bluuebunny/crossref_metadata_2025_split huggingface dataset:
Manipulations of the olfactory circuit highlight the role of sensory stimulation in regulating sleep amount
Authors: Hsu Cynthia T , Choi Juliana Tsz Yan , Sehgal Amita 
Published: December 2020

AbstractStudy ObjectivesWhile wake duration is a major sleep driver, an important question is if wake quality also contributes to controlling sleep. In particular, we sought to determine whether changes in sensory stimulation affect sleep in Drosophila. As Drosophila rely heavily on their sense of smell, we focused on manipulating olfactory input and the olfactory sensory pathway.MethodsSensory deprivation was first performed by removing antennae or applying glue to antennae. We then measured sleep in response to neural activation, via expression of the thermally gated cation channel TRPA1, or inhibition, via expression of the inward rectifying potassium channel KIR2.1, of subpopulations of neurons in the olfactory pathway. Genetically restricting manipulations to adult animals prevented developmental effects.ResultsWe find that olfactory deprivation reduces sleep, largely independently of mushroom bodies that integrate olfactory signals for memory consolidation and have previously been implicated in sleep. However, specific neurons in the lateral horn, the other third-order target of olfactory input, affect sleep. Also, activation of inhibitory second-order projection neurons increases sleep. No single neuronal population in the olfactory processing pathway was found to bidirectionally regulate sleep, and reduced sleep in response to olfactory deprivation may be masked by temperature changes.ConclusionsThese findings demonstrate that Drosophila sleep is sensitive to sensory stimulation, and identify novel sleep-regulating neurons in the olfactory circuit. Scaling of signals across the circuit may explain the lack of bidirectional effects when neuronal activity is manipulated. We propose that olfactory inputs act through specific circuit components to modulate sleep in flies.
Isoform-specific regulation of rhythmic gene expression by alternative polyadenylation
Authors: Greenwell Ben J , Beytebiere Joshua R , Lamb Teresa M , Bell-Pedersen Deborah , Merlin Christine , Menet Jerome S 
Published: December 2020

SummaryAlternative polyadenylation (APA) generates transcript isoforms with different 3’ ends. Differences in polyadenylation sites usage, which have been associated with diseases like cancer, regulate mRNA stability, subcellular localization, and translation. By characterizing APA across the 24-hour day in mouse liver, here we show that rhythmic gene expression occurs largely in an APA isoform-specific manner, and that hundreds of arrhythmically expressed genes surprisingly exhibit a rhythmic APA isoform. The underlying mechanisms comprise isoform-specific post-transcriptional regulation, transcription factor driven expression of specific isoform, co-transcriptional recruitment of RNA binding proteins that regulate mRNA cleavage and polyadenylation, and, to a lesser extent, cell subtype-specific expression. Remarkably, rhythmic expression of specific APA isoforms generates 24-hour rhythms in 3’ UTR length, with shorter UTRs in anticipation of the mouse active phase. Taken together, our findings demonstrate that cycling transcriptomes are regulated by APA, and suggest that APA strongly impacts the rhythmic regulation of biological functions.
Prion-like C-terminal domain of TDP-43 and α-Synuclein interact synergistically to generate neurotoxic hybrid fibrils
Authors: Dhakal Shailendra , Wyant Courtney E. , George Hannah E. , Morgan Sarah E. , Rangachari Vijayaraghavan 
Published: December 2020

ABSTRACTAberrant aggregation and amyloid formation of tar DNA binding protein (TDP-43) and α-synuclein (αS) underlie frontotemporal dementia (FTD) and Parkinson’s disease (PD), respectively. Amyloid inclusions of TDP-43 and αS are also commonly co-observed in amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Emerging evidence from cellular and animal models show colocalization of the TDP-43 and αS aggregates, raising the possibility of direct interactions and co-aggregation between the two proteins. In this report, we set out to answer this question by investigating the interactions between αS and prion-like pathogenic C-terminal domain of TDP-43 (TDP-43 PrLD). PrLD is an aggregation-prone fragment generated both by alternative splicing as well as aberrant proteolytic cleavage of full length TDP-43. Our results indicate that two proteins interact in a synergistic manner to augment each others aggregation towards hybrid fibrils. While monomers, oligomers and sonicated fibrils of αS seed TDP-43 PrLD monomer aggregation, TDP-43 PrLD fibrils failed to seed αS monomers indicating selective interactions. Furthermore, αS modulates liquid droplets formed by TDP-43 PrLD and RNA to promote insoluble amyloid aggregates. Importantly, the cross-seeded hybrid aggregates show greater cytotoxicity as compared to the individual homotypic aggregates suggesting that the interactions between the two proteins have a discernable impact on cellular functions. Together, these results bring forth insights into TDP-43 PrLD – αS interactions that could help explain clinical and pathological presentations in patients with co-morbidities involving the two proteins.
Enhanced reflexive eye closure is mediated by ipRGC signals and is specific to migraine with visual aura
Authors: Kaiser Eric A , McAdams Harrison , Igdalova Aleksandra , Haggerty Edda B , Cucchiara Brett , Brainard David H , Aguirre Geoffrey K 
Published: December 2020

AbstractObjectiveTo assess the contribution of the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) and the cones to reflexive eye closure as an implicit measure of interictal photophobia in migraine.MethodsWe studied twenty participants in each of three groups: headache-free (HAf) controls, migraine without aura (MwoA), and migraine with visual aura (MwA). Participants viewed spectral pulses that selectively targeted melanopsin, the cones, or their combination while we recorded orbicularis oculi electromyography (OO-EMG) and blinking rate.ResultsTime course analysis of OO-EMG demonstrated that reflexive eye closure was tightly coupled to the spectral pulses. Compared to both the MwoA and HAf control groups, the MwA group had enhanced OO-EMG and blinking activity in response to melanopsin and cone stimulation in combination and in isolation. This response scaled with the contrast of the stimulus.ConclusionsOur findings suggest that ipRGC signals, whether elicited by melanopsin stimulation or from presumed extrinsic cone input, provide the afferent input for light-induced reflexive eye closure in a photophobic state. Participants with migraine and visual aura had a distinctly different response to visual stimulation as compared to the other two groups. This is in contrast to prior findings in this same cohort in whom higher explicit ratings of visual discomfort were found for both MwA and MwoA as compared to controls. Such a dissociation suggests distinct pathophysiology in forms of migraine, interacting with separate neural pathways by which ipRGC signals elicit implicit and explicit signs of visual discomfort.
Gene family evolution underlies cell type diversification in the hypothalamus of teleosts
Authors: Shafer Maxwell E.R. , Sawh Ahilya N. , Schier Alexander F. 
Published: December 2020

ABSTRACTHundreds of cell types form the vertebrate brain, but it is largely unknown how similar these cellular repertoires are between or within species, or how cell type diversity evolves. To examine cell type diversity across and within species, we performed single-cell RNA sequencing of ∼130,000 hypothalamic cells from zebrafish (Danio rerio) and surface- and cave-morphs of Mexican tetra (Astyanax mexicanus). We found that over 75% of cell types were shared between zebrafish and Mexican tetra, which last shared a common ancestor over 150 million years ago. Orthologous cell types displayed differential paralogue expression that was generated by sub-functionalization after genome duplication. Expression of terminal effector genes, such as neuropeptides, was more conserved than the expression of their associated transcriptional regulators. Species-specific cell types were enriched for the expression of species-specific genes, and characterized by the neo-functionalization of members of recently expanded or contracted gene families. Within species comparisons revealed differences in immune repertoires and transcriptional changes in neuropeptidergic cell types associated with genomic differences between surface- and cave-morphs. The single-cell atlases presented here are a powerful resource to explore hypothalamic cell types, and reveal how gene family evolution and the neo- and sub-functionalization of paralogs contribute to cellular diversity.
TheTomato brown rugose fruit virusmovement protein overcomesTm-22resistance while attenuating viral transport
Authors: Hak Hagit , Spiegelman Ziv 
Published: December 2020

AbstractTomato brown rugose fruit virus(ToBRFV) is a new virus of theTobamovirusgenus, causing substantial damage to tomato crops in the Middle East. Reports of recent ToBRFV outbreaks from around the world indicate an emerging global epidemic. ToBRFV overcomes all tobamovirus resistances in tomato, including the durableTm-22resistance gene. Here, we show that the ToBRFV movement protein (MPToBRFV) is the cause for overcomingTm-22resistance. Transient expression of MPToBRFVfailed to activate theTm-22resistance response. Replacement of the original MP sequences ofTomato mosaic virus(ToMV) with MPToBRFVenabled this recombinant virus to overcomeTm-22resistance. Hybrid protein analysis revealed that the resistance-breaking elements are located between MPToBRFVamino acids 1 and 216, and not the C terminus as previously assumed. Interestingly, replacement ofTobacco mosaic virus(TMV) and ToMV MPs with MPToBRFVcaused an attenuation of systemic infection of both viruses. Cell-to-cell movement analysis revealed that MPToBRFVmoves less effectively compared to the TMV MP (MPTMV). These findings suggest that overcomingTm-22is associated with attenuated MP function. This viral fitness cost may explain the high durability ofTm-22resistance, which had remained unbroken for over 60 years.
5-HT2Creceptor perturbation has bidirectional influence over instrumental vigour and restraint
Authors: Härmson Oliver , Grima Laura L. , Panayi Marios C. , Husain Masud , Walton Mark E. 
Published: December 2020

AbstractThe serotonin (5-HT) system, particularly the 5-HT2Creceptor, has consistently been implicated in behavioural control. However, while some studies have focused on the role 5-HT2Creceptors plays in regulating motivation to work for reward, others have highlighted its importance in response restraint. To date, it is unclear how 5-HT transmission at this receptor regulates the balance of response invigoration and restraint in anticipation of future reward. In addition, it remains to be established how 5-HT2Creceptors gate the influence of internal versus cue-driven processes over reward-guided actions. To elucidate these issues, we investigated the effects of administering the 5-HT2Creceptor antagonist SB242084, both systemically and directly into the nucleus accumbens core (NAcC), in rats performing a Go/No-Go task for small or large rewards. The results were compared to administration ofd-amphetamine into the NAcC, which has previously been shown to promote behavioural activation. Systemic perturbation of 5-HT2Creceptors – but crucially not intra-NAcC infusions – consistently boosted rats’ performance and instrumental vigour on Go trials when they were required to act. Concomitantly, systemic administration also reduced their ability to withhold responding for rewards on No-Go trials, particularly late in the holding period. Notably, these effects were often apparent only when the reward on offer was small. By contrast, inducing a hyperdopaminergic state in the NAcC withd-amphetamine strongly impaired response restraint on No-Go trials both early and late in the holding period, as well as speeding action initiation. Together, these findings suggest that 5-HT2Creceptor transmission, outside the NAcC, shapes the vigour of ongoing goal-directed action as well as the likelihood of responding as a function of expected reward.
A novel cell culture system modeling the SARS-CoV-2 life cycle
Authors: Ju Xiaohui , Zhu Yunkai , Wang Yuyan , Li Jingrui , Zhang Jiaxing , Gong Mingli , Ren Wenlin , Li Sai , Zhong Jin , Zhang Qiangfeng Cliff , Zhang Rong , Ding Qiang 
Published: December 2020

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the global pandemic of COVID-19, and no effective antiviral agents and vaccines are available. SARS-CoV-2 is classified as a biosafety level-3 (BLS-3) agent, impeding the basic research into its biology and the development of effective antivirals. Here, we developed a biosafety level-2 (BSL-2) cell culture system for production of transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP). This trVLP expresses a reporter gene (GFP) replacing viral nucleocapsid gene (N), which is required for viral genome packaging and virion assembly (SARS-CoV-2-GFP/ΔN trVLP). The complete viral life cycle can be achieved and exclusively confined in the cells ectopically expressing SARS-CoV or SARS-CoV-2 N proteins, but not MERS-CoV N. Genetic recombination of N suppliedin transinto viral genome was not detected, as evidenced by sequence analysis after one-month serial passages in the N-expressing cells. Moreover, intein-mediated protein trans-splicing approach was utilized to split the viral N gene into two independent vectors, and the ligated viral N protein could functionin transto recapitulate entire viral life cycle, further securing the biosafety of this cell culture model. Based on this BSL-2 SARS-CoV-2 cell culture model, we developed a 96-well format high throughput screening for antivirals discovery. We identified salinomycin, tubeimoside I, monensin sodium, lycorine chloride and nigericin sodium as potent antivirals against SARS-CoV-2 infection. Collectively, we developed a convenient and efficient SARS-CoV-2 reverse genetics tool to dissect the virus life cycle under a BSL-2 condition. This powerful tool should accelerate our understanding of SARS-CoV-2 biology and its antiviral development.
Evaluation ofin vitroactivity of copper gluconate against SARS-CoV-2 using confocal microscopy-based high content screening
Authors: Rodriguez Killian , Josselin Rigaill , Audoux Estelle , Saunier Florian , Botelho-Nevers Elisabeth , Prier Amélie , Dickerscheit Yann , Pillet Sylvie , Pozzetto Bruno , Bourlet Thomas , Verhoeven Paul O. 
Published: December 2020

ABSTRACTContextSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that emerged late in 2019 is the etiologic agent of coronavirus disease 2019 (Covid-19). There is an urgent need to develop curative and preventive therapeutics to limit the current pandemic and to prevent the re-emergence of Covid-19. This study aimed to assess thein vitroactivity of copper gluconate against SRAS-CoV-2.MethodsVero E6 cells were treated with copper gluconate 18 hours before infection. Cells were infected with a recombinant GFP expressing SARS-CoV-2. Infected cells were maintained in fresh medium containing copper gluconate for an additional 48-hour period. The infection level was measured by the confocal microscopy-based high content screening method. The cell viability in presence of copper gluconate was assessed by XTT assay.ResultsThe viability of Vero E6 cells treated with copper gluconate up to 200 μM was found to be similar to that of untreated cells, but it dropped below 40% with 400 μM of this agent. The infection rate was 23.8%, 18.9%, 20.6%, 6.9%, 5.3%,5.2% in cells treated with 0, 2, 10, 25, 50 and 100 μM of copper gluconate respectively. As compared to untreated cells, the number of infected cells was reduced by 71%, 77%, and 78% with 25, 50, and 100 μM of copper gluconate respectively (p < 0.05).ConclusionCopper gluconate was found to mitigate SARS-CoV-2 infection in Vero E6 cells. Furthers studies are needed to determine whether copper homeostasis could play a role in SARS-CoV-2 infection.GRAPHICAL ABSTRACT
Identification of four linear B-cell epitopes on the SARS-CoV-2 spike protein able to elicit neutralizing antibodies
Authors: Li Lin , Zhao Zhongpeng , Yang Xiaolan , Li Wendong , Chen Shaolong , Sun Ting , Wang Lu , He Yufei , Liu Guang , Han Xiaohan , Wen Hao , Liu Yong , Chen Yifan , Wang Haoyu , Li Jing , Su Zhongyi , Du Chen , Wang Yiting , Li Xinyang , Yang Zeqian , Wang Jie , Li Min , Wang Tiecheng , Wang Ying , Fan Yubo , Wang Hui , Zhang Jing 
Published: December 2020

AbstractSARS-CoV-2 unprecedentedly threatens the public health at worldwide level. There is an urgent need to develop an effective vaccine within a highly accelerated time. Here, we present the most comprehensive S-protein-based linear B-cell epitope candidate list by combining epitopes predicted by eight widely-used immune-informatics methods with the epitopes curated from literature published between Feb 6, 2020 and July 10, 2020. We find four top prioritized linear B-cell epitopes in the hotspot regions of S protein can specifically bind with serum antibodies from horse, mouse, and monkey inoculated with different SARS-CoV-2 vaccine candidates or a patient recovering from COVID-19. The four linear B-cell epitopes can induce neutralizing antibodies against both pseudo and live SARS-CoV-2 virus in immunized wild-type BALB/c mice. This study suggests that the four linear B-cell epitopes are potentially important candidates for serological assay or vaccine development.
Distributional changes in myelin-specific MRI markers uncover dynamics in the fornix following spatial navigation training
Authors: Anaby Debbie , Tendler Benjamin C. , Treder Matthias S. , Hametner Simon , Koeck Ulrike , Tax Chantal M.W. , Parker Greg D. , Barazany Daniel , Assaf Yaniv , Jones Derek K. 
Published: December 2020

AbstractIncreasing evidence implicates white matter (WM) dynamics supporting learning in the mature brain. Recent MRI studies, mostly using diffusion tensor MRI (DT-MRI), have demonstrated learning-induced WM changes at the microstructural level. However, while DT-MRI-derived measures have sensitivity to general WM microstructural changes, they lack compartmental specificity, making them difficult to relate to underlying cellular mechanisms, stymying deeper understanding of mechanisms supporting training-induced gains in performance. Gaining a deeper understanding demands a more detailed characterization of changes in specific WM sub-components. To this end, four microstructural MRI techniques were employed to study alterations in rat brains after 5-days of water maze training: DT-MRI; Composite Hindered and Restricted Model of Diffusion (CHARMED); magnetization transfer (MT) imaging; quantitative susceptibility mapping and R2*.The hypothesis tested here was that microstructural changes would be: (i) observed in tracts supporting spatial navigation, i.e., fornix and corpus callosum (CC); and (ii) more pronounced in the myelin-specific measures.Medians and distributions of microstructural parameters were derived along the fornix, CC and cingulum (as a comparison tract) using the ‘tractometry’ approach. Summary measures were derived from different metrics using unsupervised data reduction. Significant pre-vs-post training differences were found in the medians of two principal components loading on: (i) anisotropy indices; and (ii) MT ratio. The most striking effect, however, was seen in thedistributionsof pre-vs-post training MT ratio in the fornix, consistent with the primary hypothesis, and highlighting the value of this alternative to the standard approach (i.e., comparing means/medians of DT-MRI parameters) for studying neuroplasticityin vivo.Significance statementRecent MRI-studies have demonstrated that white matter (WM) dynamics support learning, even in the mature brain. However, most studies are based on diffusion tensor MRI (DT-MRI) measures, which although providing sensitivity to WM microstructural changes, do not provide a direct translation to the underlying cellular mechanisms making interpretation difficult. Using alternative quantitative MRI approaches, this study provided more specific subcomponent microstructural insights into the brain’s WM response to water-maze training. We show that myelin-specific MR measures show more marked changes than axonal-specific and DT-MRI measures, in WM tracts responsible for spatial navigation. The results promote adoption of these alternative approaches to DT-MRI for studying neuroplasticityin vivo.
Uncovering novel mutational signatures byde novoextraction with SigProfilerExtractor
Authors: Islam S M Ashiqul , Díaz-Gay Marcos , Wu Yang , Barnes Mark , Vangara Raviteja , Bergstrom Erik N , He Yudou , Vella Mike , Wang Jingwei , Teague Jon W , Clapham Peter , Moody Sarah , Senkin Sergey , Li Yun Rose , Riva Laura , Zhang Tongwu , Gruber Andreas J , Steele Christopher D , Otlu Burçak , Khandekar Azhar , Abbasi Ammal , Humphreys Laura , Syulyukina Natalia , Brady Samuel W , Alexandrov Boian S , Pillay Nischalan , Zhang Jinghui , Adams David J , Martincorena Iñigo , Wedge David C , Landi Maria Teresa , Brennan Paul , Stratton Michael R , Rozen Steven G , Alexandrov Ludmil B 
Published: December 2020

SUMMARYMutational signature analysis is commonly performed in genomic studies surveying cancer and normal somatic tissues. Here we present SigProfilerExtractor, an automated tool for accuratede novoextraction of mutational signatures for all types of somatic mutations. Benchmarking with a total of 34 distinct scenarios encompassing 2,500 simulated signatures operative in more than 60,000 unique synthetic genomes and 20,000 synthetic exomes demonstrates that SigProfilerExtractor outperforms thirteen other tools across all datasets with and without noise. For genome simulations with 5% noise, reflecting high-quality genomic datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true positive signatures while yielding more than 5-fold less false positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome sequenced and 19,184 whole-exome sequenced cancers reveals four previously missed mutational signatures. Two of the signatures are confirmed in independent cohorts with one of these signatures associating with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting mutational signatures, and several novel mutational signatures including a signature putatively attributed to direct tobacco smoking mutagenesis in bladder cancer and in normal bladder epithelium.