bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of neural organization and rhythmogenesis during hippocampal and cortical ripples
Authors: McKenzie Sam , Nitzan Noam , English Daniel F. 
Published: April 2020

Neural activity during ripples has attracted great theoretical and experimental attention over the last three decades. Perhaps one reason for such interest is that ripples occur during quiet waking moments and during sleep, times when we reflect and dream about what has just occurred and what we expect to happen next. The hope is that understanding such ‘offline’ activity may yield insights into reflection, planning, and the purposes of sleep. This review focuses on the mechanisms by which neurons organize during these high-frequency events. In studying ripples, broader principles have emerged that relate intrinsic neural properties, network topology and synaptic plasticity in controlling neural activity. Ripples, therefore, serve as an excellent model for studying how properties of a neural network relate to neural dynamics.
This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Progress and issues in second-order analysis of hippocampal replay
Authors: van der Meer Matthijs A. A. , Kemere Caleb , Diba Kamran 
Published: April 2020

Patterns of neural activity that occur spontaneously during sharp-wave ripple (SWR) events in the hippocampus are thought to play an important role in memory formation, consolidation and retrieval. Typical studies examining the content of SWRs seek to determine whether the identity and/or temporal order of cell firing is different from chance. Such ‘first-order’ analyses are focused on a single time point and template (map), and have been used to show, for instance, the existence of preplay. The major methodological challenge in first-order analyses is the construction and interpretation of different chance distributions. By contrast, ‘second-order’ analyses involve a comparison of SWR content between different time points, and/or between different templates. Typical second-order questions include tests of experience-dependence (replay) that compare SWR content before and after experience, and comparisons or replay between different arms of a maze. Such questions entail additional methodological challenges that can lead to biases in results and associated interpretations. We provide an inventory of analysis challenges for second-order questions about SWR content, and suggest ways of preventing, identifying and addressing possible analysis biases. Given evolving interest in understanding SWR content in more complex experimental scenarios and across different time scales, we expect these issues to become increasingly pervasive.This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Electrophysiological signatures of memory reactivation in humans
Authors: Schreiner Thomas , Staudigl Tobias 
Published: April 2020

The reactivation of neural activity that was present during the encoding of an event is assumed to be essential for human episodic memory retrieval and the consolidation of memories during sleep. Pioneering animal work has already established a crucial role of memory reactivation to prepare and guide behaviour. Research in humans is now delineating the neural processes involved in memory reactivation during both wakefulness and sleep as well as their functional significance. Focusing on the electrophysiological signatures of memory reactivation in humans during both memory retrieval and sleep-related consolidation, this review provides an overview of the state of the art in the field. We outline recent advances, methodological developments and open questions and specifically highlight commonalities and differences in the neuronal signatures of memory reactivation during the states of wakefulness and sleep.
This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Binocular disparity-based learning is retinotopically specific and independent of sleep
Authors: Klinzing Jens G. , Herbrik Lena , Nienborg Hendrikje , Rauss Karsten 
Published: April 2020

Sleep supports the consolidation of recently encoded declarative and procedural memories. An important component of this effect is the repeated reactivation of neuronal ensemble activity elicited during memory encoding. For perceptual learning, however, sleep benefits have only been reported for specific tasks and it is not clear whether sleep targets low-level perceptual, higher-order temporal or attentional aspects of performance. Here, we employed a coarse binocular disparity discrimination task, known to rely on low-level stereoscopic vision. We show that human subjects improve over training and retain the same performance level across a 12-h retention period. Improvements do not generalize to other parts of the visual field and are unaffected by whether the retention period contains sleep or not. These results are compatible with the notion that behavioural improvements in binocular disparity discrimination do not additionally benefit from sleep when compared with the same time spent awake. We hypothesize that this might generalize to other strictly low-level perceptual tasks.
This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future'.
Integration of new information in memory: new insights from a complementary learning systems perspective
Authors: McClelland James L. , McNaughton Bruce L. , Lampinen Andrew K. 
Published: April 2020

According to complementary learning systems theory, integrating new memories into the neocortex of the brain without interfering with what is already known depends on a gradual learning process, interleaving new items with previously learned items. However, empirical studies show that information consistent with prior knowledge can sometimes be integrated very quickly. We use artificial neural networks with properties like those we attribute to the neocortex to develop an understanding of the role of consistency with prior knowledge in putatively neocortex-like learning systems, providing new insights into when integration will be fast or slow and how integration might be made more efficient when the items to be learned are hierarchically structured. The work relies on deep linear networks that capture the qualitative aspects of the learning dynamics of the more complex nonlinear networks used in previous work. The time course of learning in these networks can be linked to the hierarchical structure in the training data, captured mathematically as a set of dimensions that correspond to the branches in the hierarchy. In this context, a new item to be learned can be characterized as having aspects that project onto previously known dimensions, and others that require adding a new branch/dimension. The projection onto the known dimensions can be learned rapidly without interleaving, but learning the new dimension requires gradual interleaved learning. When a new item only overlaps with items within one branch of a hierarchy, interleaving can focus on the previously known items within this branch, resulting in faster integration with less interleaving overall. The discussion considers how the brain might exploit these facts to make learning more efficient and highlights predictions about what aspects of new information might be hard or easy to learn.This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Neural ensemble reactivation in rapid eye movement and slow-wave sleep coordinate with muscle activity to promote rapid motor skill learning
Authors: Eckert M. J. , McNaughton B. L. , Tatsuno M. 
Published: April 2020

Neural activity patterns of recent experiences are reactivated during sleep in structures critical for memory storage, including hippocampus and neocortex. This reactivation process is thought to aid memory consolidation. Although synaptic rearrangement dynamics following learning involve an interplay between slow-wave sleep (SWS) and rapid eye movement (REM) sleep, most physiological evidence implicates SWS directly following experience as a preferred window for reactivation. Here, we show that reactivation occurs in both REM and SWS and that coordination of REM and SWS activation on the same day is associated with rapid learning of a motor skill. We performed 6 h recordings from cells in rats' motor cortex as they were trained daily on a skilled reaching task. In addition to SWS following training, reactivation occurred in REM, primarily during the pre-task rest period, and REM and SWS reactivation occurred on the same day in rats that acquired the skill rapidly. Both pre-task REM and post-task SWS activation were coordinated with muscle activity during sleep, suggesting a functional role for reactivation in skill learning. Our results provide the first demonstration that reactivation in REM sleep occurs during motor skill learning and that coordinated reactivation in both sleep states on the same day, although at different times, is beneficial for skill learning.This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Profiles and clinical significance of immune cell infiltration in pancreatic adenocarcinoma
Authors: Mei Jie , Xu Rui , Xia Dandan , Yang Xuejing , Wang Huiyu , Liu Chaoying 
Published: April 2020

AbstractBackgroundIt has been well defined that tumor-infiltrating immune cells (TIICs) play critical roles in pancreatic cancer (PAAD) progression. The aim of this research was to comprehensively explore the composition of TIICs in PAAD and their potential clinical significance.Methods178 samples from TCGA and 63 samples from GSE57495 dataset were enrolled into our study. ImmuCellAI was applied to calculate the infiltrating abundance of 24 immune cell types in PAAD and further survival analysis revealed the prognostic values of TIICs in PAAD. Moreover, Gene ontology (GO) enticement analysis of differentially expressed genes (DEGs) between low- and high-risk groups was performed as well.ResultsDifferent kinds of TIICs had distinct infiltrating features. Besides, Specific TIICs subsets had notable prognostic values in PAAD. We further established a 6-TIICs signature to assess the prognosis of PAAD patients. Kaplan-Meier and Cox regression analyses both suggested the significant prognostic value of the signature in PAAD. We next extracted 1,334 DEGs based on the risk model, and the hub modules in the protein-protein interaction (PPI) network of DEGs were involved in regulating immune-related biological processes.ConclusionsOverall, the current study illuminated the immune cells infiltrating landscape in PAAD and developed a TIICs-dependent prognostic signature, which could be used as an effective prognostic classifier for PAAD patients.
In-silicoanalysis of SARS-CoV-2 genomes: Insights from SARS encoded non-coding RNAs
Authors: Periwal Neha , Sarma Sankritya , Arora Pooja , Sood Vikas 
Published: April 2020

AbstractRecently a novel coronavirus (SARS-CoV-2) emerged from Wuhan, China and has infected more than 571000 people leading to more than 26000 deaths. Since SARS-CoV-2 genome sequences show similarity with those of SARS, we sought to analyze all the available SARS-CoV-2 genomes based on the insights obtained from SARS genome specifically focusing on non-coding RNAs. Here, results are presented from the dual approach i.e identifying host encoded miRNAs that might regulate viral pathogenesis as well as identifying viral encoded miRNAs that might regulate host cell signaling pathways and aid in viral pathogenesis. Analysis utilizing first approach resulted in the identification of 10 host encoded miRNAs that could target the genome of both the viruses (SARS-CoV-2 and SARS reference genome). Interestingly our analysis revealed that there is significantly higher number of host miRNAs that could target SARS-CoV-2 genome as compared to the SARS reference genome. Results from second approach involving SARS-CoV-2 and SARS reference genome identified a set of virus encoded miRNAs which might regulate host signaling pathways. Our analysis further identified a similar “GA” rich motif in SARS-CoV-2 genome that was shown to play a vital role in lung pathogenesis during severe SARS infections. Hence, we successfully identified human and virus encoded miRNAs that might regulate pathogenesis of both these coronaviruses and the fact that more number of host miRNAs could target SARS-CoV-2 genomes possibly reveal as to why this virus follows mild pathogenesis in healthy individuals. We identified non-coding sequences in SARS-CoV-2 genomes that were earlier reported to contribute towards SARS pathology. The study provides insights into the overlapping sequences among these viruses for their effective inhibition as well as identifying new drug targets that could be used for development of new antivirals.
Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice
Authors: Rajeshkumar N.V , Yabuuchi Shinichi , Pai Shweta G. , Maitra Anirban , Hidalgo Manuel , Dang Chi V. 
Published: April 2020

AbstractGuided by the principle ofprimum non nocere(first do no harm), we report a cautionary note on the potential fatal toxicity of chloroquine (CQ) or hydroxychloroquine (HCQ) in combination with anti-diabetic drug metformin. We observed that the combination of CQ or HCQ and metformin, which were used in our studies as potential anti-cancer drugs, killed 30-40% of mice. While our observations in mice may not translate to toxicity in humans, the reports that CQ or HCQ has anti-COVID-19 activity, the use of CQ resulting in toxicity and at least one death, and the recent Emergency Use Authorization (EUA) for CQ and HCQ by the US Food and Drug Administration (FDA) prompted our report. Here we report the lethality of CQ or HCQ in combination with metformin as a warning of its potential serious clinical toxicity. We hope that our report will be helpful to stimulate pharmacovigilance and monitoring of adverse drug reactions with the use of CQ or HCQ, particularly in combination with metformin.
Functional maturation of the gut microbiota at weaning is influenced by maternal environment in piglets
Authors: Beaumont Martin , Cauquil Laurent , Bertide Allan , Ahn Ingrid , Barilly Céline , Gil Lisa , Canlet Cécile , Zemb Olivier , Pascal Géraldine , Samson Arnaud , Combes Sylvie 
Published: April 2020

SUMMARYThe objective of this study was to analyze in piglets the impact of weaning on the production of metabolites by gut bacteria and to determine whether early life environment influences the functional maturation of the gut microbiota. Fecal metabolome and microbiome were analyzed in piglets raised in two separate maternity farms and mixed at weaning. In piglets from both maternity farms, the relative abundance ofLactobacillusand of the predicted function “Fucose degradation” decreased after weaning while the relative abundance ofRuminococcus 2and of the predicted function “Starch degradation” increased. In piglets from the first maternity farm, the relative concentration of biogenic amines and the relative abundance ofEscherichi-Shigelladecreased after weaning while the relative concentration of short chain fatty acids and the relative abundance ofChristensenellaceae R-7 groupandRuminococcaceae UCG-002increased. These changes were not observed at weaning in piglets from the second maternity farm probably because they already had high relative concentration of short chain fatty acids and higher relative abundance ofChristensenellaceae R-7 groupandRuminococcaceae UCG-002during the suckling period. In conclusion, the functional maturation of the microbiota at weaning is highly dependent on the maternal environment in piglets.ORIGINALITY - SIGNIFICANCE STATEMENTBacterial metabolites are key molecular intermediates between the gut microbiota and host cells. Our study in piglets reveals that the metabolic activity of the gut microbiota shifts at weaning, a key developmental period for intestinal and immune health. We also show that this functional maturation of the gut microbiota is strongly influenced by maternal environment. Thus, targeting early life environmental factors is a promising strategy to program health trough the production of beneficial bacterial metabolites at the suckling-to-weaning transition.
Detecting genetic variation and base modifications together in the same single molecules of DNA and RNA at base pair resolution using a magnetic tweezer platform
Authors: Wang Zhen , Maluenda Jérôme , Giraut Laurène , Vieille Thibault , Lefevre Andréas , Salthouse David , Radou Gaël , Moulinas Rémi , Astete-Morales Sandra , d’Avezac Pol , Smith Geoff , André Charles , Allemand Jean-François , Bensimon David , Croquette Vincent , Ouellet Jimmy , Hamilton Gordon 
Published: April 2020

AbstractAccurate decoding of nucleic acid variation is important to understand the complexity and regulation of genome function. Here we introduce a single-molecule platform based on magnetic tweezer (MT) technology that can identify and map the positions of sequence variation and multiple base modifications together in the same single molecules of DNA or RNA at single base resolution. Using synthetic templates, we demonstrate that our method can distinguish the most common epigenetic marks on DNA and RNA with high sensitivity, specificity and precision. We also developed a highly specific CRISPR-Cas enrichment strategy to target genomic regions in native DNA without amplification. We then used this method to enrich native DNA from E. coli and characterized the differential levels of adenine and cytosine base modifications together in molecules of up to 5 kb in length. Finally, we enriched the 5‘UTR of FMR1 from cells derived from a Fragile X carrier and precisely measured the repeat expansion length and methylation status of each molecule. These results demonstrate that our platform can detect a variety of genetic, epigenetic and base modification changes concomitantly within the same single molecules.
Non-Canonical Targets of HIF1a Drive Cell-Type-Specific Dysfunction
Authors: Allan Kevin C. , Hu Lucille R. , Morton Andrew R. , Scavuzzo Marissa A. , Gevorgyan Artur S. , Clayton Benjamin L.L. , Bederman Ilya R. , Hung Stevephen , Bartels Cynthia F. , Madhavan Mayur , Tesar Paul J. 
Published: April 2020

SUMMARYAll mammalian cells sense and respond to insufficient oxygen, or hypoxia, through the activity of hypoxia-inducible factors (HIFs), an evolutionarily conserved family of transcriptional regulators that promote oxygen-independent energy metabolism and angiogenesis. While HIF activation is transiently protective for all cells, prolonged HIF activity drives distinct pathological responses in different tissues. How HIF achieves this pleiotropic effect is largely unknown. Here, we demonstrate that non-canonical targets of HIF1a impair the function of oligodendrocyte progenitor cells (OPCs) to generate oligodendrocytes. Beyond the canonical gene targets shared between all cell types, HIF1a also bound to and activated a unique set of targets in OPCs includingAscl2andDlx3. Each of these targets, when ectopically expressed, was sufficient to block oligodendrocyte development through suppression of the key oligodendrocyte regulatorSox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoringSox10expression without impacting canonical HIF1a activity. Collectively this work defines the mechanism by which chronic HIF1a suppresses oligodendrocyte formation. More broadly, we establish that cell-type-specific HIF1a targets, independent of the canonical hypoxia response, perturb cell function and drive disease in chronic hypoxia.
Revealing Cellular Heterogeneity andIn VitroDifferentiation Trajectory of Cultured Human Endometrial Mesenchymal-like Stem Cells Using Single-cell RNA Sequencing
Authors: Cao Dandan , Chan Rachel W.S. , Ng Ernest H.Y. , Gemzell-Danielsson Kristina , Yeung William S.B. 
Published: April 2020

ABSTRACTEndometrial mesenchymal-like stem cells (eMSCs) are adult stem cells contributing to endometrial regeneration. One set of perivascular markers (CD140b+CD146+) have been widely used to enrich eMSCs. Although eMSCs are easily accessible for regenerative medicine and have long been studied, their cellular heterogeneity and molecular program controlling their expansion and differentiation in vitro remains largely unclear. In this study, we applied 10X genomics single-cell RNA sequencing to eMSCs cultured in vitro after microbeading from 7 donors to investigate cellular heterogeneity in an unbiased manner. Corresponding clonogenic progenies of eMSCs after culture for 14 days were also sequenced to construct the in vitro differentiation trajectory of eMSCs. Transcriptomic expression based clustering revealed several subpopulations in eMSCs. Each subpopulation manifested distinct functional characteristics associated with immunomodulation, proliferation, extracellular matrix organization and cell differentiation. Pseudotime trajectory analysis on eMSCs and their differentiated progenies identifiedin vitrodifferentiation hierarchy of eMSCs. Further ligand-receptor pair analysis found that WNT signaling, NOTCH signaling, TGF-beta signaling and FGF signaling were important regulatory pathways for eMSC self-renewal and differentiation. By comparing eMSCs to Wharton’s Jelly MSCs and adipose-derived MSCs, we found these 3 kinds of MSCs expressed largely overlapping differentiation (CD) genes and highly variable genes. In summary, we reveal for the first time high molecular and cellular heterogeneity in cultured eMSCs, and identify the key signaling pathways that may be important for eMSC differentiation.