bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping
Authors: Kikuchi Masataka , Hara Norikazu , Hasegawa Mai , Miyashita Akinori , Kuwano Ryozo , Ikeuchi Takeshi , Nakaya Akihiro 
Published: September 2018

AbstractBackground:Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer’s disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops.Results:We examined enhancer locations that were predicted in 127 human tissues or cell types, including ten brain tissues, and identified chromatin-chromatin interactions by Hi-C experiments. We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes.Conclusion:Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.
Directed Nucleosome Sliding in SV40 Minichromosomes During the Formation of the Virus Particle Exposes DNA Sequences Required for Early Transcription
Authors: Kumar Meera Ajeet , Kasti Karine , Balakrishnan Lata , Milavetz Barry 
Published: September 2018

AbstractSimian Virus 40 (SV40) exists as chromatin throughout its life cycle, and undergoes typical epigenetic regulation mediated by changes in nucleosome location and associated histone modifications. In order to investigate the role of epigenetic regulation during the encapsidation of late stage minichromosomes into virions, we have mapped the location of nucleosomes containing acetylated or methylated lysines in the histone tails of H3 and H4 present in the chromatin from 48-hour post-infection minichromosomes and disrupted virions. In minichromosomes obtained late in infection, nucleosomes were found carrying various histone modifications primarily in the regulatory region with a major nucleosome located within the enhancer and other nucleosomes at the early and late transcriptional start sites. The nucleosome found in the enhancer would be expected to repress early transcription by blocking access to part of the SP1 binding sites and the left side of the enhancer in late stage minichromosomes while also allowing late transcription. In chromatin from virions, the principal nucleosome located in the enhancer was shifted ~ 70 bases in the late direction from what was found in minichromosomes and the level of modified histones was increased throughout the genome. The shifting of the enhancer-associated nucleosome to the late side would effectively serve as a switch to relieve the repression of early transcription found in late minichromosomes while likely also repressing late transcription by blocking access to necessary regulatory sequences. This epigenetic switch appeared to occur during the final stage of virion formation.
High-Throughput ChIPmentation: freely scalable, single day ChIPseq data generation from very low cell-numbers
Authors: Gustafsson Charlotte , Paepe Ayla De , Schmidl Christian , Månsson Robert 
Published: September 2018

AbstractChromatin immunoprecipitation coupled to sequencing (ChIP-seq) is widely used to map histone modifications and transcription factor binding on a genome-wide level. Here, we present high-throughput ChIPmentation (HT-ChIPmentation) that eliminates the need for DNA purification prior to library amplification and reduces reverse-crosslinking time from hours to minutes. The resulting workflow is easily established, extremely rapid, and compatible with requirements for very low numbers of FACS sorted cells, high-throughput applications and single day data generation.
Towards inferring causal gene regulatory networks from single cell expression Measurements
Authors: Qiu Xiaojie , Rahimzamani Arman , Wang Li , Mao Qi , Durham Timothy , McFaline-Figueroa José L , Saunders Lauren , Trapnell Cole , Kannan Sreeram 
Published: September 2018

AbstractSingle-cell transcriptome sequencing now routinely samples thousands of cells, potentially providing enough data to reconstruct causal gene regulatory networks from observational data. Here, we present Scribe, a toolkit for detecting and visualizing causal regulatory interactions between genes and explore the potential for single-cell experiments to power network reconstruction. Scribe employs Restricted Directed Information to determine causality by estimating the strength of information transferred from a potential regulator to its downstream target. We apply Scribe and other leading approaches for causal network reconstruction to several types of single-cell measurements and show that there is a dramatic drop in performance for "pseudotime” ordered single-cell data compared to true time series data. We demonstrate that performing causal inference requires temporal coupling between measurements. We show that methods such as “RNA velocity” restore some degree of coupling through an analysis of chromaffin cell fate commitment. These analyses therefore highlight an important shortcoming in experimental and computational methods for analyzing gene regulation at single-cell resolution and point the way towards overcoming it.
Verifying, Challenging, and Discovering New Synapses among Fully EM-Reconstructed Neurons in the Leech Ganglion
Authors: Pipkin Jason E. , Bushong Eric A. , Ellisman Mark H. , Kristan William B. 
Published: September 2018

AbstractNeural circuits underpin the production of animal behavior, largely based upon the precise pattern of synaptic connectivity among the neurons involved. For large numbers of neurons, determining such “connectomes” by direct physiological means is difficult, as physiological accessibility is ultimately required to verify and characterize the function of synapses. We collected a volume of images spanning an entire ganglion of the juvenile leech nervous system via serial blockface electron microscopy (SBEM). We validated this approach by reconstructing a well-characterized circuit of motor neurons involved in the swimming behavior of the leech by locating the synapses among them. We confirm that there are multiple synaptic contacts between connected pairs of neurons in the leech, and that these synapses are widely distributed across the region of neuropil in which the neurons’ arbors overlap. We verified the anatomical existence of connections that had been described physiologically among longitudinal muscle motor neurons. We also found that some physiological connections were not present anatomically. We then drew upon the SBEM dataset to design additional physiological experiments. We reconstructed an uncharacterized neuron and one of its presynaptic partners identified from the SBEM dataset. We subsequently interrogated this cell pair via intracellular electrophysiology in an adult ganglion and found that the anatomically-discovered synapse was also functional physiologically. Our findings demonstrate the value of combining a connectomics approach with electrophysiology in the leech nervous system.Significance StatementThe function of any nervous system depends on the arrangement of its component neurons into circuits. Determining this precise pattern requires an account of which neurons are linked by synapses, and where. Here we use serial electron microscopy to confirm, challenge, and discover synapses in the neuropil of one ganglion from a juvenile leech. Relying on the homology of the ganglion from animal to animal, we demonstrate that we can identify synapses we knew existed from previous physiological work, and that we can confirm a new anatomically-discovered synapse by subsequently recording from the same neurons in a different animal. Here we show how analyses of anatomical detail and physiologically determined interactions complementarily yield insight into how neural circuits produce behavior.
AIM-SNPtag: a computationally efficient approach for developing ancestry-informative SNP panels
Authors: Zhao Shilei , Shi Cheng-Min , Ma Liang , Liu Qi , Liu Yongming , Wu Fuquan , Chi Lianjiang , Chen Hua 
Published: September 2018

ABSTRACTInferring an individual’s ancestry or group membership using a small set of highly informative genetic markers is very useful in forensic and medical genetics. However, given the huge amount of SNP data available from a diverse of populations, it is challenging to develop informative panels by exhaustively searching for all possible SNP combination. In this study, we formulate it as an algorithm problem of selecting an optimal set of SNPs that maximizes the inference accuracy while minimizes the set size. Built on this conception, we develop a computational approach that is capable of constructing ancestry informative panels from multi-population genome-wide SNP data efficiently. We evaluate the performance of the method by comparing the panel size and membership inference accuracy of the constructed SNP panels to panels selected through empirical procedures in former studies. For the membership inference of population groups including Asian, European, African, East Asian and Southeast Asian, a 36-SNP panel developed by our approach has an overall accuracy of 99.07%, and a 21-SNP subset of the panel has an overall accuracy of 95.36%. In comparison, the existing panel requires 74 SNPs to achieve an accuracy of 94.14% on the same set of population groups. We further apply the method to four subpopulations within Europe (Finnish, British, Spain and Italia); a 175-SNP panel can discriminate individuals of those European subpopulations with an accuracy of 99.36%, of which a 68-SNP subset can achieve an accuracy of 95.07%. We expect our method to be a useful tool for constructing ancestry informative markers in forensic genetics.
Discrimination of the hierarchical structure of cortical layers in 2-photon microscopy data by combined unsupervised and supervised machine learning
Authors: Li Dong , Zavaglia Melissa , Wang Guangyu , Hu Yi , Xie Hong , Werner Rene , Guan Ji-Song , Hilgetag Claus C. 
Published: September 2018

AbstractThe laminar organization of the cerebral cortex is a fundamental characteristic of the brain, with essential implications for cortical function. Due to the rapidly growing amount of high-resolution brain imaging data, a great demand arises for automated and flexible methods for discriminating the laminar texture of the cortex. Here, we propose a combined approach of unsupervised and supervised machine learning to discriminate the hierarchical cortical laminar organization in high-resolution 2-photon microscopic neural image data without observer bias, that is, without the prerequisite of manually labeled training data. For local cortical foci, we modify an unsupervised clustering approach to identify and represent the laminar cortical structure. Subsequently, supervised machine learning is applied to transfer the resulting layer labels across different locations and image data, to ensure the existence of a consistent layer label system. By using neurobiologically meaningful features, the discrimination results are shown to be consistent with the layer classification of the classical Brodmann scheme, and provide additional insight into the structure of the cerebral cortex and its hierarchical organization. Thus, our work paves a new way for studying the anatomical organization of the cerebral cortex, and potentially its functional organization.
Niche maintenance of germline stem cells inC. elegansmales
Authors: Crittenden Sarah L. , Lee ChangHwan , Mohanty Ipsita , Battula Sindhu , Kimble Judith 
Published: September 2018

ABSTRACTStem cell maintenance by niche signaling is a common theme across phylogeny. In theCaenorhabditis elegansgonad, the broad outlines of germline stem cell (GSC) regulation are the same for both sexes: GLP-1/Notch signaling from the mesenchymal Distal Tip Cell (DTC) niche maintains GSCs in the distal gonad of both sexes (Austin andKimble1987), and does so via two key stem cell regulators, SYGL-1 and LST-1 (Kershneret al. 2014). Most analyses of niche signaling and GSC regulation have focused on XX hermaphrodites, an essentially female sex making sperm in larvae and oocytes in adults. Here we focus on XO males, which are sexually dimorphic in all tissues, including the distal gonad. The architecture of the male niche and the cellular behavior of GSCs are sex-specific. Despite these differences, males maintain a GSC pool similar to the hermaphrodite with respect to size and cell number and the male GSC response to niche signaling is also remarkably similar.
Mathematical Models for the Influence of Cytarabine on White Blood Cell Dynamics in Acute Myeloid Leukemia
Authors: Jost Felix , Schalk Enrico , Rinke Kristine , Fischer Thomas , Sager Sebastian 
Published: September 2018

AbstractWe investigate the personalisation and prediction accuracy of mathematical models for white blood cell (WBC) count dynamics during consolidation treatment using intermediate or high-dose cytarabine (Ara-C) in acute myeloid leukemia (AML). Ara-C is the clinically most relevant cytotoxic agent for AML treatment.We extend the gold-standard model of myelosuppression and a pharmacokinetic model of Ara-C with different hypotheses of Ara-C’s pharmacodynamic effects. We cross-validate 12 mathematical models using dense WBC count measurements from 23 AML patients. Surprisingly, the prediction accuracies are similarly good despite different modelling hypotheses. Therefore, we compare average clinical and calculated WBC recovery times for different Ara-C schedules as a successful methodology for model discrimination. As a result, a new hypothesis of a secondary pharmacodynamic effect on the proliferation rate seems plausible. Furthermore, we demonstrate how personalized predictions of the impact of treatment timing on subsequent nadir values could be used for clinical decision support.Author summaryThe major obstacle in accurately predicting the outcome of a medical therapy is the vast variation in individual response patterns. It concerns both the subjective experience of the patient and the objectively measurable achievement of a clinical remission with restoration of normal blood counts. Here, we address acute myeloid leukemia (AML)-chemotherapy using cytarabine (Ara-C) as this drug is this most important component of AML-treatment. In addition to the wide spectrum of genetic aberrations involved in pathogenesis leading to variations in patient response patterns, another facet of personalised medicine awaits exploration of its full potential: a systematic, mathematical approach to understand and manipulate the dynamics of relevant biomarkers. We use personalised mathematical models to describe and predict white blood cell (WBC) counts during AML consolidation treatment. We analyse why and to what extent low WBC counts, a serious adverse event during therapy, occur. In a comprehensive approach we investigate published models, compare them with our extended models and outline the impact of modelling assumptions and varying chemotherapy schedules on prediction accuracy and model discrimination. Our numerical results confirm the clinical finding that a newly proposed schedule is superior with respect to WBC recovery and shed new light on the reasons why.
Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation
Authors: Mohammadjavadi Morteza , Peiyong Ye Patrick , Xia Anping , Brown Julian , Popelka Gerald , Pauly Kim Butts 
Published: September 2018

AbstractRecent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for non-invasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. In this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration. We show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration. These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.
Towards Decoding the Metabolic Plasticity in Cancer: Coupling of Gene Regulation and Metabolic Pathways
Authors: Jia Dongya , Lu Mingyang , Jung Kwang Hwa , Park Jun Hyoung , Yu Linglin , Onuchic José N. , Kaipparettu Benny Abraham , Levine Herbert 
Published: September 2018

AbstractMetabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities for better survival. Here, we establish a theoretical framework to model the coupling of gene regulation and metabolic pathways in cancer. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis respectively, with the activities of three metabolic pathways: glucose oxidation, glycolysis and fatty acid oxidation (FAO). Guided by the model, we develop metabolic pathway signatures to quantify the activities of glycolysis, FAO and the citric acid cycle of tumor samples by evaluating the expression levels of enzymes involved in corresponding processes. The association of AMPK/HIF-1 activity with metabolic pathway activity, predicted by the model and verified by analyzing the gene expression and metabolite abundance data of patient samples, is further validated by in vitro studies of aggressive triple negative breast cancer cell lines.
V1 neurons encode the perceptual compensation of “false torsion” arising from Listing’s law
Authors: Khazali Mohammad Farhan , Thier Peter 
Published: September 2018

AbstractWe try to deploy the retinal fovea to optimally scrutinize an object of interest by directing our eyes to it. Horizontal and vertical components of these fixation eye movements are determined by the object’s location. However, fixation eye movements also involve a torsional component, which according to Listing’s law is fully determined by the 2D eye position acquired. According to Von Helmholtz knowledge of the torsion provided by this law alleviates the perceptual interpretation of the image tilt that changes with fixation, a view supported by psychophysical experiments he pioneered. We address the question where and how Listing’s law is implemented in the visual system and we show that neurons in monkey area V1 use knowledge of torsion to compensate the image tilt associated with specific eye positions as set by Listing’s law.
Modeling RNA-binding protein specificity in vivo by precisely registering protein-RNA crosslink sites
Authors: Feng Huijuan , Bao Suying , Weyn-Vanhentenryck Sebastien M. , Khan Aziz , Wong Justin , Shah Ankeeta , Flynn Elise D. , Zhang Chaolin 
Published: September 2018

AbstractRNA-binding proteins (RBPs) regulate post-transcriptional gene expression by recognizing short and degenerate sequence elements in their target transcripts. Despite the expanding list of RBPs with in vivo binding sites mapped genomewide using crosslinking and immunoprecipitation (CLIP), defining precise RBP binding specificity remains challenging. We previously demonstrated that the exact protein-RNA crosslink sites can be mapped using CLIP data at single-nucleotide resolution and observed that crosslinking frequently occurs at specific positions in RBP motifs. Here we have developed a computational method, named mCross, to jointly model RBP binding specificity while precisely registering the crosslinking position in motif sites. We applied mCross to 112 RBPs using ENCODE eCLIP data and validated the reliability of the resulting motifs by genome-wide analysis of allelic binding sites also detected by CLIP. We found that the prototypical SR protein SRSF1 recognizes GGA clusters to regulate splicing in a much larger repertoire of transcripts than previously appreciated.
The antioxidant drug N-acetylcysteine abolishes SOS-mediated mutagenesis produced by fluoroquinolones in bacteria
Authors: Rodríguez-Rosado Ana I. , Valencia Estela Ynés , Rodríguez-Rojas Alexandro , Costas Coloma , Galhardo Rodrigo S. , Blázquez Jesús , Rodríguez-Beltrán Jerónimo 
Published: September 2018

AbstractCertain antibiotics, particularly fluoroquinolones, induce the mutagenic SOS response and increase the levels of intracellular reactive oxygen species (ROS), which have been associated with antibiotic lethality. Both SOS and ROS promote bacterial mutagenesis, fueling the emergence of resistant mutants during antibiotic treatments. However, the relative contribution of ROS and SOS on this antibioticmediated mutagenesis is currently unknown. We used the antioxidant molecule N-acetylcysteine (NAC) to study the contribution of ROS on the SOS response and the mutagenesis mediated by the fluoroquinolone anti-biotic ciprofloxacin (CIP). We show that NAC is able to reduce intracellular ROS levels, as well as the SOS response caused by treatment with subinhibitory concentrations of CIP, without affecting its anti-bacterial activity. This effect reduces anti-bioticinduced mutagenesis to levels comparable to a translesion synthesis DNA-polymerases deficient strain, suggesting that ROS play a major role in SOS-induced mutagenesis. Collectively, our results shed light on the mechanisms underlying antibioticinduced mutagenesis and open the possibility for the use of NAC as adjuvant in antibiotic therapy to hinder the development of antibiotic resistance.