bluuebunny/crossref_metadata_2025_split huggingface dataset:
A curated benchmark of enhancer-gene interactions for evaluating enhancer-target gene prediction methods
Authors: Moore Jill E. , Pratt Henry , Purcaro Michael , Weng Zhiping 
Published: August 2019

ABSTRACTMany genome-wide collections of candidate cis-regulatory elements (cCREs) have been defined using genomic and epigenomic data, but it remains a major challenge to connect these elements to their target genes. To facilitate the development of computational methods for predicting target genes, we developed a Benchmark of candidate Enhancer-Gene Interactions (BENGI) by integrating the Registry of cCREs we developed recently with experimentally-derived genomic interactions. We used BENGI to test several published computational methods for linking enhancers with genes, including signal correlation and the supervised learning methods TargetFinder and PEP. We found that while TargetFinder was the best performing method, it was modestly better than a baseline distance method for most benchmark datasets while trained and tested within the same cell type and that TargetFinder often did not outperform the distance method when applied across cell types. Our results suggest that current computational methods need to be improved and that BENGI presents a useful framework for method development and testing.
Rewards interact with explicit knowledge to enhance skilled motor performance
Authors: Anderson Sean P. , Adkins Tyler J. , Gary Bradley S. , Lee Taraz G. 
Published: August 2019

AbstractFrom typing on a keyboard to playing the piano, many everyday skills require the ability to quickly and accurately perform sequential movements. It is well-known that the availability of rewards leads to increases in motivational vigor whereby people enhance both the speed and force of their movements. However, in the context of motor skills, it is unclear whether rewards also lead to more effective motor planning and action selection. Here, we trained human participants to perform four separate sequences in a skilled motor sequencing task. Two of these sequences were trained explicitly and performed with pre-cues that allow for the planning of movements, while the other two were trained implicitly. Immediately following the introduction of performance-contingent monetary incentives, participants improved their performance on all sequences consistent with enhancements in motivational vigor. However, there was a much larger performance boost for explicitly trained sequences. We replicated these results in a second, pre-registered experiment with an independent sample. We conclude from these experiments that rewards enhance both the planning of movements as well as motivational vigor.
Network models predict that pyramidal neuron hyperexcitability and synapse loss in the dlPFC lead to age-related spatial working memory impairment in rhesus monkeys
Authors: Ibañez Sara , Luebke Jennifer I. , Chang Wayne , Draguljić Danel , Weaver Christina M. 
Published: August 2019

AbstractBehavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlPFC) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased in vitro action potential firing rates (hyperexcitability), across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task (DRT), and introduce a model of memory retention in the DRSTsp. Persistent activity—and, in turn, cognitive performance—in both models was affected much more by hyperexcitability of pyramidal neurons than by a loss of synapses. Our DRT simulations predict that additional changes to the network, such as increased firing of inhibitory interneurons, are needed to account for lower firing rates during the DRT with aging reported in vivo. Synaptic facilitation was an essential feature of the DRSTsp model, but it did not compensate fully for the effects of the other age-related changes on DRT performance. Modeling pyramidal neuron hyperexcitability and synapse loss simultaneously led to a partial recovery of function in both tasks, with the simulated level of DRSTsp impairment similar to that observed in aging monkeys. This modeling work integrates empirical data across multiple scales, from synapse counts to cognitive testing, to further our understanding of aging in non-human primates.
Nanoluciferase-based Method for Detecting Gene Expression inC. elegans
Authors: Sfarcic Ivana , Bui Theresa , Daniels Erin C. , Troemel Emily R. 
Published: August 2019

AbstractGenetic reporters such as the green fluorescent protein (GFP) can facilitate measurement of promoter activity and gene expression. However, GFP and other fluorophores have limited sensitivity, particularly in tissues that autofluoresce like the intestine of the nematodeCaenorhabditis elegans. Here, we present a highly sensitive Nanoluciferase (NanoLuc)-based method in multi-well format to detect constitutive and inducible gene expression inC. elegans. We optimize detection of bioluminescent signal from NanoLuc inC. elegansand show that it can be detected at 400,000-fold over background in a population of 100 animals expressing intestinal NanoLuc driven by thevha-6promoter. We can reliably detect signal in singlevha-6p::Nanoluc-expressing worms from all developmental stages. Furthermore, we can detect signal from 1/100 dilution of lysate from a singlevha-6p::Nanoluc-expressing adult and from a singlevha-6p::Nanoluc-expressing adult “hidden” in a pool of 5,000 N2 wild-type animals. We also optimized various steps of this protocol, which involves a lysis step that can be performed in minutes. As a proof of concept, we used NanoLuc to monitor promoter activity of thepals-5stress/immune reporter and we were able to measure 300 and 50-fold increased NanoLuc activity after proteasome blockade and infection with microsporidia, respectively. Altogether, these results indicate that NanoLuc provides a highly sensitive genetic reporter for rapidly monitoring gene expression inC. elegans.
Different clones for different contexts: Hippocampal cognitive maps as higher-order graphs of a cloned HMM
Authors: Gothoskar Nishad , Guntupalli J. Swaroop , Rikhye Rajeev V. , Lázaro-Gredilla Miguel , George Dileep 
Published: August 2019

AbstractHippocampus encodes cognitive maps that support episodic memories, navigation, and planning. Under-standing the commonality among those maps as well as how those maps are structured, learned from experience, and used for inference and planning is an interesting but unsolved problem. We propose higher-order graphs as the general principle and present, as a plausible model, a cloned hidden Markov model (HMM) that can learn these graphs efficiently from experienced sequences. In our experiments, we use the cloned HMM for learning spatial and abstract representations. We show that inference and planning in the learned CHMM encapsulates many of the key properties of hippocampal cells observed in rodents and humans. Cloned HMM thus provides a new frame-work for understanding hippocampal function.
Effect of synaptic cell-to-cell transmission and recombination on the evolution of double mutants in HIV
Authors: Kreger Jesse , Komarova Natalia L. , Wodarz Dominik 
Published: August 2019

AbstractRecombination in HIV infection can impact virus evolutionin vivoin complex ways, as has been shown both experimentally and mathematically. The effect of free virus versus synaptic, cell-to-cell transmission on the evolution of double mutants, however, has not been investigated. Here we do so by using a stochastic agent-based model. Consistent with data, we assume spatial constraints for synaptic but not for free-virus transmission. Two important effects of the viral spread mode are observed: (i) For disadvantageous mutants, synaptic transmission protects against detrimental effects of recombination on double mutant persistence. Under free virus transmission, recombination increases double mutant levels for negative epistasis, but reduces them for positive epistasis. This reduction for positive epistasis is much diminished under pre-dominantly synaptic transmission, and recombination can in fact lead to increased mutant levels. (ii) The mode of virus spread also directly influences the evolutionary fate of double mutants. For disadvantageous mutants, double mutant production is the predominant driving force, and hence synaptic transmission leads to highest double mutant levels due to increased transmission efficiency. For advantageous mutants, double mutant spread is the most important force, and hence free virus transmission leads to fastest invasion due to better mixing. For neutral mutants, both production and spread of double mutants are important, and hence an optimal mixture of free virus and synaptic transmission maximizes double mutant fractions. Therefore, both free virus and synaptic transmission can enhance or delay double mutant evolution. Implications for drug resistance in HIV are discussed.
Structural basis for EPC1-mediated recruitment of MBTD1 into the NuA4/TIP60 acetyltransferase complex
Authors: Zhang Heng , Devoucoux Maëva , Song Xiaosheng , Li Li , Ayaz Gamze , Cheng Harry , Tempel Wolfram , Dong Cheng , Loppnau Peter , Côté Jacques , Min Jinrong 
Published: August 2019

SummaryMBTD1, a H4K20me reader, has recently been identified as a component of the NuA4/TIP60 acetyltransferase complex, regulating gene expression and DNA repair. NuA4/TIP60 inhibits 53BP1 binding to chromatin through recognition of the H4K20me mark by MBTD1 and acetylation of H2AK15, blocking the ubiquitination mark required for 53BP1 localization at DNA breaks. The NuA4/TIP60 non-catalytic subunit EPC1 enlists MBTD1 into the complex, but the detailed molecular mechanism remains incompletely explored. Here, we present the crystal structure of the MBTD1-EPC1 complex, revealing a hydrophobic C-terminal fragment of EPC1 engaging the MBT repeats of MBTD1 in a site distinct from the H4K20me binding site. Different cellular assays validate the physiological significance of the key residues involved in the MBTD1-EPC1 interaction. Our study provides a structural framework for understanding the mechanism by which MBTD1 recruits the NuA4/TIP60 acetyltransferase complex to influence transcription and DNA repair pathway choice.
Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin+ cortical interneurons
Authors: Angara Kartik , Pai Emily Ling-Lin , Bilinovich Stephanie M , Stafford April M , Nguyen Julie T , Paul Anirban , Rubenstein John L , Vogt Daniel 
Published: August 2019

SummaryNeurofibromatosis-1 (NF-1) is a monogenic disorder caused by mutations in theNF1gene, which encodes the protein, Neurofibromin, an inhibitor of Ras GTPase activity. While NF-1 is often characterized by café-au-lait skin spots and benign tumors, the mechanisms underlying cognitive changes in NF-1 are poorly understood. Cortical GABAergic interneurons (CINs) are implicated in NF-1 pathology but cellular and molecular changes to CINs are poorly understood. We deletedNf1from the medial ganglionic eminence (MGE), which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Loss ofNf1led to a persistence of immature oligodendrocytes that prevented later born oligodendrocytes from occupying the cortex. Moreover, PV+ CINs were uniquely lost, without changes in SST+ CINs. We discovered that loss ofNf1results in a graded decrease inLhx6expression, the transcription factor necessary to establish SST+ and PV+ CINs, revealing a mechanism wherebyNf1regulates a critical CIN developmental milestone.
PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease
Authors: Nackenoff Alex G. , Hohman Timothy J. , Neuner Sarah M. , Akers Carolyn S. , Weitzel Nicole C. , Shostak Alena , Ferguson Shawn , Bennett David A. , Schneider Julie A. , Jefferson Angela L. , Kaczorowski Catherine C. , Schrag Matthew S. 
Published: August 2019

ABSTRACTPhospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD-affected brain, to describe its subcellular localization, and to evaluate its molecular function. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition.
The translation inhibitor cycloheximide affects ribosome profiling data in a species-specific manner
Authors: Sharma Puneet , Nilges Benedikt S. , Wu Jie , Leidel Sebastian A. 
Published: August 2019

AbstractRibosome profiling provides genome-wide snapshots of translation dynamics by determining ribosomal positions at sub-codon resolution. To maintain this positional information, the translation inhibitor cycloheximide (CHX) has been widely used to arrest translating ribosomes prior to library preparation. Several studies have reported CHX-induced biases in yeast data casting uncertainty about its continued use and questioning the accuracy of many ribosome profiling studies. However, the presence of these biases has not been investigated comprehensively in organisms other than Saccharomyces cerevisiae. Here, we use a highly standardized and optimized protocol to compare different CHX-treatment conditions in yeast and human cells. Our data suggest that unlike in S. cerevisiae, translating ribosomes in human cells are not susceptible to conformational restrictions by CHX. Furthermore, CHX-induced codon-specific effects on ribosome occupancy are not detectable in human cells nor in other model organisms including Schizosaccharomyces pombe and Candida albicans. In fact, we find that even in S. cerevisiae most biases can be avoided by omitting CHX pre-treatment, indicating that other parameters of library generation contribute to differences between ribosome profiling experiments. Together our findings provide a framework for researchers who plan their own ribosome profiling experiments or who analyze published datasets to draw judicious conclusions.
Introns Control Stochasticity in Metazoan Gene Expression
Authors: Sands Bryan , Yun Soo , Mendenhall Alexander R. 
Published: August 2019

AbstractIntrons are noncoding DNA elements found in between coding exons of most genes in most metazoans. Introns are known to both increase expression levels and provide means for making different protein products from the same gene via alternative splicing. It is thought that evolution has selected for these functions of introns. Here we present evidence for an additional reason why so many metazoan genes have introns, and why some do not. We found that introns control stochasticity in metazoan gene expression. They do this by controlling stochastic autosomal allele bias. We determined this by measuring the expression of differently colored reporter alleles with and without introns. We find that introns control stochastic autosomal allele biases using a 5’-position dependent mechanism. Intron control of allele expression noise provides an additional mechanism to consider when pondering why so many metazoan genes have introns and why some have lost them.
Herpes Simplex viral nucleoprotein creates a competitive transcriptional environment facilitating robust viral transcription and host shut off
Authors: Dremel Sarah E. , DeLuca Neal A. 
Published: August 2019

SummaryHerpes simplex virus-1 (HSV-1) replicates within the nucleus coopting the host’s RNA Polymerase II (Pol II) machinery for production of viral mRNAs culminating in host transcriptional shut off. The mechanism behind this rapid reprogramming of the host transcriptional environment is largely unknown. We identified ICP4 as responsible for preferential recruitment of the Pol II machinery to the viral genome. ICP4 is a viral nucleoprotein which binds double stranded DNA. We determined ICP4 discriminately binds the viral genome due to the absence of cellular nucleosomes and high density of cognate binding sites. We posit that ICP4’s ability to recruit not just Pol II, but also more limiting essential components, such as TBP and Mediator create a competitive transcriptional environment. These distinguishing characteristics ultimately result in a rapid and efficient reprogramming of the host’s transcriptional machinery, which does not occur in the absence of ICP4.HighlightsHSV-1 ICP4 coats the viral genome promoting robust recruitment of Pol II transcription machinery.ICP4 prefers the viral genome due to the absence of nucleosomes and density of binding motifs.At high concentrations ICP4 promiscuously binds DNA including euchromatic host promoters.ICP4 is required for host transcriptional shut off, independent of genome replication.
Hormone Levels Are Related to Altered Functional Connectivity in Prolactinomas
Authors: Yao Shun , Cao Chenglong , Lin Pan , Juvekar Parikshit , Zhang Ru-Yuan , Vera Matthew , Zeng Ailiang , Golby Alexandra J. , Xu Guozheng , Tie Yanmei , Song Jian 
Published: August 2019

ABSTRACTBackground and ObjectiveProlactinomas may cause drastic hormone fluctuations throughout the body. It is not fully understood how endogenous hormone disorders such as prolactinomas reshape the patient’s brain. By employing the resting-state functional magnetic resonance imaging technique, we aimed to investigate the whole-brain functional connectivity (FC) and its relationship with hormone levels in patients with prolactinomas.MethodsUsing whole-brain and seed-based functional connectivity analyses, we compared FC metrics between 33 prolactinoma patients and 31 healthy controls matched with age, sex, and handedness. Then we performed partial correlation analysis to examine the relationship between FC metrics and hormone levels.ResultsCompared to healthy controls, we found that prolactinoma patients showed significantly increased thalamocortical (visual cortex) and cerebellar-cerebral connectivity. In addition, endogenous hormone levels were positively correlated with the increased FC, and the hormone-FC relationships showed sex difference in prolactinoma patients.ConclusionsOur findings are the first to reveal the altered FC patterns and sex-dependent hormone-FC relationships in prolactinoma patients, indicating the important role of hormone levels in the neural mechanism of brain reorganization and hyperactive intrinsic connections in prolactinomas.
Complex symbiont-pathogen interactions inhibit intestinal repair
Authors: Fast David , Petkau Kristina , Ferguson Meghan , Shin Minjeong , Galenza Anthony , Kostiuk Benjamin , Pukatzki Stefan , Foley Edan 
Published: August 2019

SUMMARYPathogen-mediated damage to the intestinal epithelium activates compensatory growth and differentiation repair programs in progenitor cells. Accelerated progenitor growth replenishes damaged tissue and maintains barrier integrity. Despite the importance of epithelial renewal to intestinal homeostasis, we know little about the effects of pathogen-commensal interactions on progenitor growth. We found that the enteric pathogen Vibrio cholerae, blocks critical growth and differentiation pathways in Drosophila progenitors despite extensive damage to the epithelial tissue. We showed that inhibition of epithelial repair requires interactions of the Vibrio cholerae type six secretion system with a complex community of symbiotic bacteria, and that elimination of the gut microbiome is sufficient to restore homeostatic growth in infected intestines. Together, this work highlights the importance of pathogen-symbiont interactions on intestinal immune responses and outlines a previously undescribed impact of the type six secretion system on pathogenesis.
A robust deep neural network for denoising task-based fMRI data: An application to working memory and episodic memory
Authors: Yang Zhengshi , Zhuang Xiaowei , Sreenivasan Karthik , Mishra Virendra , Curran Tim , Cordes Dietmar 
Published: August 2019

ABSTRACTIn this study, a deep neural network (DNN) is proposed to reduce the noise in task-based fMRI data without explicitly modeling noise. TheDNNartificial neural network consists of one temporal convolutional layer, one long short-term memory (LSTM) layer, one time-distributed fully-connected layer, and one unconventionalselectionlayer in sequential order. The LSTM layer takes not only the current time point but also what was perceived in a previous time point as its input to characterize the temporal autocorrelation of fMRI data. The fully-connected layer weights the output of the LSTM layer, and the output denoised fMRI time series is selected by theselectionlayer. Assuming that task-related neural response is limited to gray matter, the model parameters in theDNNnetwork are optimized by maximizing the correlation difference between gray matter voxels and white matter or ventricular cerebrospinal fluid voxels. Instead of targeting a particular noise source, the proposed neural network takes advantage of the task design matrix to better extract task-related signal in fMRI data. TheDNNnetwork, along with other traditional denoising techniques, has been applied on simulated data, working memory task fMRI data acquired from a cohort of healthy subjects and episodic memory task fMRI data acquired from a small set of healthy elderly subjects. Qualitative and quantitative measurements were used to evaluate the performance of different denoising techniques. In the simulation, DNN improves fMRI activation detection and also adapts to varying hemodynamic response functions across different brain regions. DNN efficiently reduces physiological noise and generates more homogeneous task-response correlation maps in real data.