bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Voluntary Adolescent Alcohol Consumption on Encoding of Decision-Related Variables in Prefrontal Cortex
Authors: Corwin Samantha , Roitman Jamie D 
Published: March 2021

ABSTRACTThe medial and orbitofrontal regions of prefrontal cortex (PFC) have been implicated in guiding optimal behavior and updating the economic value of rewards that result from choice behaviors. Both regions mature through adolescence into early adulthood and are thus vulnerable to exposure to neurotoxins, such as alcohol, during this critical developmental window. We sought to examine how voluntary alcohol consumption during adolescence would alter long-term PFC function and subsequent decision-making behavior in adulthood. Male and female rats were given adolescent intermittent ethanol (AIE) exposure to provide voluntary access to alcohol during the period of PFC maturation. In adulthood, we assessed the long-term effects on decision-making behavior using a risk task in adulthood, while concurrently recording neural activity in orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC). While control animals’ preferences for risky rewards increased with the likelihood of their delivery, AIE animals showed an overall reduction in their preferences for the risky option with higher levels of alcohol consumption, suggesting reduced discriminability of uncertain rewards and a shift away from the potential for reward omission. During task performance, neurons in mPFC and OFC responded to events (lever press, reward delivery). In mPFC, neurons with phasic increases at the time of lever press showed a reversal from larger elevations for risky presses in control animals to larger elevations for certain presses as prior alcohol consumption increased. Neurons in mPFC generally showed less discrimination of reward outcome with increased alcohol consumption as well. In OFC, responses to lever press were largely unaffected by AIE exposure. However, encoding of reward size in OFC showed differential effects in males and females. With higher alcohol consumption in males, OFC neurons showed largest excursions from baseline activity in response to largest reward, and smallest excursions for reward omission. This discrimination was reduced as prior alcohol consumption increased. In females, neurons with increased reward-activity, showed an overall higher level of activity due to stronger responses to certain rewards that were selected more frequently. Collectively the results show diminished capacity of PFC to encode decision-related elements to guide adaptive behavior and further clarify the lasting impact of adolescent alcohol use on neural function and behavior, even in the absence of continued use.
The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2
Authors: Cathcart Andrea L. , Havenar-Daughton Colin , Lempp Florian A. , Ma Daphne , Schmid Michael A. , Agostini Maria L. , Guarino Barbara , Di iulio Julia , Rosen Laura E. , Tucker Heather , Dillen Joshua , Subramanian Sambhavi , Sloan Barbara , Bianchi Siro , Pinto Dora , Saliba Christian , Culap Katja , Wojcechowskyj Jason A , Noack Julia , Zhou Jiayi , Kaiser Hannah , Lee Sooyoung , Farhat Nisar , Chase Arthur , Montiel-Ruiz Martin , Dellota Exequiel , Park Arnold , Spreafico Roberto , Sahakyan Anna , Lauron Elvin J. , Czudnochowski Nadine , Cameroni Elisabetta , Ledoux Sarah , Kawaoka Yoshihiro , Werts Adam , Colas Christophe , Soriaga Leah , Telenti Amalio , Purcell Lisa A. , Hwang Seungmin , Snell Gyorgy , Virgin Herbert W. , Corti Davide , Hebner Christy M. 
Published: March 2021

ABSTRACTSotrovimab (VIR-7831) and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sotrovimab and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) survivor. Both mAbs contain an “LS” mutation in the Fc region to prolong serum half-life. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection. Sotrovimab and VIR-7832 neutralize wild-type and variant pseudotyped viruses and authentic virus in vitro. In addition, they retain activity against monoclonal antibody resistance mutations conferring reduced susceptibility to previously authorized mAbs. The sotrovimab/VIR-7832 epitope continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept wildtype SARS-CoV-2 infection model, animals treated with sotrovimab had less weight loss, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that sotrovimab and VIR-7832 are key agents in the fight against COVID-19.
The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity
Authors: Snoznik Carley , Medvedeva Valentina , Mojsilovic-Petrovic Jelena , Rudich Paige , Oosten James , Kalb Robert G. , Lamitina Todd 
Published: March 2021

AbstractA hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Unconventional translation of the C9orf72 repeat produces dipeptide repeat proteins (DPRs). Previously, we showed that the DPRs (PR)50 and (GR)50 are highly toxic when expressed inC. elegansand this toxicity depends on nuclear localization of the DPR. In an unbiased genome-wide RNAi screen for suppressors of (PR)50 toxicity, we identified 12 genes that consistently suppressed either the developmental arrest and/or paralysis phenotype evoked by (PR)50 expression. All of these genes have vertebrate homologs and 7/12 contain predicted nuclear localization signals. One of these genes wasspop-1, theC. eleganshomolog of SPOP, a nuclear localized E3 ubiquitin ligase adaptor only found in metazoans. SPOP is also required for (GR)50 toxicity and functions in a genetic pathway that includescul-3, which is the canonical E3 ligase partner for SPOP. Genetic or pharmacological inhibition of SPOP in mammalian primary spinal cord motor neurons suppressed DPR toxicity without affecting DPR expression levels. Finally, we find that genetic inhibition ofbet-1, theC. eleganshomolog of the known SPOP ubiquitination targets BRD2/3/4, suppresses the protective effect of SPOP mutations. Together, these data suggest a model in which SPOP promotes the DPR-dependent ubiquitination and degradation of BRD proteins. We speculate the pharmacological manipulation of this pathway, which is currently underway for multiple cancer subtypes, could also represent a novel entry point for therapeutic intervention to treat C9 FTD/ALS.Significance statementThe G4C2 repeat expansion in theC9orf72gene is a major cause of Fronto-Temporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Unusual translation of the repeat sequence produces two highly toxic dipeptide repeat proteins, PRXand GRX, which accumulate in the brain tissue of individuals with these diseases. Here, we show that PR and GR toxicity in bothC. elegansand mammalian neurons depends on the E3 ubiquitin ligase adaptor SPOP. SPOP acts through the bromodomain protein BET-1 to mediate dipeptide toxicity. SPOP inhibitors, which are currently being developed to treat SPOP-dependent renal cancer, also protect neurons against DPR toxicity. Our findings identify a highly conserved and ‘druggable’ pathway that may represent a new strategy for treating these currently incurable diseases.
RNA-silencing induces target gene relocalization toward a specialized nuage domain
Authors: Yang Yuchen , Grunwald David , Priess James R. , Mello Craig C. 
Published: March 2021

The authors wish to withdraw this manuscript and apologize for errors in the initial submission. All the original experiments were performed by YY. Unfortunately, JP and members of the Mello lab have not been able to replicate some aspects of the study. JP has failed to independently reproduce the specific results showing RNAi-triggered relocalization of target RNA, and P granule specific accumulation of (the P granule component GLH-1) as reported. The conditions/strains analyzed by JP were as follows: (1)oma-1FISH on WT worms [control, 6 hr and 12 hroma-1(RNAi)]. (2)oma-1FISH on OMA-1:GFP worms [control, 6 hr oma-1(RNAi), or 6 hr gfp(RNAi)]. (3)oma-1FISH on WT worms [control, 4hr, 6hr, 8 hr, and 10 hroma-1(RNAi)]. 10-23 gonads were analyzed per experiment. Fixation conditions were essentially as described, with the only known difference being that gonads were not exposed to detergent prior to fixation. Using YYs reagents and protocol the Mello lab has not observed an obvious relocalization of target RNA to P granules (marked by GFP::GLH-1) after 6 hrsoma-1(RNAi);n=92 gonads. CM, JP and DG consider that the published images accurately represent the image stacks provided by YY as representative, raw data, but JP and CM note configurations of FISH signals in germ nuclei and gonad anatomy that they consider unusual. CM, JP and DG have not detected any evidence of image manipulation.YY states that none of the raw image data were manipulated beyond standard adjustments for brightness and contrast prior to processing images for publication as described. However, YY reports that the images were not representative of the majority of sample gonads, and instead were pre-selected under low magnification for rare examples with asymmetrical, expanded P granules.Efforts to identify conditions that explain the rare gonads imaged by YY continue in the Mello lab, as do efforts to reproduce independently each of the other reported results; we plan to provide an update in the near future.
A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation
Authors: Lee Younghwan , Itahana Yoko , Ong Choon Chen , Itahana Koji 
Published: March 2021

AbstractAccelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the selective therapeutic targeting of this vulnerability has yielded mixed results owing to the different sensitivities of each cancer type to glucose removal and lack of insight into the underlying mechanisms of glucose deprivation-induced cell death.Here, we screened multiple cell lines to determine their sensitivities to glucose deprivation and found that the cell lines most sensitive to glucose deprivation failed to activate AMPK, a major regulator of metabolic adaptation, resulting in metabolic catastrophe.Notably, glucose deprivation-induced AMPK dysregulation and rapid cell death were observed only in cancer cell lines with high expression of cystine/glutamate antiporter xCT. While this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. We found that cystine uptake and glutamate export through xCT under glucose deprivation contributes to rapid NADPH depletion, leading to the collapse of the redox system, which subsequently inactivates AMPK by inhibitory oxidation and phosphorylation. This AMPK dysregulation caused a failure of metabolic switch to fatty acid oxidation upon glucose deprivation, resulting in mitochondrial dysfunction and cell death.Taken together, these findings suggest a novel cross-talk between the metabolic and signal transduction and reveal a metabolic vulnerability in xCT-high expressing cancer cells to glucose deprivation and provide a rationale for targeting glucose metabolism in these cancer cells.
ExoBow: A transgenic strategy to study CD63 exosomesin vivo
Authors: Adem Bárbara , Bastos Nuno , Ruivo Carolina F. , F. Vieira Patrícia , Seidler Barbara , C. Machado José , Saur Dieter , Cai Dawen , Melo Sonia A. 
Published: March 2021

ABSTRACTExosomes are described as central players in a myriad of biological processes. However, the available methodologies to study their function in complex biological systemsin vivoare still very limited. The biodistribution of endogenously produced exosomes, the ability to trace their spontaneous flow in order to identify the cell types they interact with, remains a major challenge. New tools to identify comprehensive networks of communication established by exosomes originated in distinct cell typesin vivo, are fundamental for a better understanding of their biology. Here, we describe the development of a genetically engineered mouse model that allows the expression of the mouse CD63 exosomal marker fused with one (monocolor) or up to four fluorescent proteins (multireporter), the ExoBow. The genetic design of the ExoBow transgene allows the conditional expression of the reporters in any tissue/cell-type in an inducible or non-inducible fashion. In addition, communication mediated by CD63 positive (CD63+) exosomes can be identified amongst the same tissue/cell types using the multireporter version of the model, in order to map intra-organ/tissue communication. We demonstrate the applicability of the ExoBow transgene in normal physiological conditions and in the context of cancer, using pancreas as a working model. The ExoBow comprises a unique strategy to identify intra- and inter-organ/cell-type communication mediated by CD63+exosomes. We believe this tool will contribute for a better understanding of the complex interactions occurringin vivothat underly the biology of exosomes in health and disease.
An updated genome-scale metabolic network reconstruction ofPseudomonas aeruginosaPA14 to characterize mucin-driven shifts in bacterial metabolism
Authors: Payne Dawson D. , Renz Alina , Dunphy Laura J. , Lewis Taylor , Dräger Andreas , Papin Jason A. 
Published: March 2021

AbstractMucins are present in mucosal membranes throughout the body and play a key role in the microbe clearance and infection prevention. Understanding the metabolic responses of pathogens to mucins will further enable the development of protective approaches against infections. We update the genome-scale metabolic network reconstruction (GENRE) of one such pathogen,Pseudomonas aeruginosaPA14, through metabolic coverage expansion, format update, extensive annotation addition, and literature-based curation to produce iPau21. We then validate iPau21 through MEMOTE, growth rate, carbon source utilization, and gene essentiality testing to demonstrate its improved quality and predictive capabilities. We then integrate the GENRE with transcriptomic data in order to generate context-specific models ofP. aeruginosametabolism. The contextualized models recapitulated known phenotypes of unaltered growth and a differential utilization of fumarate metabolism, while also revealing an increased utilization of propionate metabolism upon MUC5B exposure. This work serves to validate iPau21 and demonstrate its utility for providing biological insights.
Developmental innovations promote species diversification in mushroom-forming fungi
Authors: Varga Torda , Földi Csenge , Bense Viktória , Nagy László G. 
Published: March 2021

AbstractFungi evolved complex fruiting body (‘mushroom’) morphologies as adaptations to efficient spore dispersal in terrestrial habitats. Mushroom-forming fungi (Agaricomycetes) display a graded series of developmental innovations related to fruiting body morphology, however, how these evolved is largely unknown, leaving the functional biology and evolutionary principles of complex multicellularity in the third largest multicellular kingdom poorly known. Here, we show that developmental innovations of mushroom-forming fungi that enclose the spore-producing surface (hymenophore) in a protected environment display significant asymmetry in their evolution and are associated with increased diversification rates. ‘Enclosed’ development and related tissues (partial and universal veils) evolved convergently and became a widespread developmental type in clades in which it emerged. This probably mirrors increased fitness for protected fruiting body initials in terrestrial habitats, by better coping with environmental factors such as desiccation or predators, among others. We observed similar patterns in the evolution of complex hymenophore architectures, such as gills, pores or teeth, which optimize biomass-to-propagule number ratios and were found to spur diversification in mushrooms. Taken together, our results highlight new morphological traits associated with the adaptive radiation of mushroom-forming fungi and present formal phylogenetic testing of hypotheses on the reproductive ecology of a poorly known but hyperdiverse clade.
The rise and fall of the photoinhibition-related energy dissipation qI
Authors: Nawrocki Wojciech J. , Liu Xin , Raber Bailey , Hu Chen , de Vitry Catherine , Bennett Doran I. G. , Croce Roberta 
Published: March 2021

AbstractPhotosynthesis converts sunlight into chemical energy, sustaining the vast majority of the biosphere. Photosystem II (PSII), the oxygen-forming enzyme that initiates photosynthesis, is however particularly prone to light-induced damage in a process known as photoinhibition, which limits the productivity of both aquatic and land photosynthesis. Photoinhibition is associated with an energy dissipation process of unknown origin, termed qI. Here, we present a detailed biophysical and biochemical in vivo study of qIin model green alga Chlamydomonas reinhardtii. Time-resolved fluorescence measurements demonstrate the origin of qI, and indicate the PSII reaction centre as the site of the quencher. Oxygen-dependence of quenching site formation, but not photoinhibition itself, is shown, suggesting that two types of PSII damage – donor and acceptor-side impairment – can be separated. We then demonstrate that the quenching loss takes place in the absence of PSII repair, and is mediated by the degradation of photoinhibited PSII cores by the FtsH protease. Finally, we integrate data ranging from picoseconds to hours in the context of structure-function excitation energy-transferring membrane patches, revealing the extent of PSII heterogeneity from the onset of photoinhibition until the breakdown of damaged PSII.Graphical AbstractHighlightsUpon photoinhibition, oxygen sensitization results in an irreversible formation of quenching (qI) and inactivation of Photosystem IIqItakes place in the PSII reaction centrePhotoinhibition-induced D1 cleavage is much slower than qIformationFtsH metalloprotease is required to degrade quenching PSII reaction centresA multiscale energy transfer model describes heterogeneity of PSII during photoinhibition
A genome-annotated bacterial collection of the barley rhizosphere microbiota
Authors: Robertson-Albertyn Senga , Concas Federico , Brown Lynn H , Orr Jamie N , Abbott James C , George Timothy S , Bulgarelli Davide 
Published: March 2021

ABSTRACTWe generated a bacterial collection from the rhizosphere of cultivated barley (Hordeum vulgareL. ssp.vulgare) to assess taxonomic distribution of culturable members of the barley microbiota and their plant growth-promoting potential. From this we retrieved strains belonging to the dominant phyla of the plant microbiota— Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria—and gathered evidence they code for functional genes implicated in nitrogen fixation, hydrogen cyanide channels and phosphate solubilisation. Here we present an initial comparative genomic analysis of the collection revealing that plant growth-promoting potential of the culturable barley bacterial microbiota appears to have a relatively broad phylogenetic base while retaining some strain-specificity.
Mitochondrial genome sequencing of marine leukemias reveals cancer contagion between clam species in the Seas of Southern Europe
Authors: Garcia-Souto Daniel , Bruzos Alicia L. , Diaz Seila , Rocha Sara , Pequeño Ana , Roman-Lewis Camila F. , Alonso Juana , Rodriguez Rosana , Costas Damian , Rodriguez-Castro Jorge , Villanueva Antonio , Silva Luis , Valencia Jose Maria , Annona Giovanni , Tarallo Andrea , Ricardo Fernando , Cetinic Ana Bratos , Posada David , Pasantes Juan Jose , Tubio Jose M. C. 
Published: March 2021

ABSTRACTClonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukemia-like transmissible cancers, called hemic neoplasia, have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with hemic neoplasia, from two sampling points located more than 1,000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis in tumour tissues from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe.
Coding Recognition of the Dose-Effect Interdependence of Small Biomolecules Encrypted on Paired Chromatographic-Based Microassay Arrays
Authors: Deng Yifeng , Lin Zhenpeng , Cheng Yuan 
Published: March 2021

AbstractThe discovery of small biomolecules suffers from the lack of a comprehensive framework to express the intrinsic correlation between bioactivity and contributing small molecules in complex samples with molecular and bioactivity diversity. Here, by mapping a sample’s 2D-HPTLC fingerprint to microplates, the paired chromatographic-based microassay arrays are created, which can be used as quasi-chip to characterize multiple attributes of chromatographic components; and as the array differential expression of the bioactivity and molecular attributes of irregular chromatographic spots for dose-effect interdependent encoding; and also as the automatic-collimated array mosaics of the multi-attributes of each component itself encrypted by its chromatographic fingerprint. Based on this homologous framework, we propose a correlating recognition strategy for small-biomolecules through their self-consistent chromatographic behavior characteristics. In the approach, the small-biomolecule recognition in diverse compounds is transformed into a constraint satisfaction problem, which is addressed through examining the dose-effect interdependence of the homologous 2D code pairs by array matching algorithm, instead of preparing diverse compound monomers of complex test sample for identifying item-by-item. Furtherly, considering the dose-effect interdependent 2D code pairs as links and the digital-specific quasimolecular ions as nodes, an extendable self-consistent framework that correlates mammalian cell phenotypic and target-based bioassays with small biomolecules is established. Therefore, the small molecule contributions and the correlations of bioactivities, as well as their pathway can be comprehensively revealed, so as to improve the reliability and efficiency of screening. This strategy was successfully applied to galangal, and practiced the high-throughput digital preliminary screening of small-biomolecules in a natural product.HighlightRapid self-recognition of small biomolecules in diverse samples without pre-isolation Recognized by dose-effect interdependency developed from homologous TLC fingerprint Matching of HPTLC-based molecular imprinting and bioautography on microassay arrays Microarray-based differential expression of substance attributes instead of spot scan An array framework for combining phenotype-based and target-based assays with TLC-MSToC graphic