bluuebunny/crossref_metadata_2025_split huggingface dataset:
Building a schizophrenia genetic network: Transcription Factor 4 regulates genes involved in neuronal development and schizophrenia risk
Authors: Xia Hanzhang , Jahr Fay M. , Kim Nak-Kyeong , Xie Linying , Shabalin Andrey A. , Bryois Julien , Sweet Douglas H. , Kronfol Mohamad M. , Palasuberniam Preetha , McRae MaryPeace , Riley Brien P. , Sullivan Patrick F. , van den Oord Edwin J. , McClay Joseph L. 
Published: November 2017

ABSTRACTThe transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SZ association findings. We identified 11,322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes down-regulated in TCF4 siRNA knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among 1) Gene Ontology categories such as axon/neuronal development, 2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex, and 3) genes down-regulated in post-mortem brain tissue from SZ patients (OR=2.8, permutation p<4x10−5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA binding proteins such as FOXP2 and the SZ-associated EP300. TCF4 binding sites were modestly enriched among SZ risk loci from the Psychiatric Genomic Consortium (OR=1.56, p=0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point towards functional interactions with potential relevance for SZ.
Electrical stimulation in hippocampus and entorhinal cortex impairs spatial and temporal memory
Authors: Goyal Abhinav , Miller Jonathan , Watrous Andrew J. , Lee Sang Ah , Coffey Tom , Sperling Michael R. , Sharan Ashwini , Worrell Gregory , Berry Brent , Lega Bradley , Jobst Barbara , Davis Kathryn A. , Inman Cory , Sheth Sameer A. , Wanda Paul A. , Ezzyat Youssef , Das Sandhitsu R. , Stein Joel , Gorniak Richard , Jacobs Joshua 
Published: November 2017

AbstractThe medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects’ abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.Significance StatementNumerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.
Identifying the phenotypic effect of rare variants by including between-pedigree coancestry in variance components linkage analysis
Authors: Hicks J.E. , Province M. A. 
Published: November 2017

AbstractThe contribution of rare variants to disease burden has become an important focus in genetic epidemiology. These effects are difficult to detect in population-based datasets, and as a result, interest in family-based study designs has resurfaced. Linkage analysis tools will need to be updated to accommodate the scale of data generated by modern genotyping and sequencing technologies.In conventional linkage analysis individuals in different pedigrees are assumed to be independent of each other. However, cryptic relatedness is often present in populations and haplotypes that harbor rare variants may be shared between pedigrees as well as within them.With millions of polymorphisms, Identity-by-descent (IBD) states across the genome can now be inferred without use of pedigree information. This is done by identifying long runs of identical-by-state genotypes which are unlikely to arise without IBD. Previously, IBD had to be estimated in pedigrees from recombination events in a sparse set of markers.We present a method for variance-components linkage that can incorporate large number of markers and allows for between-pedigree relatedness. We replace the IBD matrix generated from pedigree-based analysis with one generated from a genotype-based method. All pedigrees in a dataset are considered jointly, allowing between-pedigree IBD to be included in the model.In simulated data, we show that power is increased in the scenario when there is a haplotype shared IBD between members of different pedigrees. If there is no between-pedigree IBD, the analysis reduces to conventional variance-components analysis. By determining IBD states by long runs of dense IBS genotypes, linkage signals can be determined from their physical position, allowing more precise localization.
Control of Genetic Parasites Mediated Through Nucleoporin Evolution
Authors: Rowley Paul A. , Patterson Kurt , Sandmeyer Suzanne B. , Sawyer Sara L. 
Published: November 2017

AbstractYeasts serve as long-term hosts to several types of genetic parasites. Few studies have addressed the evolutionary trajectory of yeast genes that control the stable co-existence of these parasites with their host cell. InSaccharomycesyeasts, the retrovirus-like Ty retrotransposons must access the nucleus. We show that several genes encoding components of the yeast nuclear pore complex have experienced natural selection for substitutions that change the encoded protein sequence. By replacing theseS. cerevisiaegenes with orthologs from otherSaccharomycesspecies, we discovered that natural sequence changes have affected the control of Ty retrotransposons. Specifically, changing the genetic sequence ofNUP84orNUP82to what is found in otherSaccharomycesspecies alters the retrotransposition ofS. cerevisiaeTy1 and Ty3, respectively. Importantly, all tested housekeeping functions ofNUP84andNUP82remained equivalent across species. The nuclear pore complex is the gatekeeper of the nucleus. It appears that nucleoporins are adapting to modulate the control of genetic parasites which access the nucleus, which is achieved despite the strict constraints imposed by host nuclear pore complex function.
Panaconda: Application of pan-synteny graph models to genome content analysis
Authors: Warren Andrew S. , Davis James J. , Wattam Alice R. , Machi Dustin , Setubal João C. , Heath Lenwood S. 
Published: November 2017

AbstractMotivationWhole-genome alignment and pan-genome analysis are useful tools in understanding the similarities and differences of many genomes in an evolutionary context. Here we introduce the concept of pan-synteny graphs, an analysis method that combines elements of both to represent conservation and change of multiple prokaryotic genomes at an architectural level. Pan-synteny graphs represent a reference free approach for the comparison of many genomes and allows for the identification of synteny, insertion, deletion, replacement, inversion, recombination, missed assembly joins, evolutionary hotspots, and reference based scaffolding.ResultsWe present an algorithm for creating whole genome multiple sequence comparisons and a model for representing the similarities and differences among sequences as a graph of syntenic gene families. As part of the pan-synteny graph creation, we first create a de Bruijn graph. Instead of the alphabet of nucleotides commonly used in genome assembly, we use an alphabet of gene families. This de Bruijn graph is then processed to create the pan-synteny graph. Our approach is novel in that it explicitly controls how regions from the same sequence and genome are aligned and generates a graph in which all sequences are fully represented as paths. This method harnesses previous computation involved in protein family calculation to speed up the creation of whole genome alignment for many genomes. We provide the software suite Panaconda, for the calculation of pan-synteny graphs given annotation input, and an implementation of methods for their layout and visualization.AvailabilityPanaconda is available athttps://github.com/aswarren/pangenome_graphsand datasets used in examples are available athttps://github.com/aswarren/pangenome_examplesContactAndrew Warrenanwarren@vt.edu
Preparation for mental effort recruits Dorsolateral Prefrontal Cortex: an fNIRS investigation
Authors: Vassena Eliana , Gerrits Robin , Demanet Jelle , Verguts Tom , Siugzdaite Roma 
Published: November 2017

AbstractPreparing for a mentally demanding task calls upon cognitive and motivational resources. The underlying neural implementation of these mechanisms is receiving growing attention, given the implications for professional, social, and medical contexts. While several fMRI studies converge in assigning a crucial role to a cortico-subcortical network including Anterior Cigulate Cortex (ACC) and striatum, the involvement of Dorsolateral Prefrontal Cortex (DLPFC) during mental effort anticipation has yet to be replicated. This study was designed to target DLPFC contribution using functional Near Infrared Spectroscopy (fNIRS), as a more cost-effective tool measuring cortical hemodynamics. We adapted a validated mental effort task, where participants performed easy and difficult mental calculation, while measuring DLPFC activity during the anticipation phase. As hypothesized, DLPFC activity increased during preparation for a hard task as compared to an easy task. Besides replicating a previous fMRI study, these results establish fNIRS as an effective tool to investigate cortical contributions to preparation for effortful behavior. This is especially useful if one requires testing large samples (e.g., to target individual differences), populations with contraindication for functional MRI (e.g., infants or patients with metal implants), or subjects in more naturalistic environments (e.g., work or sport).
Formation and disassembly of a contractile actomyosin network mediates content release from large secretory vesicles
Authors: Segal Dagan , Zaritsky Assaf , Schejter Eyal D. , Shilo Ben-Zion 
Published: November 2017

AbstractSecretion of adhesive glycoproteins to the lumen ofDrosophilalarval salivary glands is carried out by contraction of an actomyosin network that is assembled around large secretory vesicles, following their fusion to the apical membranes. We have identified a cycle of actin coat nucleation and disassembly that is independent of myosin. Recruitment of active Rho1 to the fused vesicle triggers activation of the formin Diaphanous and nucleation of linear actin. This, in turn, leads to actin-dependent localization of a RhoGAP protein that locally shuts off Rho1, promoting disassembly of the actin coat. Recruitment of the branched actin nucleation machinery is also required for effective Rho1 inactivation. Interestingly, different blocks to actin coat disassembly arrested vesicle contraction, indicating that actin turnover is an integral part of the actomyosin contraction cycle. The capacity of F-actin to trigger a negative feedback on its own production may be utilized in a variety of scenarios, to coordinate a succession of morphogenetic events or maintain homeostasis.SummaryThis work identified a cycle of actin assembly and disassembly in large secretory vesicles ofDrosophilasalivary glands. Actin disassembly is triggered by actin-dependent recruitment of a RhoGAP protein, and is essential for the contractility of the vesicle leading to content release to the lumen.
Multiplexed temporally focused light shaping for high-resolution multi-cell targeting
Authors: Accanto Nicolò , Tanese Dimitrii , Ronzitti Emiliano , Molinier Clément , Newman Zachary L. , Wyart Claire , Isacoff Ehud , Papagiakoumou Eirini , Emiliani Valentina 
Published: November 2017

AbstractPatterning light at the single-cell level over multiple neurons in the brain is crucial for optogenetic photostimulation that can recapitulate natural activity patterns and, thereby, determine the role of specific components of brain activity in behavior. To this end we have developed a method for projecting three-dimensional, 2-photon excitation patterns that are confined to many individual neurons. The new versatile optical scheme generates multiple extended excitation spots in a large volume with micrometric lateral and axial resolution. Two-dimensional temporally focused shapes are multiplexed several times over selected positions, thanks to the precise spatial phase modulation of the pulsed beam. This permits, under multiple configurations, the generation of tens of axially confined spots in an extended volume, spanning a range in depth of up to 500 μm. We demonstrate the potential of the approach by performing multi-cell volumetric excitation of photoactivatable GCaMP in the central nervous system of Drosophila larvae, a challenging structure with densely arrayed and small diameter neurons, and by photoconverting the fluorescent protein Kaede in zebrafish larvae. Our technique paves the way for the optogenetic manipulation of a large number of neurons in intact circuits.
Differential polarization of cortical pyramidal neuron dendrites through weak extracellular fields
Authors: Aspart Florian , Remme Michiel W.H. , Obermayer Klaus 
Published: November 2017

AbstractThe rise of transcranial current stimulation (tCS) techniques have sparked an increasing interest in the effects of weak extracellular electric fields on neural activity. These fields modulate ongoing neural activity through polarization of the neuronal membrane. While the somatic polarization has been investigated experimentally, the frequency-dependent polarization of the dendritic trees in the presence of alternating (AC) fields has received little attention yet. Using a biophysically detailed model with experimentally constrained active conductances, we analyze the subthreshold response of cortical pyramidal cells to weak AC fields, as induced during tCS. We observe a strong frequency resonance around 10-20 Hz in the apical dendrites sensitivity to polarize in response to electric fields but not in the basal dendrites nor the soma. To disentangle the relative roles of the cell morphology and active and passive membrane properties in this resonance, we perform a thorough analysis using simplified models, e.g. a passive pyramidal neuron model, simple passive cables and reconstructed cell model with simplified ion channels. We attribute the origin of the resonance in the apical dendrites to (i) a locally increased sensitivity due to the morphology and to (ii) the high density of h-type channels. Our systematic study provides an improved understanding of the subthreshold response of cortical cells to weak electric fields and, importantly, allows for an improved design of tCS stimuli.
The microbiome and resistome of hospital sewage during passage through the community sewer system
Authors: Buelow Elena , Bayjanov Jumamurat R. , Willems Rob J.L. , Bonten Marc J.M. , Schmitt Heike , van Schaik Willem 
Published: November 2017

AbstractEffluents from wastewater treatment plants (WWTPs) have been proposed to act as point sources of antibiotic-resistant bacteria (ARB) and antimicrobial resistance genes (ARGs) in the environment. Hospital sewage may contribute to the spread of ARB and ARGs as it contains the feces and urine of hospitalized patients, who are more frequently colonized with multi-drug resistant bacteria than the general population. However, whether hospital sewage noticeably contributes to the quantity and diversity of ARGs in the general sewerage system has not yet been determined.Here, we employed culture-independent techniques, namely 16S rRNA and nanolitre-scale quantitative PCRs, to describe the role of hospital effluent as a point source of ARGs in the sewer system, through comparing microbiota composition and levels of ARGs in hospital sewage with WWTP influent, WWTP effluent and the surface water in which the effluent is released.Compared to other sample sites, hospital sewage was richest in human-associated bacteria and contained the highest relative levels of ARGs. Yet, the abundance of ARGs was comparable in WWTPs with and without hospital wastewater, suggesting that hospitals do not contribute to the spread of ARGs in countries with a functioning sewerage system.
Transcriptional profiling reveals extraordinary diversity among skeletal muscle tissues
Authors: Terry Erin E , Zhang Xiping , Hoffmann Christy , Hughes Laura D , Lewis Scott A , Li Jiajia , Riley Lance , Lahens Nicholas F , Gong Ming , Andrade Francisco , Esser Karyn A , Hughes Michael E. 
Published: November 2017

AbstractSkeletal muscle comprises a family of diverse tissues with highly specialized morphology, function, and metabolism. Many acquired diseases – including HIV, COPD, cancer cachexia, critical illness myopathy, and sepsis – affect specific muscles while sparing others. Even monogenic muscular dystrophies tend to selectively affect certain muscle groups, despite their causative genetic mutations being present in all tissues. These observations suggest that factors intrinsic to muscle tissues influence their susceptibility to various disease mechanisms. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNA sequencing (RNA-seq) to profile global mRNA expression in a wide array of skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. This diversity is only partly explained by fiber type composition and developmental history, suggesting that specialized transcriptional profiles establish the functional identity of muscle tissues. We find conservation in the transcriptional profiles across species as well as between males and females, indicating that these data may be useful in predicting gene expression in related species. Notably, thousands of differentially expressed genes in skeletal muscle are associated with human disease, and hundreds of these genes encode targets of drugs on the market today. We detect mRNA expression of hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. In addition to demonstrating the intrinsic diversity of skeletal muscles, these data provide a resource for generating testable hypotheses regarding the mechanisms that establish differential disease susceptibility in muscle.Significance StatementSkeletal muscles are a diverse family of tissues with a common contractile function but divergent morphology, development, and metabolism. One need only reflect on the different functions of limb muscles and the diaphragm to realize the highly specialized nature of these tissues. Nevertheless, every study of global gene expression has analyzed at most one representative skeletal muscle. Here we measure gene expression from 11 different skeletal muscles in mice and rats. We show that there is no such thing as a representative skeletal muscle, as gene expression profiles vary widely among the tissues analyzed. These data are an important resource for pharmacologists, tissue engineers, and investigators studying the mechanisms of cellular specialization.
AptaBlocks: Accelerating the Design of RNA-based Drug Delivery Systems
Authors: Wang Yijie , Hoinka Jan , Swiderski Piotr , Przytycka Teresa M 
Published: November 2017

AbstractSynthetic RNA molecules are increasingly used to alter cellular functions. These successful applications indicate that RNA-based therapeutics might be able to target currently undruggable genes. However, to achieve this promise, an effective method for delivering therapeutic RNAs into specific cells is required. Recently, RNA aptamers emerged as promising delivery agents due to their ability of binding specific cell receptors. Crucially, these aptamers can frequently be internalized into the cells expressing these receptors on their surfaces. This property is leveraged in aptamer based drug delivery systems by combining such receptor-specific aptamers with a therapeutic “cargo” such that the aptamer facilitates the internalization of the cargo into the cell. The advancement of this technology however is contingent on an efficient method to produce stable molecular complexes that include specific aptamers and cargoes. A recently proposed experimental procedure for obtaining such complexes relies on conjugating the aptamer and the cargo with complementary RNA strands so that when such modified molecules are incubated together, the complementary RNA strands hybridize to form a double-stranded “sticky bridge” connecting the aptamer with its cargo. However, designing appropriate sticky bridge sequences guaranteeing the formation and stability of the complex while simultaneously not interfering with the aptamer or the cargo as well as not causing spurious aggregation of the molecules during incubation has proven highly challenging. To fill this gap, we developed AptaBlocks, a computational method to design sticky bridges to connect RNA-based molecules (blocks). AptaBlocks relies on a biophysically inspired theoretical model capturing the complex objectives of the design and yet is simple enough to allow for efficient parameter estimation. Given this model, the sticky bridge sequence is optimized using a Monte Carlo algorithm based on heat-bath transitions. The effectiveness of the algorithm has been verified computationally and experimentally. AptaBlocks can be used in variety of experimental settings and its preliminary version has already been leveraged to design an aptamer based delivery system for a cytotoxic drug targeting Pancreatic ductal adenocarcinoma cells. It is thus expected that AptaBlocks will play a substantial role in accelerating RNA-based drug delivery design.AptaBlocks is available at https://github.com/wyjhxq/AptaBlocks.