bluuebunny/crossref_metadata_2025_split huggingface dataset:
Significant abundance ofcisconfigurations of mutations in diploid human genomes
Authors: Hoehe Margret R. , Herwig Ralf , Mao Qing , Peters Brock A. , Drmanac Radoje , Church George M. , Huebsch Thomas 
Published: November 2017

AbstractTo fully understand human genetic variation, one must assess the specific distribution of variants between the two chromosomal homologues of genes, and any functional units of interest, as the phase of variants can significantly impact gene function and phenotype. To this end, we have systematically analyzed 18,121 autosomal protein-coding genes in 1,092 statistically phased genomes from the 1000 Genomes Project, and an unprecedented number of 184 experimentally phased genomes from the Personal Genome Project. Here we show that mutations predicted to functionally alter the protein, and coding variants as a whole, are not randomly distributed between the two homologues of a gene, but do occur significantly more frequently incis-thantrans-configurations, withcis/transratios of ∼60:40. Significantcis-abundance was observed in virtually all individual genomes in all populations. Nearly all variable genes exhibited eithercis, ortransconfigurations of protein-altering mutations in significant excess, allowing distinction ofcis- andtrans-abundant genes. These common patterns of phase were largely constituted by a shared, global set of phase-sensitive genes. We show significant enrichment of this global set with gene sets indicating its involvement in adaptation and evolution. Moreover,cis- andtrans-abundant genes were found functionally distinguishable, and exhibited strikingly different distributional patterns of protein-altering mutations. This work establishes common patterns of phase as key characteristics of diploid human exomes and provides evidence for their potential functional significance. Thus, it highlights the importance of phase for the interpretation of protein-coding genetic variation, challenging the current conceptual and functional interpretation of autosomal genes.
USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia
Authors: Maat Henny , Jaques Jennifer , Rodríguez López Aida , Hogeling Shanna M. , Vries Marcel P. de , Gravesteijn Chantal , Brouwers-Vos Annet Z. , van der Meer Nisha , Huls Gerwin , Vellenga Edo , van den Boom Vincent , Schuringa Jan Jacob 
Published: November 2017

ABSTRACTAcute myeloid leukemia (AML) is a highly heterogeneous disease in which genetic and epigenetic changes disturb regulatory mechanisms controlling stem cell fate and maintenance. AML still remains difficult to treat, in particular in poor risk AML patients carrying TP53 mutations. Here, we identify the deubiquitinase USP7 as an integral member of non-canonical PRC1.1 and show that targeting of USP7 provides an alternative therapeutic approach for AML. USP7 inhibitors effectively induced apoptosis in (primary) AML cells, also independent of the USP7-MDM2-TP53 axis, whereby survival of both the cycling as well as quiescent populations was affected. MLL-AF9-induced leukemia was significantly delayed in vivo in human leukemia xenografts. We previously showed that non-canonical PRC1.1 is critically important for leukemic stem cell self-renewal, and that genetic knockdown of the PRC1.1 chromatin binding component KDM2B abrogated leukemia development in vitro and in vivo [1]. Here, by performing KDM2B interactome studies in TP53mut cells we identify that USP7 is an essential component of PRC1.1 and is required for its stability and function. USP7 inhibition results in disassembly of the PRC1.1 complex and consequently loss of binding to its target loci. Loss of PRC1.1 binding coincided with reduced H2AK119ub and H3K27ac levels and diminished gene transcription, whereas H3K4me3 levels remained unaffected. Our studies highlight the diverse functions of USP7 and link it to Polycomb-mediated epigenetic control. USP7 inhibition provides an efficient therapeutic approach for AML, also in the most aggressive subtypes with mutations in TP53.Key pointsUSP7 is a therapeutic target in leukemia, including poor risk TP53mut AML.USP7 is an essential component of non-canonical PRC1.1 and is required for its stability and function.
glactools: a command-line toolset for the management of genotype likelihoods and allele counts
Authors: Renaud Gabriel 
Published: November 2017

AbstractMotivationResearch projects involving population genomics routinely need to store genotyping information, population allele frequencies, combine files from different samples, query the data and export it to various formats. This is often done using bespoke in-house scripts which cannot be easily adapted to new projects and seldom constitute reproducible workflows.ResultsWe introduce glactools, a set of command-line utilities which can import data from genotypes or population-wide allele frequencies into an intermediate representation, compute various operations on it and export the data to several file formats used by population genetics software. This intermediate format can take 2 forms, one to store per-individual genotype likelihoods and a second for allele counts from one or more individuals. glactools allows users to perform operations such as intersecting datasets, merging individuals into populations, creating subsets, perform queries (e.g. return sites where a given population does not share an allele with a second one) and compute summary statistics to answer biologically relevant questions.Availabilityglactools is freely available for use under the GPL. It requires a C++ compiler and the htslib library. (https://grenaud.github.io/glactools/).Contactgabriel.reno@gmail.comSupplementary informationSupplementary methods and results are available at Bioinformatics online.
Multi-Funnel Landscape of the Fold-Switching Protein RfaH-CTD
Authors: Bernhardt Nathan A. , Hansmann Ulrich H.E. 
Published: November 2017

AbstractProteins such as the transcription factor RfaH can change biological function by switching between distinct three-dimensional folds. RfaH regulates transcription if the C-terminal domain folds into a double helix bundle, and promotes translation when this domain assumes a β-barrel form. This fold-switch has been also observed for the isolated domain, dubbed by us RfaH-CTD, and is studied here with a variant of the RET approach recently introduced by us. We use the enhanced sampling properties of this technique to map the free energy landscape of RfaH-CTD and to propose a mechanism for the conversion process.TOC Image
Selective attention modulates surface filling-in
Authors: Harrison William J. , Ayeni Alvin J. , Bex Peter J. 
Published: November 2017

AbstractThe visual system is required to compute objects from partial image structure so that figures can be segmented from their backgrounds. Although early clinical, behavioral, and modeling data suggested that such computations are performed pre-attentively, recent neurophysiological evidence suggests that surface filling-in is influenced by attention. In the present study we developed a variant of the classical Kanizsa illusory triangle to investigate whether voluntary attention modulates perceptual filling-in. Our figure consists of “pacmen” positioned at the tips of an illusory 6-point star and alternating in polarity such that two illusory triangles are implied to compete with one another within the figure. On each trial, observers were cued to attend to only one triangle, and then compared its lightness with a matching texture-defined triangle. We found that perceived lightness of the illusory shape depended on the polarity of pacmen framing the attended triangle, although the magnitude of this effect was weaker than when all inducers were of the same polarity. Our findings thus reveal that voluntary attention can influence lightness filling-in, and provide important data linking neurophysiological effects to phenomenology.
Deficiency of nucleotide excision repair explains mutational signature observed in cancer
Authors: Jager Myrthe , Blokzijl Francis , Kuijk Ewart , Bertl Johanna , Vougioukalaki Maria , Janssen Roel , Besselink Nicolle , Boymans Sander , Ligt Joep de , Pedersen Jakob Skou , Hoeijmakers Jan , Pothof Joris , Boxtel Ruben van , Cuppen Edwin 
Published: November 2017

ABSTRACTNucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Tumors deficient in NER are more sensitive to cisplatin treatment. Characterization of the mutational consequences of NER-deficiency may therefore provide important diagnostic opportunities. Here, we analyzed the somatic mutational profiles of adult stem cells (ASCs) from NER-deficientErcc1-/Δmice, using whole-genome sequencing analysis of clonally derived organoid cultures. Our results indicate that NER-deficiency increases the base substitution load in liver, but not in small intestinal ASCs, which coincides with a tissue-specific aging-pathology observed in these mice. The mutational landscape changes as a result of NER-deficiency in ASCs of both tissues and shows an increased contribution of Signature 8 mutations, which is a pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the acquired base substitutions indicates that deficiency of global-genome NER (GG-NER) is responsible for the altered mutational landscape. In line with this, we observed increased Signature 8 mutations in a GG-NER-deficient human organoid culture in whichXPCwas deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations may therefore serve as a biomarker for NER-deficiency and could improve personalized cancer treatment strategies.
Stopping Transformed Growth with Cytoskeletal Proteins: Turning a Devil into an Angel
Authors: Yang Bo , Wolfenson Haguy , Nakazawa Naotaka , Liu Shuaimin , Hu Junqiang , Sheetz Michael P. 
Published: November 2017

SummaryThe major hallmark of cancer cells is uncontrollable growth on soft matrices (transformed growth), which indicates that they have lost the ability to properly sense the rigidity of their surroundings. Recent studies of fibroblasts show that local contractions by cytoskeletal rigidity sensor units block growth on soft surfaces and their depletion causes transformed growth. The contractile system involves many cytoskeletal proteins that must be correctly assembled for proper rigidity sensing. We tested the hypothesis that cancer cells lack rigidity sensing due to their inability to assemble contractile units because of altered cytoskeletal protein levels. In four widely different cancers, there were over ten-fold fewer rigidity-sensing contractions compared with normal fibroblasts. Restoring normal levels of cytoskeletal proteins restored rigidity sensing and rigidity-dependent growth in transformed cells. Most commonly, this involved restoring balanced levels of the tropomyosins 2.1 (often depleted by miR-21) and 3 (often overexpressed). Restored cells could be transformed again by depleting other cytoskeletal proteins including myosin IIA. Thus, the depletion of rigidity sensing modules enables growth on soft surfaces and many different perturbations of cytoskeletal proteins can disrupt rigidity sensing thereby causing transformed growth of cancer cells.
The evolution of social life in family groups
Authors: Kramer Jos , Meunier Joël 
Published: November 2017

ABSTRACTFamily life forms an integral part of the life-history of species across the animal kingdom, and plays a crucial role in the evolution of animal sociality. Our current understanding of family life, however, is almost exclusively based on studies that (i) focus on parental care and associated family interactions (such as those arising from sibling rivalry and parent-offspring conflict), and (ii) investigate these phenomena in the advanced family systems of mammals, birds, and eusocial insects. Here, we argue that these historical biases have fostered the neglect of key processes shaping social life in ancestral family systems, and thus profoundly hamper our understanding of the (early) evolution of family life. Based on a comprehensive survey of the literature, we first illustrate that the strong focus on parental care in advanced social systems has deflected scrutiny of other important social processes such as sibling cooperation, parent-offspring competition and offspring assistance. We then show that accounting for these neglected processes – and their changing role in the course of evolution – could profoundly change our understanding of the evolutionary origin and subsequent consolidation of family life. Finally, we outline how this diachronic perspective on the evolution of family living could provide novel insights into general processes driving social evolution. Overall, we infer that the explicit consideration of thus far neglected facets of family life, together with their study across the whole diversity of family systems, are crucial to advance our understanding of the processes that shape the evolution of social life.
LRRTM1 underlies synaptic convergence in visual thalamus
Authors: Monavarfeshani Aboozar , Stanton Gail , Name Jonathan Van , Su Kaiwen , Mills William A. , Swilling Kenya , Kerr Alicia , Su Jianmin , Fox Michael A. 
Published: November 2017

AbstractIt has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision.
Human-specific NOTCH-like genes in a region linked to neurodevelopmental disorders affect cortical neurogenesis
Authors: Fiddes Ian T , Lodewijk Gerrald A , Mooring Meghan , Bosworth Colleen M , Ewing Adam D , Mantalas Gary L , Novak Adam M , van den Bout Anouk , Bishara Alex , Rosenkrantz Jimi L , Lorig-Roach Ryan , Field Andrew R , Haeussler Maximillian , Russo Lotte , Bhaduri Aparna , Nowakowski Tomasz J. , Pollen Alex A. , Dougherty Max L. , Nuttle Xander , Addor Marie-Claude , Zwolinski Simon , Katzman Sol , Kreigstein Arnold , Eichler Evan E. , Salama Sofie R , Jacobs Frank MJ , Haussler David 
Published: November 2017

SummaryGenetic changes causing dramatic brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and a determinant of neuronal number in the mammalian cortex. We find three paralogs of human-specific NOTCH2NL are highly expressed in radial glia cells. Functional analysis reveals different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation. NOTCH2NL genes provide the breakpoints in typical cases of 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism, and deletions with microcephaly and schizophrenia. Thus, the emergence of hominin-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger hominin neocortex accompanied by loss of genomic stability at the 1q21. 1 locus and a resulting recurrent neurodevelopmental disorder.
Heterogeneous origins of human sleep spindles in different cortical layers
Authors: Hagler Donald J. , Ulbert Istvan , Wittner Lucia , Erőss Lorand , Madsen Joseph R. , Devinsky Orrin , Doyle Werner , Fabo Daniel , Cash Sydney S. , Halgren Eric 
Published: November 2017

AbstractSleep spindles are a cardinal feature in human slow wave sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in humans by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but about half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.Significance StatementBursts of ∼14Hz oscillations, lasting about a second, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.
Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor
Authors: Hu Amelié , Rai Myriam , Donatello Simona , Pandolfo Massimo 
Published: November 2017

AbstractEpigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at theFXNlocus is the key pathogenic event in Friedreich ataxia (FRDA), a recessive neurodegenerative and systemic disease. FXN is involved in iron-sulfur (Fe-S) cluster biogenesis in mitochondria, its deficiency causes multiple Fe-S protein deficiencies, mitochondrial dysfunction and oxidative stress. Primary sensory neurons (PSNs) in the dorsal root ganglia (DRGs) are the most vulnerable cells in FRDA, whose abnormal development and degeneration leads to the onset and early progression of ataxia. We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.
LEM-3 is a midbody-tethered DNA nuclease that resolves chromatin bridges during cytokinesis
Authors: Hong Ye , Sonneville Remi , Wang Bin , Scheidt Viktor , Meier Bettina , Woglar Alexander , Demetriou Sarah , Labib Karim , Jantsch Verena , Gartner Anton 
Published: November 2017

AbstractFaithful chromosome segregation and genome maintenance requires the removal of all DNA bridges that physically link chromosomes before cells divide. Using C. elegans embryos we show that the LEM-3/Ankle1 nuclease defines a new genome integrity mechanism by processing DNA bridges right before cells divide. LEM-3 acts at the midbody, the structure where abscission occurs at the end of cytokinesis. LEM-3 localization depends on factors needed for midbody assembly, and LEM-3 accumulation is increased and prolonged when chromatin bridges are trapped at the cleavage plane. LEM-3 locally processes chromatin bridges that arise from incomplete DNA replication, unresolved recombination intermediates or the perturbance of chromosome structure. Proper LEM-3 midbody localization and function is regulated by AIR-2/Aurora B kinase. Strikingly, LEM-3 act cooperatively with the BRC-1/BRCA1 homologous recombination factor to promote genome integrity. These findings provide a molecular basis for the suspected role of the LEM-3 orthologue Ankle1 in human breast cancer.
Clust: automatic extraction of optimal co-expressed gene clusters from gene expression data
Authors: Abu-Jamous Basel , Kelly Steven 
Published: November 2017

AbstractIdentification of co-expressed gene clusters can provide evidence for genetic or physical interactions between genes. Thus, co-expression clustering is a routine step in large-scale analyses of gene expression data. We show that commonly used clustering methods produce results that substantially disagree with each other, and do not match the biological expectations of co-expressed gene clusters. Furthermore, these clusters can contain up to 50% unreliably assigned genes. Consequently, downstream analyses of these clusters (e.g. functional term enrichment analysis) suffer from high error rates. We present clust, an automated method that solves these problems by extracting clusters that match the biological expectations of co-expressed genes. Using 100 datasets from five model organisms we demonstrate that clusters generated by clust are better than those produced by other methods, both numerically and for use in functional analysis. Finally, we show that clust can simultaneously cluster multiple datasets, enabling users to leverage the large quantity of public expression data for novel comparative analysis.