J P Ottervanger, Ahe Maas, M Mouden, J R Timmer, S Knollema, P L Jager, S M Sanja Mazic, B Lazovic, Mdj Marina Djelic, J S Jelena Suzic Lazic, T A Tijana Acimovic, M D Milica Deleva, Z H Vesnina, N Zafrir, T Bental, I Mats, A Solodky, A Gutstein, Y Hasid, D Belzer, R Kornowski, Rim Ben Said, N Ben Mansour, H Ibn Haj Amor, C Chourabi, A Hagui, W Fehri, H Hawala, Z Shugushev, A Patrikeev, D Maximkin, A Chepurnoy, V Kallianpur, A Mambetov, G Dokshokov, A Teresinska, O Wozniak, A Maciag, J Wnuk, A Dabrowski, A Czerwiec, J Jezierski, K Biernacka, J Robinson, J Prosser, Gsm Cheung, S Allan, G Mcmaster, S Reid, A Tarbuck, W Martin, R C Queiroz, A Falcao, McP Giorgi, R Imada, S A Nogueira, W A Chalela, R Kalil Filho, W A Meneghetti, V V Matveev, A S Bubyenov, V I Podzolkov, Z Shugushev, D Maximkin, A Chepurnoy, V Baranovich, A Faibushevich, Y Kolzhecova, O Volkova, V Kallianpur, A Peix, L O Cabrera, K Padron, L Rodriguez, J Fernandez, G Lopez, E Mena, Y Fernandez, M Dondi, D Paez, Cjt Butcher, E Reyes, M B Al-Housni, R Green, H Santiago, F Ghiotto, S Hinton-Taylor, A Pottle, M Mason, S R Underwood, I Casans Tormo, R Diaz-Exposito, E Plancha-Burguera, K Elsaban, Hijji Alsakhri, K Yoshinaga, N Ochi, Y Tomiyama, C Katoh, M Inoue, M Nishida, E Suzuki, O Manabe, Y M Ito, N Tamaki, A Tahilyani, Fahim Jafary, H H Ho Hee Hwa, S Ozdemir, B Kirilmaz, A Barutcu, Y Z Tan, F Celik, S Sakgoz, M Cabada Gamboa, A Puente Barragan, N Morales Vitorino, M A Medina Servin, C Hindorf, S Akil, F Hedeer, J Jogi, H Engblom, V D Martire, E R Pis Diez, M V Martire, D O Portillo, C M Hoff, A Balche, J Majgaard, L P Tolbod, H J Harms, K Bouchelouche, J Soerensen, J Froekiaer, L C Gormsen, F Nudi, G Neri, E Procaccini, A Pinto, M Vetere, G Biondi-Zoccai, A Falcao, W A Chalela, McP Giorgi, R Imada, J Soares, R Do Val, M A Oliveira, R Kalil Filho, J C Meneghetti, Y Tekabe, T Anthony, Q Li, A M Schmidt, L Johnson, M Groenman, M Tarkia, M Kakela, P Halonen, T Kiviniemi, M Pietila, S Yla-Herttuala, J Knuuti, A Roivainen, A Saraste, S Nekolla, S Swirzek, T Higuchi, S Reder, S Schachoff, M Bschorner, I Laitinen, S Robinson, B Yousefi, M Schwaiger, T Kero, L Lindsjo, G Antoni, P Westermark, K Carlson, G Wikstrom, J Sorensen, M Lubberink, F Rouzet, T Cognet, K Guedj, M Morvan, F El Shoukr, L Louedec, C Choqueux, A Nicoletti, D Le Guludec, A Jimenez-Heffernan, F Munoz-Beamud, E Sanchez De Mora, C Borrachero, C Salgado, C Ramos-Font, J Lopez-Martin, M L Hidalgo, R Lopez-Aguilar, E Soriano, A Okizaki, M Nakayama, S Ishitoya, J Sato, K Takahashi, I Burchert, F Caobelli, T Wollenweber, M Nierada, J Fulsche, C Dieckmann, F M Bengel, S Shuaib, D Mahlum, S Port, D Gemma, E Refoyo, E Cuesta, G Guzman, T Lopez, S Valbuena, M Fernandez-Velilla, S Del Prado, M Moreno, J L Lopez-Sendon, M Harbinson, L Donnelly, A J Einstein, L L Johnson, A J Deluca, A C Kontak, D W Groves, J Stant, T Pozniakoff, B Cheng, L E Rabbani, S Bokhari, F Caobelli, C Schuetze, M Nierada, J Fulsche, C Dieckmann, F M Bengel, S Aguade-Bruix, M N Pizzi, G Romero-Farina, M Terricabras, D Villasboas, J Castell-Conesa, J Candell-Riera, S Brunner, L Gross, A Todica, S Lehner, A Di Palo, A Niccoli Asabella, C Magarelli, A Notaristefano, C Ferrari, G Rubini, A Sellem, S Melki, W Elajmi, H Hammami, M C Ziadi, J Montero, J L Ameriso, R L Villavicencio, T F Benito Gonzalez, A Mayorga Bajo, R Gutierrez Caro, M Rodriguez Santamarta, L Alvarez Roy, E Martinez Paz, C Barinaga Martin, J Martin Fernandez, D Alonso Rodriguez, I Iglesias Garriz, D Gemma, E Refoyo, E Cuesta, G Guzman, S Valbuena, S Rosillo, S Del Prado, M Torres, M Moreno, J L Lopez-Sendon, S Taleb, G Cherkaoui Salhi, Y Regbaoui, M Ait Idir, A Guensi, A Puente, S Rosales, C Martinez, M Cabada, T F Benito Gonzalez, A Mayorga Bajo, R Gutierrez Caro, M Rodriguez Santamarta, L Alvarez Roy, E Martinez Paz, C E Martin Lopez, M Castano Ruiz, J Martin Fernandez, I Iglesias Garriz
No abstract text is available yet for this article.
May 2015: European Heart Journal Cardiovascular Imaging
Fran Supek, Ben Lehner
Cancer genome sequencing has revealed considerable variation in somatic mutation rates across the human genome, with mutation rates elevated in heterochromatic late replicating regions and reduced in early replicating euchromatin. Multiple mechanisms have been suggested to underlie this, but the actual cause is unknown. Here we identify variable DNA mismatch repair (MMR) as the basis of this variation. Analysing ∼17 million single-nucleotide variants from the genomes of 652 tumours, we show that regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression...
May 7, 2015: Nature
Angela V Krüger, Rob Jelier, Oleh Dzyubachyk, Timo Zimmerman, Erik Meijering, Ben Lehner
Chromatin regulators are widely expressed proteins with diverse roles in gene expression, nuclear organization, cell cycle regulation, pluripotency, physiology and development, and are frequently mutated in human diseases such as cancer. Their inhibition often results in pleiotropic effects that are difficult to study using conventional approaches. We have developed a semi-automated nuclear tracking algorithm to quantify the divisions, movements and positions of all nuclei during the early development of Caenorhabditis elegans and have used it to systematically study the effects of inhibiting chromatin regulators...
February 15, 2015: Developmental Biology
Sergio Barberán-Soler, Laura Fontrodona, Anna Ribó, Ayelet T Lamm, Camilla Iannone, Julián Cerón, Ben Lehner, Juan Valcárcel
Many eukaryotic genes contain embedded antisense transcripts and repetitive sequences of unknown function. We report that male germline-specific expression of an antisense transcript contained in an intron of C. elegans Target of Rapamycin (TOR, let-363) is associated with (1) accumulation of endo-small interfering RNAs (siRNAs) against an embedded Helitron transposon and (2) activation of an alternative 3' splice site of TOR. The germline-specific Argonaute proteins PRG-1 and CSR-1, which participate in self/nonself RNA recognition, antagonistically regulate the generation of these endo-siRNAs, TOR mRNA levels, and 3' splice-site selection...
September 25, 2014: Cell Reports
Fran Supek, Ben Lehner, Petra Hajkova, Tobias Warnecke
It has long been known that methylated cytosines deaminate at higher rates than unmodified cytosines and constitute mutational hotspots in mammalian genomes. The repertoire of naturally occurring cytosine modifications, however, extends beyond 5-methylcytosine to include its oxidation derivatives, notably 5-hydroxymethylcytosine. The effects of these modifications on sequence evolution are unknown. Here, we combine base-resolution maps of methyl- and hydroxymethylcytosine in human and mouse with population genomic, divergence and somatic mutation data to show that hydroxymethylated and methylated cytosines show distinct patterns of variation and evolution...
September 2014: PLoS Genetics
Jennifer I Semple, Ben Lehner
The use of drugs and drug resistance genes is a powerful method to select for the presence of a transgene. Unlike methods that require the complementation of a genetic mutation, this system can be used on any genetic background. Drug selection does not require extensive manipulation or costly equipment, yet it is very rapid and can achieve extremely high efficiency, selecting a small number of transgenic worms from among millions of non-transgenic worms. Introducing integrated transgenes into Caenorhabditis elegans by microparticle bombardment represents just such a challenge...
August 1, 2014: Methods: a Companion to Methods in Enzymology
Fran Supek, Belén Miñana, Juan Valcárcel, Toni Gabaldón, Ben Lehner
Synonymous mutations change the sequence of a gene without directly altering the sequence of the encoded protein. Here, we present evidence that these "silent" mutations frequently contribute to human cancer. Selection on synonymous mutations in oncogenes is cancer-type specific, and although the functional consequences of cancer-associated synonymous mutations may be diverse, they recurrently alter exonic motifs that regulate splicing and are associated with changes in oncogene splicing in tumors. The p53 tumor suppressor (TP53) also has recurrent synonymous mutations, but, in contrast to those in oncogenes, these are adjacent to splice sites and inactivate them...
March 13, 2014: Cell
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