bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gliotransmission of D-serine promotes thirst-directed behaviors inDrosophila
Authors: Park Annie , Croset Vincent , Otto Nils , Agarwal Devika , Treiber Christoph D. , Meschi Eleanora , Sims David , Waddell Scott 
Published: March 2022

AbstractThirst emerges from a range of cellular changes that ultimately motivate an animal to consume water. Although thirst-responsive neuronal signals have been reported, the full complement of brain responses is unclear. Here we identify molecular and cellular adaptations in the brain using single-cell sequencing of water deprivedDrosophila. Water deficiency primarily altered the glial transcriptome. Screening the regulated genes revealed astrocytic expression of theastray-encoded phosphoserine phosphatase to bi-directionally regulate water consumption. Astray synthesizes the gliotransmitter D-serine and vesicular release from astrocytes is required for drinking. Moreover, dietary D-serine rescuesaay-dependent drinking deficits while facilitating water consumption and expression of water-seeking memory. D-serine action requires binding to neuronal NMDA-type glutamate receptors. Fly astrocytes contribute processes to tripartite synapses and the proportion of astrocytes that are themselves activated by glutamate increases with water deprivation. We propose that thirst elevates astrocytic D-serine release, which awakens quiescent glutamatergic circuits to enhance water procurement.
TOR coordinates Cytokinin and Gibberellin signals mediating development and defense
Authors: Marash Iftah , Gupta Rupali , Anand Gautam , Leibman-Markus Meirav , Lindner Naomi , Israeli Alon , Nir Dov , Avni Adi , Bar Maya 
Published: March 2022

AbstractPlants constantly perceive and process environmental signals and balance between the energetic demands of growth and defense. Growth arrest upon pathogen attack was previously suggested to result from a redirection of the plants’ metabolic resources towards the activation of plant defense. The energy sensor Target of Rapamycin (TOR) kinase is a conserved master coordinator of growth and development in all eukaryotes. Although TOR is positioned at the interface between development and defense, little is known about the mechanisms in which TOR may potentially regulate the relationship between these two modalities. The plant hormones cytokinin (CK) and gibberellin (GA) execute various aspects of plant development and defense. The ratio between CK and GA was reported to determine the outcome of developmental programs. Here, investigating the interplay between TOR-mediated development and TOR-mediated defense in tomato, we found thatTORsilencing resulted in rescue of several different aberrant developmental phenotypes, demonstrating that TOR is required for the execution of developmental cues. In parallel,TORinhibition enhanced immunity in genotypes with a low CK/GA ratio but not in genotypes with a high CK/GA ratio. TOR-inhibition mediated disease resistance was found to depend on developmental status, and was abolished in strongly morphogenetic leaves, while being strongest in mature, differentiated leaves. CK repressed TOR activity, suggesting that CK-mediated immunity may rely on TOR downregulation. At the same time, TOR activity was promoted by GA, andTORsilencing reduced GA sensitivity, indicating that GA signaling requires normal TOR activity. Our results demonstrate that TOR likely acts in concert with CK and GA signaling, executing signaling cues in both defense and development. Thus, differential regulation of TOR or TOR-mediated processes could regulate the required outcome of development-defense prioritization.
Plastid-specific RsmD methyltransferase and ribosome maturation factor RimM are crucial for 16S rRNA maturation and proteostasis
Authors: Liu Kaiwei , Lee Keun Pyo , Duan Jianli , Kim Eun Yu , Singh Rahul Mohan , Di Minghui , Meng Zhuoling , Kim Chanhong 
Published: March 2022

ABSTRACTChloroplast pre-ribosomal RNA (rRNA) undergoes maturation, which is critical for ribosome assembly. While the central and auxiliary factors in rRNA maturation have been elucidated in bacteria, their mode of action remains largely unexplored in chloroplasts. We now reveal chloroplast-specific factors involved in 16S rRNA maturation, RsmD methyltransferase (AtRsmD) and ribosome maturation factor RimM-like protein (AtRimM) in Arabidopsis thaliana. A forward genetic screen aimed to find suppressors of the Arabidopsis yellow variegated 2 (var2) mutant defective in photosystem II (PSII) quality control found a causal nonsense mutation in AtRsmD. The substantially impaired 16S rRNA maturation and translation due to the mutation rescued the leaf variegation phenotype by lowering the levels of PSII core proteins in var2. The subsequent co-immunoprecipitation coupled with mass spectrometry analyses and bimolecular fluorescence complementation assay found that AtRsmD interacts with AtRimM. Consistent with their interaction, loss of AtRimM also considerably impairs 16S rRNA maturation, with less methylation in m2G915 in 16S rRNA catalyzed by AtRsmD. The atrimM mutation also rescued var2 mutant phenotypes, corroborating the functional interplay between AtRsmD and AtRimM towards 16S rRNA maturation and chloroplast proteostasis.
Protease Activity Analysis: A Toolkit for Analyzing Enzyme Activity Data
Authors: Soleimany Ava P. , Alonso Carmen Martin , Anahtar Melodi , Wang Cathy S. , Bhatia Sangeeta N. 
Published: March 2022

AbstractAnalyzing the activity of proteases and their substrates is critical to defining the biological functions of these enzymes and to designing new diagnostics and therapeutics that target protease dysregulation in disease. While a wide range of databases and algorithms have been created to better predict protease cleavage sites, there is a dearth of computational tools to automate analysis of in vitro and in vivo protease assays. This necessitates individual researchers to develop their own analytical pipelines, resulting in a lack of standardization across the field. To facilitate protease research, here we present Protease Activity Analysis (PAA), a toolkit for the preprocessing, visualization, machine learning analysis, and querying of protease activity datasets. PAA leverages a Python-based object-oriented implementation that provides a modular framework for streamlined analysis across three major components. First, PAA provides a facile framework to query datasets of synthetic peptide substrates and their cleavage susceptibilities across a diverse set of proteases. To complement the database functionality, PAA also includes tools for the automated analysis and visualization of user-input enzyme-substrate activity measurements generated through in vitro screens against synthetic peptide substrates. Finally, PAA can supports a set of modular machine learning functions to analyze in vivo protease activity signatures that are generated by activity-based sensors. Overall, PAA offers the protease community a breadth of computational tools to streamline research, taking a step towards standardizing data analysis across the field and in chemical biology and biochemistry at large.
Helix 8 in chemotactic receptors of the complement system
Authors: Wisniewski Szymon , Dragan Paulina , Makal Anna , Latek Dorota 
Published: March 2022

AbstractHost response to infection involves activation of the complement system leading to producing of anaphylotoxins C3a and C5a. A complement factor C5a exerts its effect through activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and allosteric antagonists of C5aR1 are a novel strategy for anti-inflammatory therapies. Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures. Analysis of mutual interactions of subunits in the C5aR1 - G protein complex has provided new insights into the activation mechanism of this distinct receptor. By comparison of C5aR1 and its homolog C5aR2 we explained differences between their signaling pathways on the molecular level. A comparison of microsecond MD trajectories started from active and inactive receptor conformations also enabled to elucidate details of local and global changes in the transmembrane domain induced by interactions with the Gα subunit and to explain the impact of inverted H8 on the receptor activation.
Sequential epiretinal stimulation improves discrimination in simple shape discrimination tasks only
Authors: Christie Breanne , Sadeghi Roksana , Kartha Arathy , Caspi Avi , Tenore Francesco V. , Klatzky Roberta L. , Dagnelie Gislin , Billings Seth 
Published: March 2022

AbstractObjectiveElectrical stimulation of the retina can elicit flashes of light called phosphenes, which can be used to restore rudimentary vision for people with blindness. Functional sight requires stimulation of multiple electrodes to create patterned vision, but phosphenes tend to merge together in an uninterpretable way. Sequentially stimulating electrodes in human visual cortex has recently demonstrated that shapes could be “drawn” with better perceptual resolution relative to simultaneous stimulation. The goal of this study was to evaluate if sequential stimulation would also form clearer shapes when the retina is the neural target.ApproachTwo human participants with retinitis pigmentosa who had Argus® II retinal prostheses participated in this study. We evaluated different temporal parameters for sequential stimulation in phosphene shape mapping and forced-choice discrimination tasks. For the discrimination tasks, performance was compared between stimulating electrodes simultaneously versus sequentially.Main resultsPhosphenes elicited by different electrodes were reported as vastly different shapes. Sequential electrode stimulation outperformed simultaneous stimulation in simple discrimination tasks, in which shapes were created by stimulating 3-4 electrodes, but not in more complex discrimination tasks involving 5+ electrodes. For sequential stimulation, the optimal pulse train duration was 200 ms when stimulating at 20 Hz and the optimal gap interval was tied between 0 and 50 ms. Efficacy of sequential stimulation also depended strongly on selecting electrodes that elicited phosphenes with similar shapes and sizes.SignificanceAn epiretinal prosthesis can produce coherent simple shapes with a sequential stimulation paradigm, which can be used as rudimentary visual feedback. However, success in creating more complex shapes, such as letters of the alphabet, is still limited. Sequential stimulation may be most beneficial for epiretinal prostheses in simple tasks, such as basic navigation, rather than complex tasks such as object identification.
Metabolic changes induced by pharmacological castration of young, healthy men: a study of the plasma metabolome
Authors: Guedes Jéssica de Siqueira , Pla Indira , Sahlin K. Barbara , Monnerat Gustavo , Appelqvist Roger , Marko-Varga György , Giwercman Aleksander , Domont Gilberto Barbosa , Sanchez Aniel , Nogueira Fábio César Sousa , Malm Johan 
Published: March 2022

ABSTRACTTestosterone is a hormone that plays a key role in carbohydrate, fat, and protein metabolism. Testosterone deficiency is associated with multiple comorbidities, e.g., metabolic syndrome and type 2 diabetes. Despite its importance in many metabolic pathways, the mechanisms by which it controls metabolism are not fully understood. The present study investigated the short-term metabolic changes of pharmacologically induced castration and testosterone supplementation in healthy young males. Thirty subjects were submitted to testosterone depletion (TD) followed by testosterone supplementation (TS). Plasma samples were collected three times corresponding to basal, low, and restored testosterone levels. An untargeted metabolomics study was performed by liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) to monitor the metabolic changes induced by the altered hormone levels. Our results demonstrated that TD is associated with major metabolic changes partially restored by TS. Carnitine and amino acid metabolism were the metabolic pathways most impacted by variations in testosterone. Furthermore, our results also indicate that LH and FSH might strongly alter the plasma levels of indoles and lipids, especially glycerophospholipids and sphingolipids. Our results demonstrate major metabolic changes induced by low testosterone that may be important for understanding the mechanisms behind the association of testosterone deficiency and its comorbidities.
Selection of optimum formulation of RBD-based protein sub-unit covid19 vaccine (Corbevax) based on safety and immunogenicity in an open-label, randomized Phase-1 and 2 clinical studies
Authors: Thuluva Subhash , Paradkar Vikram , Turaga Kishore , Gunneri SubbaReddy , Yerroju Vijay , Mogulla Rammohan , Kyasani Mahesh , Manoharan Senthil Kumar , Medigeshi Guruprasad , Singh Janmejay , Shaman Heena , Singh Chandramani , Venkateshwar Rao A 
Published: March 2022

ABSTRACTBackgroundWe present the data from an open-label study involved in the selection of optimum formulation of RBD-based protein sub-unit COVID-19 vaccine.MethodsThe randomized Phase-1/2 trial followed by a Phase-2 trial was carried out to assess safety and immunogenicity of different formulation of COVID-19 vaccine (Corbevax) and select an optimum formulation for a phase 3 study. Healthy adults without a history of Covid-19 vaccination or SARS-CoV-2 infection, were enrolled.FindingsLow incidence of adverse events were reported post-vaccination of different Corbevax formulations and majority were mild in nature and no Grade-3 or serious adverse events were observed. All formulations in Phase-1/2 study showed similar profile of humoral and cellular immune-response with higher response associated with increasing CpG1018 adjuvant content at same RBD protein content. Hence, high concentration of CpG1018 was tested in phase-2 study, which showed significant improvement in immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, nAb-titers and cellular immune-responses while maintaining the safety profile. Interestingly, binding and neutralizing antibody titers were persisted consistently till 6 months post second vaccine dose.InterpretationsCorbevax was well tolerated with no observed safety concerns. Neutralizing antibody titers were suggestive of high vaccine effectiveness compared with human convalescent plasma or protective thresholds observed during vaccine efficacy trials of other COVID-19 vaccines. The study was prospectively registered with clinical trial registry of India-CTRI/2021/06/034014 and CTRI/2020/11/029032.FundingBill & Melinda Gates Foundation, BIRAC-division of Department of Biotechnology, Govt of India, and the Coalition for Epidemic Preparedness Innovations funded the study.
Booster vaccination protection against SARS-CoV-2 infections in young adults during an Omicron BA.1-predominant period: a retrospective cohort study
Authors: Wan Jiayue , Cazer Casey L. , Clarkberg Marin E. , Henderson Shane G. , Lee Scarlett E. , Meredith Genevive , Osman Marwan , Shmoys David B. , Frazier Peter I. 
Published: March 2022

AbstractBackgroundWhile booster vaccinations clearly reduce the risk of severe COVID-19 and death, the impact of boosters on SARS-CoV-2 infection has not been fully characterized: doing so requires understanding their impact on asymptomatic and mildly symptomatic infections that often go unreported but nevertheless play an important role in spreading SARS-CoV-2. We sought to estimate the impact of COVID-19 booster doses on SARS-CoV-2 infection in a vaccinated population of young adults during an Omicron BA.1-predominant period.Methods and FindingsWe implemented a cohort study of young adults in a college environment (Cornell University’s Ithaca campus) from a period when Omicron BA.1 was the predominant SARS-CoV-2 variant on campus (December 5 to December 31, 2021). Participants included 15,800 university students who completed an initial vaccination series with a vaccine approved by the World Health Organization for emergency use, were enrolled in mandatory at-least-weekly surveillance PCR testing, and had no positive SARS-CoV-2 PCR test within 90 days before the start of the study period. Robust multivariable Poisson regression with the main outcome of a positive SARS-CoV-2 PCR test was performed to compare those who completed their initial vaccination series and a booster dose to those without a booster dose.1,926 unique SARS-CoV-2 infections were identified in the study population. Controlling for sex, student group membership, date of completion of initial vaccination series, initial vaccine type, and temporal effect during the study period, our analysis estimates that receiving a booster dose further reduces the rate of having a PCR-detected SARS-CoV-2 infection relative to an initial vaccination series by 56% (95% confidence interval [42%, 67%], P <0.001). While most individuals had recent booster administration before or during the study period (a limitation of our study), this result is robust to the assumed delay over which a booster dose becomes effective (varied from 1 day to 14 days). The mandatory active surveillance approach used in this study, under which 86% of the person-days in the study occurred, reduces the likelihood of outcome mis-classification. Key limitations of our methodology are that we did not have ana prioriprotocol or statistical analysis plan because the analysis was initially done for institutional research purposes, and some analysis choices were made after observing the data.ConclusionsWe observed that boosters are effective, relative to completion of initial vaccination series, in further reducing the rate of SARS-CoV-2 infections in a college student population during a period when Omicron BA.1 was predominant; booster vaccinations for this age group may play an important role in reducing incidence of COVID-19.
Epidemiology and genomic analysis of Klebsiella oxytoca from a single hospital network in Australia
Authors: Stewart James , Judd Louise M. , Jenney Adam , Holt Kathryn E. , Wyres Kelly L. , Hawkey Jane 
Published: March 2022

AbstractInfections caused by Klebsiella oxytoca are the second most common cause of Klebsiella infections in humans. Most studies to date have focused on K. oxytoca outbreaks and few have examined the broader clinical context of K. oxytoca. Here, we collected all clinical isolates identified as K. oxytoca in a hospital microbiological diagnostic lab across a 15-month period (n=239). The majority of isolates were sensitive to antimicrobials, however 22 isolates were resistant to third-generation cephalosporins (3GCR), of which five were also carbapenem resistant. Whole genome sequencing of a subset of 92 isolates (all invasive, 3GCR and non-urinary isolates collected >48h after admission) showed those identified as K. oxytoca by the clinical laboratory actually encompassed four distinct species (K. oxytoca, Klebsiella michiganensis, Klebsiella grimontii and Klebsiella pasteurii), referred to as the K. oxytoca species complex (KoSC). There was significant diversity within the population, with only 10/67 multi-locus sequence types (STs) represented by more than one isolate. Strain transmission was rare, with only a single likely event identified. Six isolates had either extended spectrum beta-lactamase (blaSHV-12 and/or blaCTX-M-9) or carbapenemase (blaIMP-4) genes. One pair of K. michiganensis and K. pasteurii genomes carried an identical blaIMP-4 IncL/M plasmid, indicative of plasmid transmission. Whilst antimicrobial resistance was rare, the resistance plasmids were similar to those found in other Enterobacterales, demonstrating that KoSC has access to the same plasmid reservoir and thus there is potential for multi-drug resistance. Further genomic studies are required to improve our understanding of the KoSC population and facilitate investigation into the attributes of successful nosocomial isolates.
Cell Surface-Bound La Protein Regulates The Cell Fusion Stage Of Osteoclastogenesis
Authors: Whitlock Jarred M. , Leikina Evgenia , Melikov Kamran , De Castro Luis Fernandez , Mattijssen Sandy , Maraia Richard J. , Collins Michael T. , Chernomordik Leonid V. 
Published: March 2022

AbstractMultinucleated osteoclasts, essential for skeletal remodeling in health and diseases, are formed by fusion of osteoclast precursors with each fusion event raising their bone-resorbing activity. Here we report that nuclear RNA chaperone, La protein moonlights as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. Then La reappears as a proteasecleaved species at the cell surface where it promotes fusion by mechanisms independent of La-RNA interactions. Appearance-and-disappearance of cell-surface La act as an on-and-off switch of the fusion activity with fusion slowing down when surface La is replaced in mature osteoclasts by full-length nuclear La. Inhibiting surface La in a novel explant model of fibrous dysplasia inhibits excessive osteoclast formation characteristic of this disease, highlighting La’s potential as a therapeutic target.One-Sentence SummaryA nuclear RNA chaperon moves to the surface of osteoclasts to control their formation and function in bone metabolism.
Multi-omics profiling, in vitro and in vivo enhancer assays dissect the cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy
Authors: Van de Sompele Stijn , Small Kent W. , Cicekdal Munevver Burcu , Soriano Víctor López , D’haene Eva , Shaya Fadi S. , Agemy Steven , Van der Snickt Thijs , Rey Alfredo Dueñas , Rosseel Toon , Van Heetvelde Mattias , Vergult Sarah , Balikova Irina , Bergen Arthur A. , Boon Camiel J. F. , De Zaeytijd Julie , Inglehearn Chris F. , Kousal Bohdan , Leroy Bart P. , Rivolta Carlo , Vaclavik Veronika , van den Ende Jenneke , van Schooneveld Mary J. , Gómez-Skarmeta José Luis , Tena Juan J. , Martinez-Morales Juan R. , Liskova Petra , Vleminckx Kris , De Baere Elfride 
Published: March 2022

AbstractNorth Carolina macular dystrophy (NCMD) is a rare autosomal dominant disease affecting macular development. The disease is caused by non-coding single nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1.To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 gene promoters, and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays.Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two novel NCMD-associated non-coding SNVs that we identified. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, putting forward this region as a PRDM13 enhancer.Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis.Overall, this study gained insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.Graphical abstract