bluuebunny/crossref_metadata_2025_split huggingface dataset:
The dorsal hippocampus is required for the formation of long-term duration memories in rats
Authors: Hata Toshimichi , Yamashita Tatsuya , Kamada Taisuke 
Published: December 2020

ABSTRACTInterval timing—the perception of durations mainly in seconds or minutes—is a ubiquitous behavior in organisms. Animal studies have suggested that the hippocampus plays an essential role in duration memory; however, the memory processes involved are unclear. To clarify the role of the dorsal hippocampus in the acquisition of long-term duration memories, we adapted the “time-shift paradigm” to a peak-interval procedure. After a sufficient number of training with an initial target duration (20 s), the rats underwent “shift sessions” with a new target duration (40 s) under a muscimol (0.5 μg per side) infusion into the bilateral dorsal hippocampus. The memory of the new target duration was then tested in drug-free “probe sessions,” including trials in which no lever presses were reinforced. In the probe sessions, the mean response rate distribution of the muscimol group was located leftward to the control group, but these two response rate distributions were superimposed on the standardized time axis, suggesting a scalar property. In the session-by-session analysis, the mean peak time (an index of timing accuracy) of the muscimol group was lower than that of the control group in the probe sessions, but not in the shift sessions. These findings suggest that the dorsal hippocampus is required for the formation of long-term duration memories within the range of interval timing.
The evolutionary history of topological variations in the CPA/AT superfamily
Authors: Govindarajan Sudha , Bassot Claudio , Lamb John , Shu Nanjiang , Huang Yan , Elofsson Arne 
Published: December 2020

AbstractCPA/AT transporters consist of two structurally and evolutionarily related inverted repeat units, each of them with one core and one scaffold subdomain. During evolution, these families have undergone substantial changes in structure, topology and function. Central to the function of the transporters is the existence of two non-canonical helices that are involved in the transport process. In different families, two different types of these helices have been identified, reentrant and broken. Here, we use an integrated topology annotation method to identify novel topologies in the families. It combines topology prediction, similarity to families with known structure, and the difference in positively charged residues present in inside and outside loops in alternative topological models. We identified families with diverse topologies containing broken or reentrant helix. We classified all families based on 3 distinct evolutionary groups that each share a structurally similar C-terminal repeat unit newly termed as “Fold-types”. Using the evolutionary relationship between families we propose topological transitions including, a transition between broken and reentrant helices, complete change of orientation, changes in the number of scaffold helices and even in some rare cases, losses of core helices. The evolutionary history of the repeat units shows gene duplication and repeat shuffling events to result in these extensive topology variations. The novel structure-based classification, together with supporting structural models and other information, is presented in a searchable database, CPAfold (cpafold.bioinfo.se). Our comprehensive study of topology variations within the CPA superfamily provides better insight about their structure and evolution.
Factors contributing to the disease ecology of brown crab (Cancer pagurus) in a temperate marine protected area
Authors: Davies Charlotte E. , Johnson Andrew F. , Wootton Emma C. , Greenwood Spencer J. , Clark K. Fraser , Vogan Claire L. , Rowley Andrew F. 
Published: December 2020

ABSTRACTMarine ecosystems are affected by multiple, well-known stressors like fishing and climate change, but a less documented concern is disease. Marine reserves have been successful in replenishing stocks and aiding recruitment but studies have shown that high population abundances in marine reserves may lead to unwanted secondary effects such as increase in predators and competition, altering trophic webs, and disease. Here, we investigate factors contributing to disease prevalence in a brown crab (Cancer pagurus) population around Lundy Island (the UK’s first MPA) after 7 years of no-take protection. Population parameters (size, sex, and abundance), disease (shell disease,Hematodiniumspp. infection) and injury presence (a known precursor to some disease conditions) were assessed over two years in both fished and unfished areas of the MPA. We found no significant difference in prevalence between the disease prevalence in fished and unfished areas, however overall, the number of injured crabs increased significantly over the two years (12%), as did the prevalence of shell disease (15%). The probability of crabs having shell disease increased significantly in male crabs, and in those missing limbs. The probability of crabs being injured increased significantly in crabs below the minimum landing size. In terms of population parameters, crabs were more prevalent in the fished area compared to the unfished area, thought to be a result of an increase in the predatory European lobster. The findings of the present study highlight potential secondary community changes as a result of MPA implementation. Therefore, surveillance for such changes, as part of MPA management, would provide useful information on the health and overall function of the protected ecosystem.
Total recall: episodic memory retrieval, choice, and memory confidence in the rat
Authors: Joo Hannah R. , Liang Hexin , Chung Jason E. , Geaghan-Breiner Charlotte , Fan Jiang Lan , Nachman Benjamin P. , Kepecs Adam , Frank Loren M. 
Published: December 2020

AbstractEpisodic memory enables recollection of past experiences to guide future behavior. Humans know which memories to trust (high confidence) and which to doubt (low confidence). How memory retrieval, memory confidence, and memory-guided decisions are related, however, is not understood. Additionally, whether animals can assess confidence in episodic memories to guide behavior is unknown. We developed a spatial episodic memory task in which rats were incentivized to gamble their time: betting more following a correct choice yielded greater reward. Rat behavior reflected memory confidence, with higher temporal bets following correct choices. We applied modern machine learning to identify a memory decision variable, and built a generative model of memories evolving over time that accurately predicted both choices and confidence reports. Our results reveal in rats an ability thought to exist exclusively in primates, and introduce a unified model of memory dynamics, retrieval, choice, and confidence.
Diverse modes of binocular interactions in the mouse superior colliculus
Authors: Russell Ashley L. , Dixon Karen G. , Triplett Jason W. 
Published: December 2020

AbstractThe superior colliculus (SC) integrates visual and other sensory information to regulate critical reflexive and innate behaviors, such as prey capture. In the mouse, the vast majority of retinal ganglion cells (RGCs) innervate the SC, including inputs from both the contralateral (contra-RGCs) and ipsilateral (ipsi-RGCs) eye. Despite this, previous studies revealed minimal neuronal responses to ipsilateral stimulation and few binocular interactions in the mouse SC. More recent work suggests that ipsi-RGC function and innervation of the SC are critical for efficient prey capture, raising the possibility that binocular interactions in the mouse SC may be more prevalent than previously thought. To explore this possibility, we investigated eye-specific and binocular influences on visual responses and tuning of SC neurons, focusing on the anteromedial region. While the majority of SC neurons were primarily driven by contralateral eye stimulation, we observed that a substantial proportion of units were influenced or driven by ipsilateral stimulation. Clustering based on differential responses to eye-specific stimulus presentation revealed five distinct putative subpopulations and multiple modes of binocular interaction, including facilitation, summation, and suppression. Each of the putative subpopulations exhibited selectivity for orientation, and differences in spatial frequency tuning and spatial summation properties were observed between subpopulations. Further analysis of orientation tuning under different ocular conditions supported differential modes of binocular interaction between putative subtypes. Taken together, these data suggest that binocular interactions in the mouse SC may be more prevalent and diverse than previously understood.
deepBlink: Threshold-independent detection and localization of diffraction-limited spots
Authors: Eichenberger Bastian Th. , Zhan YinXiu , Rempfler Markus , Giorgetti Luca , Chao Jeffrey A. 
Published: December 2020

AbstractDetection of diffraction-limited spots is traditionally performed with mathematical operators designed for idealized spots. This process requires manual tuning of parameters that is time-consuming and not always reliable. We have developed deepBlink, a neural network-based method to detect and localize spots automatically and demonstrate that deepBlink outperforms state-of-the-art methods across six publicly available datasets. deepBlink is open-sourced on PyPI and GitHub (https://github.com/BBQuercus/deepBlink) as a ready-to-use command-line interface.
A blueprint for high affinity SARS-CoV-2 Mpro inhibitors from activity-based compound library screening guided by analysis of protein dynamics
Authors: Gossen Jonas , Albani Simone , Hanke Anton , Joseph Benjamin P. , Bergh Cathrine , Kuzikov Maria , Costanzi Elisa , Manelfi Candida , Storici Paola , Gribbon Philip , Beccari Andrea R. , Talarico Carmine , Spyrakis Francesca , Lindahl Erik , Zaliani Andrea , Carloni Paolo , Wade Rebecca C. , Musiani Francesco , Kokh Daria B. , Rossetti Giulia 
Published: December 2020

AbstractThe SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unfortunately, unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ~30,000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ~200 virtual screenings of compound libraries on selected protein structures, we redefine the protein’s druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.
BiG-MAP: an automated pipeline to profile metabolic gene cluster abundance and expression in microbiomes
Authors: Pascal Andreu Victoria , Augustijn Hannah E. , van den Berg Koen , van der Hooft Justin J. J. , Fischbach Michael A. , Medema Marnix H. 
Published: December 2020

AbstractMicrobial gene clusters encoding the biosynthesis of primary and secondary metabolites play key roles in shaping microbial ecosystems and driving microbiome-associated phenotypes. Although effective approaches exist to evaluate the metabolic potential of such bacteria through identification of metabolic gene clusters in their genomes, no automated pipelines exist to profile the abundance and expression levels of such gene clusters in microbiome samples to generate hypotheses about their functional roles and to find associations with phenotypes of interest. Here, we describe BiG-MAP, a bioinformatic tool to profile abundance and expression levels of gene clusters across metagenomic and metatranscriptomic data and evaluate their differential abundance and expression between different conditions. To illustrate its usefulness, we analyzed 47 metagenomic samples from healthy and caries-associated human oral microbiome samples and identified 58 gene clusters, including unreported ones, that were significantly more abundant in either phenotype. Among them, we found themucoperon, a gene cluster known to be associated to tooth decay. Additionally, we found a putative reuterin biosynthetic gene cluster from aStreptococcusstrain to be enriched but not exclusively found in healthy samples; metabolomic data from the same samples showed masses with fragmentation patterns consistent with (poly)acrolein, which is known to spontaneously form from the products of the reuterin pathway and has been previously shown to inhibit pathogenicStreptococcus mutansstrains. Thus, we show how BiG-MAP can be used to generate new hypotheses on potential drivers of microbiome-associated phenotypes and prioritize the experimental characterization of relevant gene clusters that may mediate them.ImportanceMicrobes play an increasingly recognized role in determining host-associated phenotypes by producing small molecules that interact with other microorganisms or host cells. The production of these molecules is often encoded in syntenic genomic regions, also known as gene clusters. With the increasing numbers of (multi-)omics datasets that can help understanding complex ecosystems at a much deeper level, there is a need to create tools that can automate the process of analyzing these gene clusters across omics datasets. The current study presents a new software tool called BiG-MAP, which allows assessing gene cluster abundance and expression in microbiome samples using metagenomic and metatranscriptomic data. In this manuscript, we describe the tool and its functionalities, and how it has been validated using a mock community. Finally, using an oral microbiome dataset, we show how it can be used to generate hypotheses regarding the functional roles of gene clusters in mediating host phenotypes.
The septate junction protein Snakeskin is critical for epithelial barrier function and tissue homeostasis in the Malpighian tubules of adultDrosophila
Authors: Dornan A.J. , Halberg K.A. , Beuter L.-K. , Davies S.-A. , Dow J.A.T. 
Published: December 2020

ABSTRACTTransporting epithelia provide a protective physical barrier while directing appropriate transport of ions, solutes and water. In invertebrates, epithelial integrity is dependent on formation, and maintenance, of ‘tight’ septate junctions (SJs). We demonstrated thatDrosophilaMalpighian (renal) tubules undergo an age-dependent decline in secretory transport capacity, which correlates with mislocalisation of SJ proteins and coincident progressive degeneration in cellular morphology and tissue homeostasis. By restrictively impairing, in adult tubules, the cell adhesion protein Snakeskin, which is essential for smooth SJ formation, we observed progressive changes in cellular and tissue morphology that phenocopied these effects, including mislocalisation of junctional proteins with concomitant loss of cell polarity and barrier function. Resulting in significant accelerated decline in tubule secretory capacity and organismal viability. Our investigations highlight the tubule’s essential role in maintenance of organismal health, while providing measurable markers of compromised epithelial barrier and tissue function that manifest in advanced morbidity and death.Abstract FigureModel for epithelial dysfunction arising from failure of smooth septate junctional complexes as a consequence of impairedSnakeskinexpression.
Nutrition or nature: disentangling the complex forces shaping prokaryote pan-genomes
Authors: Garza Daniel R. , von Meijenfeldt F. A. Bastiaan , van Dijk Bram , Boleij Annemarie , Huynen Martijn A. , Dutilh Bas E. 
Published: December 2020

AbstractMicrobial pan-genomes are shaped by a complex combination of stochastic and deterministic forces. Even closely related genomes often exhibit extensive variation in their gene content. Understanding what drives this variation requires exploring the interactions of genes with each other and with their external environments. However, to date, conceptual models of pan-genome dynamics often represent genes as independent units and provide limited information about their mechanistic interactions. Here, we use pan-reactomes as proxies for pan-genomes since they can explicitly represent the interactions between the genes that code for metabolic reactions and simulate complex phenotypes that interact with the metabolic environment. We interpreted pan-reactomes as dynamic pools of metabolic reactions that are potentially gained or lost and simulated the routes along which different lineages lose reactions in alternative environments. We performed these simulations on the pan-reactomes of 46 bacterial and archaeal families covering a broad taxonomic range. These simulations allowed us to disentangle metabolic reactions whose presence does, and does not depend on the metabolite composition of the external environment, allowing us to identify reactions constrained “by nutrition” and “by nature”, respectively. By comparing the frequency of reactions from the first group with their observed frequencies in bacterial and archaeal families, we predicted the metabolic niches that shaped the genomic composition of these lineages in their evolutionary past. Moreover, we found that the lineages that were shaped by a more diverse metabolic niche also occur in more diverse biomes as assessed by global environmental sequencing datasets. Together, we introduce a computational framework for analyzing and interpreting pan-reactomes that provides new insights into the ecological and evolutionary drivers of pan-genome composition.
Characterization of hormone-producing cell types in the teleost pituitary gland using single-cell RNA-seq
Authors: Siddique Khadeeja , Ager-Wick Eirill , Fontaine Romain , Weltzien Finn-Arne , Henkel Christiaan V. 
Published: December 2020

AbstractThe pituitary is the vertebrate endocrine gland responsible for the production and secretion of several essential peptide hormones. These, in turn, control many aspects of an animal’s physiology and development, including growth, reproduction, homeostasis, metabolism and stress responses. In teleost fish, each hormone is presumably produced by a specific cell type. However, key details on the regulation of, and communication between these cell types remain to be resolved. We have therefore used single-cell sequencing to generate gene expression profiles for 2592 and 3804 individual cells from the pituitaries of female and male adult medaka (Oryzias latipes), respectively. Based on expression profile clustering, we define 15 and 16 distinct cell types in the female and male pituitary, respectively, of which ten are involved in the production of a single peptide hormone. Collectively, our data provide a high-quality reference for studies on pituitary biology and the regulation of hormone production, both in fish and in vertebrates in general.
Brain networks and cognitive impairment in Parkinson’s disease
Authors: Rucco Rosaria , Lardone Anna , Liparoti Marianna , Lopez Emahnuel Troisi , De Micco Rosa , Tessitore Alessandro , Granata Carmine , Mandolesi Laura , Sorrentino Giuseppe , Sorrentino Pierpaolo 
Published: December 2020

AbstractAimThe aim of the present study is to investigate the relations between both functional connectivity and brain networks with cognitive decline, in patients with Parkinson’s disease (PD).IntroductionPD phenotype is not limited to motor impairment but, rather, a wide range of non-motor disturbances can occur, cognitive impairment being one of the commonest. However, how the large-scale organization of brain activity differs in cognitively impaired patients, as opposed to cognitively preserved ones, remains poorly understood.MethodsStarting from source-reconstructed resting-state magnetoencephalography data, we applied the PLM to estimate functional connectivity, globally and between brain areas, in PD patients with and without cognitive impairment (respectively PD-CI and PD-NC), as compared to healthy subjects (HS). Furthermore, using graph analysis, we characterized the alterations in brain network topology and related these, as well as the functional connectivity, to cognitive performance.ResultsWe found reduced global and nodal PLM in several temporal (fusiform gyrus, Heschl’s gyrus and inferior temporal gyrus), parietal (postcentral gyrus), and occipital (lingual gyrus) areas within the left hemisphere, in the gamma band, in PD-CI patients, as compared to PD-NC and HS. With regard to the global topological features, PD-CI patients, as compared to HS and PD-NC patients, showed differences in multi frequencies bands (delta, alpha, gamma) in the Leaf fraction, Tree hierarchy (both higher in PD-CI) and Diameter (lower in PD-CI). Finally, we found statistically significant correlations between the MoCA test and both the Diameter in delta band and the Tree Hierarchy in the alpha band.ConclusionOur work points to specific large-scale rearrangements that occur selectively in cognitively compromised PD patients and correlated to cognitive impairment.
A developmental transition in the sensory coding of limb kinematics in primary motor cortex
Authors: Glanz Ryan M. , Dooley James C. , Sokoloff Greta , Blumberg Mark S. 
Published: December 2020

AbstractPrimary motor cortex (M1) undergoes protracted development in mammals, functioning initially as a sensory structure. Throughout the first postnatal week in rats, M1 is strongly activated by self-generated forelimb movements—especially by the twitches that occur during active sleep. Here, we quantify the kinematic features of forelimb movements to reveal receptive-field properties of individual units within the forelimb region of M1. At postnatal day (P) 8, nearly all units were strongly modulated by movement amplitude, especially during active sleep. By P12, only a minority of units continued to exhibit amplitude-tuning, regardless of behavioral state. At both ages, movement direction also modulated M1 activity, though to a lesser extent. Finally, at P12, M1 population-level activity became more sparse and decorrelated, along with a substantial alteration in the statistical distribution of M1 responses to limb movements. These findings reveal a transition toward a more complex and informationally rich representation of movement long before M1 develops its motor functionality.