bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2
Authors: Eaton Muriel , Zhang Jingliang , Ma Zhixiong , Park Anthony C. , Lietzke Emma , Romero Chloé Maricela , Liu Yushuang , Coleman Emily Rose , Chen Xiaoling , Xiao Tiange , Huang Zhuo , Skarnes William C. , Koss Wendy A. , Yang Yang 
Published: June 2020

ABSTRACTRecent large-scale genomic studies have revealedSCN2Aas one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability.SCN2Aencodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) ofScn2ais perinatal lethal, whereas heterozygous knockout ofScn2aresults in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction ofScn2aexpression, we characterized aScn2adeficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-functionSCN2Adisorders. This model produces viable homozygous mice (Scn2agtKO/gtKO) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. AlthoughScn2agtKO/gtKOadult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novelScn2agene trap knockout mouse thus provides a unique model to study pathophysiology associated withScn2adeficiency.
A graph-based approach identifies dynamic H-bond communication networks in spike protein S of SARS-CoV-2
Authors: Karathanou Konstantina , Lazaratos Michalis , Bertalan Éva , Siemers Malte , Buzar Krzysztof , Schertler Gebhard F.X. , del Val Coral , Bondar Ana-Nicoleta 
Published: June 2020

AbstractCorona virus spike protein S is a large homo-trimeric protein embedded in the membrane of the virion particle. Protein S binds to angiotensin-converting-enzyme 2, ACE2, of the host cell, followed by proteolysis of the spike protein, drastic protein conformational change with exposure of the fusion peptide of the virus, and entry of the virion into the host cell. The structural elements that govern conformational plasticity of the spike protein are largely unknown. Here, we present a methodology that relies upon graph and centrality analyses, augmented by bioinformatics, to identify and characterize large H-bond clusters in protein structures. We apply this methodology to protein S ectodomain and find that, in the closed conformation, the three protomers of protein S bring the same contribution to an extensive central network of H-bonds, has a relatively large H-bond cluster at the receptor binding domain, and a cluster near a protease cleavage site. Markedly different H-bonding at these three clusters in open and pre-fusion conformations suggest dynamic H-bond clusters could facilitate structural plasticity and selection of a protein S protomer for binding to the host receptor, and proteolytic cleavage. From analyses of spike protein sequences we identify patches of histidine and carboxylate groups that could be involved in transient proton binding.
Spatiotemporal whole-brain dynamics of auditory patterns recognition
Authors: Bonetti L. , Brattico E. , Carlomagno F. , Cabral J. , Stevner A. , Deco G. , Whybrow P.C. , Pearce M. , Pantazis D. , Vuust P. , Kringelbach M.L 
Published: June 2020

ABSTRACTMusic is a non-verbal human language, built on logical structures and articulated in balanced hierarchies between sounds, offering excellent opportunities to explore how the brain creates meaning for complex spatiotemporal auditory patterns. Using the high temporal resolution of magnetoencephalography in 70 participants, we investigated their unfolding brain dynamics during the recognition of previously memorized J.S. Bach’s musical patterns from prelude in C minor BWV 847 compared to novel patterns matched in terms of entropy and information content. Remarkably, the recognition of the memorized music ignited a widespread brain network comprising primary auditory cortex, superior temporal gyrus, insula, frontal operculum, cingulate gyrus, orbitofrontal cortex, basal ganglia, thalamus and hippocampus. Furthermore, measures of both brain activity and functional connectivity presented an overall increase over time, following the evolution and unfolding of the memorized musical patterns. Specifically, while the auditory cortex responded mainly to the first tones of the patterns, the activity and synchronization of higher-order brain areas such as cingulate, frontal operculum, hippocampus and orbitofrontal cortex largely increased over time, arguably representing the key whole-brain mechanisms for conscious recognition of auditory patterns as predicted by the global neuronal workspace hypothesis. In conclusion, our study described the fine-grained whole-brain activity and functional connectivity dynamics responsible for processing and recognition of previously memorized music. Further, the study highlights how the use of musical patterns in combination with a wide array of analytical tools and neuroscientific measures spanning from decoding to fast neural phase synchronization can shed new light on meaningful, complex cognitive processes.
Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2
Authors: Custódio Tânia F. , Das Hrishikesh , Sheward Daniel J , Hanke Leo , Pazicky Samuel , Pieprzyk Joanna , Sorgenfrei Michèle , Schroer Martin , Gruzinov Andrey , Jeffries Cy , Graewert Melissa , Svergun Dmitri , Dobrev Nikolay , Remans Kim , Seeger Markus A. , McInerney Gerald M , Murrell Ben , Hällberg B. Martin , Löw Christian 
Published: June 2020

AbstractThe coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC50of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed a novel conformation of the spike where two RBDs are in the ‘up’ ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.
Rapid molecular evolution ofSpiroplasmasymbionts ofDrosophila
Authors: Gerth Michael , Martinez-Montoya Humberto , Ramirez Paulino , Masson Florent , Griffin Joanne S. , Aramayo Rodolfo , Siozios Stefanos , Lemaitre Bruno , Mateos Mariana , Hurst Gregory D.D. 
Published: June 2020

AbstractSpiroplasmaare a group of Mollicutes whose members include plant pathogens, insect pathogens, and endosymbionts of animals.Spiroplasmaphenotypes have been repeatedly observed to be spontaneously lost inDrosophilacultures, and several studies have documented a high genomic turnover inSpiroplasmasymbionts and plant pathogens. These observations suggest thatSpiroplasmaevolves quickly in comparison to other insect symbionts. Here, we systematically assess evolutionary rates and patterns ofSpiroplasma poulsonii, a natural symbiont ofDrosophila. We analysed genomic evolution ofsHy within flies, andsMel withinin vitroculture over several years. We observed thatS. poulsoniisubstitution rates are among the highest reported for any bacteria, and around two orders of magnitude higher compared with other inherited arthropod endosymbionts. The absence of mismatch repair locimutSandmutLis conserved acrossSpiroplasmaand likely contributes to elevated substitution rates. Further, the closely related strainssMel andsHy (>99.5% sequence identity in shared loci) show extensive structural genomic differences, which potentially indicates a higher degree of host adaptation insHy, a protective symbiont ofDrosophila hydei. Finally, comparison across diverseSpiroplasmalineages confirms previous reports of dynamic evolution of toxins, and identifies loci similar to the male-killing toxin Spaid in severalSpiroplasmalineages and other endosymbionts. Overall, our results highlight the peculiar nature ofSpiroplasmagenome evolution, which may explain unusual features of its evolutionary ecology.
TIR-1/SARM1 Inhibits Axon Regeneration
Authors: Julian Victoria , Byrne Alexandra B. 
Published: June 2020

AbstractAn injured axon has two choices, regenerate or degenerate. In many neurons, the result is catastrophic axon degeneration and a failure to regenerate. To coerce the injured nervous system to regenerate, the molecular mechanisms that regulate both axon regeneration and degeneration need to be defined. We found that TIR-1/SARM1, a key regulator of axon degeneration, inhibits regeneration of injured motor axons. Loss oftir-1function both reduces the frequency with which severed axon fragments degenerate and increases the frequency of axon regeneration. The increased regeneration intir-1mutants is not a secondary consequence of its effects on degeneration. Rather, TIR-1 carries out each of these opposing functions cell autonomously by regulating independent downstream genetic pathways. While promoting axon degeneration with the DLK-1 mitogen activated protein kinase (MAPK) signaling cascade, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade. Our finding that TIR-1 regulates both axon regeneration and degeneration provides critical insight into how axons coordinately regulate the two key responses to injury, consequently informing approaches to manipulate the balance between these responses towards repair.
Bridging the gap – Spontaneous fluctuations shape stimulus-evoked spectral power
Authors: Wainio-Theberge Soren , Wolff Annemarie , Northoff Georg 
Published: June 2020

AbstractSpontaneous fluctuations of neural activity have been shown to influence trial-by-trial variation in perceptual, cognitive, and behavioural outcomes. This implies that these fluctuations affect stimulus-related neural processes, and hence should affect stimulus-evoked neural activity. However, the mechanisms by which spontaneous neural activity shapes stimulus-evoked neural activity have rarely been examined. Employing a large-scale magnetoencephalographic dataset, as well as an electroencephalographic replication dataset, we observed that for high-frequency power, high pre-stimulus activity leads to greater evoked desynchronization (negative interaction); in contrast, for low-frequency power, high pre-stimulus activity induces greater event-related synchronization (positive interaction). We show that both positive and negative interactions are manifest primarily in cortical oscillations, rather than scale-free activity, and can also be observed in the time domain. In summary, we demonstrate positive and negative spontaneous-evoked interaction in multiple electrophysiological processes; these mechanisms “bridge the gap” between spontaneous and evoked activity and provide novel insights into how spontaneous activity influences behaviour and cognition.
Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts
Authors: Zhu Kaiyi , Cai Lingyi , Cui Chenqian , Anastassiou Dimitris 
Published: June 2020

AbstractDuring the last ten years, many research results have been referring to a particular type of cancer-associated fibroblasts associated with poor prognosis, invasiveness, metastasis and resistance to therapy in multiple cancer types, characterized by a gene expression signature with prominent presence of genes COL11A1, THBS2 and INHBA. Identifying the underlying biological mechanisms responsible for their creation may facilitate the discovery of targets for potential pan-cancer therapeutics. Using a novel computational approach for single-cell gene expression data analysis identifying the dominant cell populations in a sequence of samples from patients at various stages, we conclude that these fibroblasts are produced by a pan-cancer cellular transition originating from a particular type of adipose-derived stromal cells naturally present in the stromal vascular fraction of normal adipose tissue, having a characteristic gene expression signature. Focusing on a rich pancreatic cancer dataset, we provide a detailed description of the continuous modification of the gene expression profiles of cells as they transition from APOD-expressing adipose-derived stromal cells to COL11A1-expressing cancer-associated fibroblasts, identifying the key genes that participate in this transition. These results also provide an explanation to the well-known fact that the adipose microenvironment contributes to cancer progression.Author summaryComputational analysis of rich gene expression data at the single-cell level from cancer biopsies can lead to biological discoveries about the nature of the disease. Using a computational methodology that identifies the gene expression profile of the dominant cell population for a particular cell type in the microenvironment of tumors, we observed that there is a remarkably continuous modification of this profile among patients, corresponding to a cellular transition. Specifically, we found that the starting point of this transition has a unique characteristic signature corresponding to cells that are naturally residing in normal adipose tissue. We also found that the endpoint of the transition has another characteristic signature corresponding to a particular type of cancer-associated fibroblasts with prominent expression of gene COL11A1, which has been found strongly associated with invasiveness, metastasis and resistance to therapy in multiple cancer types. Our results provide an explanation to the well-known fact that the adipose tissue contributes to cancer progression, shedding light on the biological mechanism by which tumor cells interact with the adipose microenvironment. We provide a detailed description of the changing profile during the transition, identifying associated genes as potential targets for pan-cancer therapeutics inhibiting the underlying mechanism.
Proto-sex locus in large yellow croaker provides insights into early evolution of the sex chromosome
Authors: Wang Zhiyong , Xiao Shijun , Cai Mingyi , Han Zhaofang , Li Wanbo , Xie Yangjie , Xu Guicai , Lin Aiqiang , Zhang Yan , Ye Kun , Luo Huiyu , Liao Mengxiang , Han Fang , Liu Xiande , Zhang Dongling , Wang Qiurong , Wang Bi , Li Weiming , Li Jiong-Tang 
Published: June 2020

AbstractAutosomal origins of heterogametic sex chromosomes have been inferred frequently from suppressed recombination and gene degeneration manifested in incompletely differentiated sex chromosomes. However, the initial transition of an autosome region to a proto-sex locus has been not explored in depth. By assembling and analyzing a chromosome-level draft genome, we found a recent (evolved 0.26 million years ago), highly homologous, anddmrt1containing sex-determination locus with slightly reduced recombination in large yellow croaker (Larimichthys crocea), a teleost species with genetic sex determination (GSD) and with undifferentiated sex chromosomes. We observed genomic homology and polymorphic segregation of the proto-sex locus between sexes. Expression ofdmrt1showed a stepwise increase in the development of testis, but not in the ovary. We infer that the inception of the proto-sex locus involves a few divergences in nucleotide sequences and slight suppression of recombination in an autosome region. In androgen-induced sex reversal of genetic females, in addition todmrt1, genes in the conserveddmrt1cluster, and the rest of the sex determination network were activated. We provided evidence that broad functional links were shared by genetic sex determination and environmental sex reversal.
Gene expression imputation provides insight into the genetic architecture of frontotemporal dementia
Authors: Reus Lianne M. , Pasaniuc Bogdan , Posthuma Danielle , Boltz Toni ,   International FTD-Genomics Consortium (IFGC), Pijnenburg Yolande A.L. , Ophoff Roel A 
Published: June 2020

AbstractThe etiology of genetically sporadic frontotemporal dementia is poorly understood. Although genome-wide association studies for frontotemporal dementia have identified a small number of candidate risk regions, most of the risk genes remain largely unknown. To identify candidate genes with predicted expression levels associated with frontotemporal dementia, we integrated genome-wide summary statistics with external reference gene expression data, using a transcriptome-wide association studies approach.FUSION software was used to leverage summary statistics on frontotemporal dementia (n=2,340 cases, n=7,252 controls) and clinical subtypes (behavioral variant frontotemporal dementia n=1,337 cases/2,754 controls; semantic dementia n=308 cases/616 controls; progressive non-fluent aphasia n=269 cases/538 controls, frontotemporal dementia with motor neuron disease n=200 cases/400 controls) from the International Frontotemporal Dementia Genomics Consortium with 53 expression quantitative loci tissue type panels (n=12,205 from five consortia). Significance was assessed using a 5% false discovery rate threshold. We identified 73 significant gene-tissue associations for frontotemporal dementia, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n=19 genes, 26%). Furthermore, the 17q21.31 inversion locus contained 23 significant associations, representing six unique genes whose predicted expression associated with frontotemporal dementia. Other top hits includedSEC22Bon chromosome 1, a gene involved in vesicle trafficking,TRGV5on chromosome 17 andZNF302on chromosome 19. A single gene finding was observed for behavioral variant frontotemporal dementia (i.e.,RAB38on chromosome 11) with evidence from multiple tissue types. For the other clinical subtypes no significant associations were observed.We used transcriptome-wide association studies to prioritize candidate genes for frontotemporal dementia and identified a number of specific genes, including potential novel candidate genes (such asSEC22B) and previously reported risk regions (e.g., 17q.21.31). Most significant associations were observed in the dorsolateral prefrontal cortex, despite the modest sample size of the gene expression reference panel of this tissue type. This suggests that our findings are specific to frontotemporal dementia and are likely to be biologically relevant highlights of genes at different frontotemporal dementia risk loci that are contributing to the disease pathology.
Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons
Authors: Allodi Ilary , Montañana-Rosell Roser , Selvan Raghavendra , Löw Peter , Kiehn Ole 
Published: June 2020

AbstractALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle fibers exhibit preferential degeneration. The reason for differential vulnerability of fast motor neurons, and its consequence on motor output is not known. Here, we show that fast motor neurons receive more inhibitory synaptic inputs than slow motor neurons, and loss of inhibitory synapses onto fast motor neurons precedes disease progression in theSOD1G93Amouse model of ALS. Loss of inhibitory synapses on fast motor neurons is accounted for by a loss of synapses from inhibitory V1 spinal interneurons. Deficits in V1-motor neuron connectivity appear prior to motor neuron death and are paralleled by development of specificSOD1G93Alocomotor deficits. These distinctSOD1G93Alocomotor deficits are phenocopied by silencing of inhibitory V1 spinal interneurons in wild-type mice. Silencing inhibitory V1 spinal interneurons does not exacerbateSOD1G93Alocomotor deficits, suggesting phenotypic pathway interaction. Our study identifies a potential cell non-autonomous source of motor neuronal vulnerability in ALS, and links ALS-induced changes in locomotor phenotypes to inhibitory V1 interneurons.
A rapid, highly sensitive and open-access SARS-CoV-2 detection assay for laboratory and home testing
Authors: Kellner Max J. , Ross James J. , Schnabl Jakob , Dekens Marcus P.S. , Heinen Robert , Grishkovskaya Irina , Bauer Benedikt , Stadlmann Johannes , Menéndez-Arias Luis , Straw Andrew D. , Fritsche-Polanz Robert , Traugott Marianna , Seitz Tamara , Zoufaly Alexander , Födinger Manuela , Wenisch Christoph , Zuber Johannes ,   Vienna Covid-19 Detection Initiative (VCDI), Pauli Andrea , Brennecke Julius 
Published: June 2020

AbstractGlobal efforts to combat the Covid-19 pandemic caused by SARS-CoV-2 still heavily rely on RT-qPCR-based diagnostic tests. However, their high cost, moderate throughput and reliance on sophisticated equipment limit widespread implementation. Loop-mediated isothermal amplification after reverse transcription (RT-LAMP) is an alternative detection method that has the potential to overcome these limitations. We present a rapid, robust, sensitive and versatile RT-LAMP based SARS-CoV-2 detection assay. Our forty-minute procedure bypasses a dedicated RNA isolation step, is insensitive to carry-over contamination, and uses a hydroxynaphthol blue (HNB)-based colorimetric readout, which allows robust SARS-CoV-2 detection from various sample types. Based on this assay, we have substantially increased sensitivity and scalability by a simple nucleic acid enrichment step (bead-LAMP), established a pipette-free version for home testing (HomeDip-LAMP), and developed open source enzymes that can be produced in any molecular biology setting. Our advanced, universally applicable RT-LAMP assay is a major step towards population-scale SARS-CoV-2 testing.
Data integration uncovers the metabolic bases of phenotypic variation in yeast
Authors: Petrizzelli Marianyela , de Vienne Dominique , Nidelet Thibault , Noûs Camille , Dillmann Christine 
Published: June 2020

The relationship between different levels of integration is a key feature for understanding the genotype-phenotype map.Here, we describe a novel method of integrated data analysis that incorporates protein abundance data into constraint-based modeling to elucidate the biological mechanisms underlying phenotypic variation. Specifically, we studied yeast genetic diversity at three levels of phenotypic complexity in a population of yeast obtained by pairwise crosses of eleven strains belonging to two species,Saccha-romyces cerevisiaeandS. uvarum. The data included protein abundances, integrated traits (life-history/fermentation) and computational estimates of metabolic fluxes.Results highlighted that the negative correlation between production traits such as population carrying capacity (K) and traits associated with growth and fermentation rates (Jmax) is explained by a differential usage of energy production pathways: a highKwas associated with high TCA fluxes, while a highJmaxwas associated with high glycolytic fluxes. Enrichment analysis of protein sets confirmed our results.This powerful approach allowed us to identify the molecular and metabolic bases of integrated trait variation, and therefore has a broad applicability domain.