bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benefits of Surveillance Testing and Quarantine in a SARS-CoV-2 Vaccinated Population of Students on a University Campus
Authors: Motta Francis C. , McGoff Kevin A. , Deckard Anastasia , Wolfe Cameron R. , Moody M. Anthony , Cavanaugh Kyle , Denny Thomas N. , Harer John , Haase Steven B. 
Published: June 2021

AbstractSurveillance testing and quarantine have been effective measures for limiting SARS-CoV-2 transmission on university campuses. However, the importance of these measures needs to be re-evaluated in the context of a complex and rapidly changing environment that includes vaccines, variants, and waning immunity. Also, recent guidelines from the CDC suggest that vaccinated students do not need to participate in surveillance testing. We used an agent-based SEIR model to evaluate the utility of surveillance testing and quarantine in a fully vaccinated student population where vaccine effectiveness may be impacted by the type of vaccination, the presence of variants, and the loss of vaccine-induced or natural immunity over time. We found that weekly surveillance testing at 90% vaccine effectiveness only marginally reduces viral transmission as compared to no testing. However, at 50%-75% effectiveness, surveillance testing can provide over 10-fold reduction in the number of infections on campus over the course of the semester. We also show that a 10-day quarantine protocol for exposures has limited effect on infections until vaccine effectiveness drops to 50%, and that increased surveillance testing for exposures is at least as effective as quarantine at limiting infections. Together these findings provide a foundation for universities to design appropriate mitigation protocols for the 2021-2022 academic year.
Use of real-world evidence data to evaluate the comparative effectiveness of second-line type 2 diabetes medications on chronic kidney disease
Authors: Deng Yu , Ghamsari Farhad , Lu Alice , Yu Jingzhi , Zhao Lihui , Kho Abel N 
Published: June 2021

AbstractChronic kidney disease (CKD) is a common complication of type 2 diabetes mellitus (T2DM). Approximately one-third of patients with T2DM also have CKD. In clinical trial studies, several anti-diabetic medications (ADM) show evidence of preventing the progression of CKD. Biguanides (e.g., metformin) are widely accepted as the first line medication. However, the comparativeness effectiveness of second line ADMs on CKD outcomes in T2DM is unclear. In addition, results from clinical trials may not generalize into routine clinical practice. In this study, we aimed to investigate the association of second line ADMs with incident CKD and CKD hospitalization in T2DM patients using real-world data from electronic health records. Our study found that treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors was significantly associated with a lower risk of CKD incidence in both primary analysis (hazard ratio, 0.43; 95% CI, [0.22;0.87]; p-value,0.02) (SU) as a second-line ADM. Treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor was significantly associated with lower CKD incidence (hazard ratio, 0.7; 95% CI, [0.53;0.96]; p-value, 0.03) and lower CKD hospitalization events (hazard ratio, 0.6; 95% CI, [0.37; 0.96]; p-value, 0.04) in the primary analysis. However, both associations were not significant in the sensitivity analysis. We did not observe significant association between use of GLP-1, TZD, insulin and CKD incidence or hospitalization compared to use of SU as the second-line ADM.
A novel hyperinflammation clinical risk tool, HI5-NEWS2, predicts mortality following early dexamethasone use in an observational cohort of hospitalised COVID-19 patients
Authors: Ardern-Jones Michael R , Phan Hang T.T. , Borca Florina , Stammers Matt , Batchelor James , Reading Isabel C. , Fletcher Sophie V. , Smith Trevor , Duncombe Andrew S 
Published: June 2021

AbstractBackgroundThe success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19.MethodsBlood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status.FindingsOf 1265 patients, high risk of HI (high HI5-NEWS2) (n=367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n= 455, 36.0%). An intermediate risk group (n= 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p=0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p=0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p=0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p =0.31).InterpretationThe HI5-NEWS2 measured at COVID-19 diagnosis, strongly predicts mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention.FundingNo external funding.
Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and obesity
Authors: Carrasquilla Germán D. , García-Ureña Mario , Fall Tove , Sørensen Thorkild I.A. , Kilpeläinen Tuomas O. 
Published: June 2021

AbstractPhysical inactivity is associated with excess weight gain in observational studies. However, some longitudinal studies indicate reverse causality where weight gain leads to physical inactivity. As observational studies suffer from reverse causality, it is challenging to assess the true causal directions. Here, we assess the bidirectional causality between physical inactivity and obesity by bidirectional Mendelian randomization analysis. We used results from genome-wide association studies for accelerometer-based physical activity and sedentary time in 91,105 individuals and for body mass index (BMI) in 806,834 individuals. We implemented Mendelian randomization using CAUSE method that accounts for pleiotropy and sample overlap using full genome-wide data. We also applied inverse variance-weighted, MR-Egger, weighted median, and weighted mode methods using genome-wide significant variants only. We found evidence of bidirectional causality between sedentary time and BMI: longer sedentary time was causally associated with higher BMI [beta (95%CI) from CAUSE method: 0.11 (0.02, 0.2), P=0.02], and higher BMI was causally associated with longer sedentary time (0.13 (0.08, 0.17), P=6.3.×10-4). Our analyses suggest that higher moderate and vigorous physical activity are causally associated with lower BMI (moderate: -0.18 (-0.3,-0.05), P=0.006; vigorous: -0.16 (-0.24,-0.08), P=3.8×10-4), but indicate that the association between higher BMI and lower levels of physical activity is due to horizontal pleiotropy. The bidirectional, causal relationship between sedentary time and BMI suggests that decreasing sedentary time is beneficial for weight management, but also that targeting obesity may lead to additional health benefits by reducing sedentary time.
Identification of essential genes in Caenorhabditis elegans through whole genome sequencing of legacy mutant collections
Authors: Li-Leger Erica , Feichtinger Richard , Flibotte Stephane , Holzkamp Heinke , Schnabel Ralf , Moerman Donald G. 
Published: June 2021

ABSTRACTIt has been estimated that 15-30% of the ∼20,000 genes in C. elegans are essential, yet many of these genes remain to be identified or characterized. With the goal of identifying unknown essential genes, we performed whole genome sequencing on complementation pairs from legacy collections of maternal-effect lethal and sterile mutants. This approach uncovered maternal genes required for embryonic development and genes with putative sperm-specific functions. In total, 58 essential genes were identified on chromosomes III, IV, and V, of which 49 genes are represented by novel alleles in this collection. Of these 49 genes, 19 (40 alleles) were selected for further functional characterization. The terminal phenotypes of embryos were examined, revealing defects in cell division, morphogenesis, and osmotic integrity of the eggshell. Mating assays with wild-type males revealed previously unknown male-expressed genes required for fertilization and embryonic development. The result of this study is a catalogue of mutant alleles in essential genes that will serve as a resource to guide further study toward a more complete understanding of this important model organism. As many genes and developmental pathways in C. elegans are conserved and essential genes are often linked to human disease, uncovering the function of these genes may also provide insight to further our understanding of human biology.
Claustral Projections to Anterior Cingulate Cortex Modulate Engagement with the External World
Authors: Atlan Gal , Matosevich Noa , Peretz-Rivlin Noa , Yvgi Idit , Chen Eden , Kleinman Timna , Bleistein Noa , Sheinbach Efrat , Groysman Maya , Nir Yuval , Citri Ami 
Published: June 2021

AbstractEngagement is a major determinant of performance. Hyper-engagement risks impulsivity and is fatiguing over time, while hypo-engagement could lead to missed opportunities. Even in sleep, when engagement levels are minimal, sensory responsiveness varies. Thus, maintaining an optimal engagement level with the environment is a fundamental cognitive ability. The claustrum, and in particular its reciprocal connectivity with executive regions in the frontal cortex, has been associated with salience, attention and sleep. These apparently disparate roles can be consolidated within the context of engagement. Here we describe the activity of claustro-frontal circuits in a task imposing a tradeoff between response inhibition and sensory acuity (‘ENGAGE’). Recording calcium fiber photometry during >80,000 trials, we characterize claustrum recruitment during salient behavioral events, and find that a moderate level of activity in claustro-cingulate projections defines optimal engagement. Low activity of this pathway is associated with impulsive actions, while high activity is associated with behavioral lapses. Chemogenetic activation of cingulate-projecting claustrum neurons suppressed impulsive behavior and reduced the engagement of mice in the task. This relationship became even clearer upon addressing individual variability in the strategy mice employed during the ENGAGE task. Furthermore, this association of claustrum activity and engagement extends into sleep. Using simultaneous EEG and photometry recordings in the claustrum, we find that cingulate projecting claustrum neurons are most active during deep unresponsive slow-wave sleep, when mice are less prone to awakening by sensory stimuli.
Stromal cell sialylation suppresses T cells in inflammatory tumour microenvironments: A new tumour stromal cell immune checkpoint?
Authors: Egan Hannah , Treacy Oliver , Lynch Kevin , Leonard Niamh A , O’Malley Grace , De Veirman Kim , Vanderkerken Karin , Craughwell Michael , Egan Laurence J , Ritter Thomas , Hogan Aisling M , Redmond Keara , Sheehan Margaret , Canney Aoife , Hynes Sean , Kerr Emma , Dunne Philip D , O’Dwyer Michael E , Ryan Aideen E 
Published: June 2021

AbstractImmunosuppressive tumour microenvironments (TME) reduce the effectiveness of immune responses in cancer. Non-haematopoietic mesenchymal stromal cells (MSC), the precursor to cancer associated fibroblasts (CAFs), dictate tumour progression by enhancing immune cell suppression. Hyper-sialylation of glycans promotes immune evasion in cancer, but the role of sialyation in stromal cell-mediated immunosuppression is unknown.Here we study changes in sialyltransferase (ST) enzymes and associated surface expressed sialic acid in stromal cells following inflammatory and tumour secretome conditioning. We show that tumour conditioned stromal cells have increased levels of sialyltransferases, α2,3/6 linked sialic acid and siglec ligands. In tumour models of solid (colorectal cancer) and haematological (multiple myeloma) stromal rich tumours, stromal cell sialylation is associated with enhanced immunosuppression. Using datasets and patient samples, we confirm that targeting sialylation in tumour stromal cells reverses immune cell exhaustion. Targeting stromal cell sialylation may represent a novel immune checkpoint to reactivate anti-tumour immunity.
Arabidopsis stomatal polarity protein BASL mediates distinct processes before and after cell division to coordinate cell size and fate asymmetries
Authors: Gong Yan , Alassimone Julien , Muroyama Andrew , Amador Gabriel , Varnau Rachel , Liu Ao , Bergmann Dominique C. 
Published: June 2021

ABSTRACTIn many land plants, asymmetric cell divisions (ACDs) create and pattern differentiated cell types on the leaf surface. In the Arabidopsis stomatal lineage, BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL) regulates multiple aspects of ACD including division plane placement and cell fate enforcement. Polarized subcellular localization of BASL is initiated before the ACD and persists for many hours after the division in one of the two daughters. Untangling the respective contributions of polarized BASL before and after division is essential to gain a better understanding of its roles in regulating stomatal lineage ACDs and to uncover the rules that guide leaf pattern. Here we combine quantitative imaging and lineage tracking with genetic tools that provide temporally-restricted BASL expression. We find that pre-division BASL is required for division orientation, whereas BASL polarity post-division ensures proper cell fate commitment. These genetic manipulations allowed us to uncouple daughter-cell size asymmetry from polarity crescent inheritance, revealing independent effects of these two asymmetries on subsequent cell behavior. Finally, we show that there is coordination between the division frequencies of sister cells produced by ACDs, and this coupling requires BASL as an effector of peptide signaling.
Exploration of molecular mechanism underlying the self-flocculation of Zymomonas mobilis through comparative omics analyses and experimental validations for developing robust production systems
Authors: Cao Lian-Ying , Yang Yongfu , Liu Chen-Guang , Chen Yunhao , Zhang Xue , Wang Xia , Xia Juan , Yang Shihui , Bai Feng-Wu 
Published: June 2021

AbstractZymomonas mobilis metabolizes sugar through the Entner-Doudoroff pathway with less ATP generated for lower biomass accumulation and more substrate to product formation with improved yield, since ATP is dissipated predominately through growth for intracellular energy homeostasis, making it a platform to be engineered as microbial cell factories, particularly for producing bulk commodities with major cost from feedstock consumption. ZM401, a self-flocculating mutant, presents advantages for production including cost-effective biomass recovery through gravity sedimentation, self-immobilization within bioreactors for high cell density to improve productivity and enhanced tolerance to environmental stresses for high product titers, but molecular mechanism underlying this phenotype is largely unknown. In this work, we sequenced and assembled the genome of ZM401 to explore genetic basis for the self-flocculation of the bacterial cells through comparative genomic and transcriptomic analyses, molecular docking simulations for enzymes encoded by functional genes and their substrates/activators, and experimental validations. Our results demonstrated that the single nucleotide deletion in ZMO1082 disrupted its stop codon for the putative gene being fused with ZMO1083, which created an exciting gene encoding the subunit A of the bacterial cellulose synthase with unique function for synthesizing cellulose microfibrils to flocculate the bacterial cells, and the single nucleotide mutation in ZMO1055 compromised the function of bifunctional diguanylate cyclase/phosphodiesterase encoded by the gene on the degradation of c-di-GMP for its intracellular accumulation to activate the cellulose biosynthesis. These discoveries are significant not only for optimizing the self-flocculation of Z. mobilis, but also engineering other bacteria with the self-flocculating phenotype for robust production.
Genomic islands targeting dusA in Vibrio species are distantly related to Salmonella Genomic Island 1 and mobilizable by IncC conjugative plasmids
Authors: Durand Romain , Deschênes Florence , Burrus Vincent 
Published: June 2021

AbstractSalmonella Genomic Island 1 (SGI1) and its variants are significant contributors to the spread of antibiotic resistance among Gammaproteobacteria. All known SGI1 variants integrate at the 3’ end of trmE, a gene coding for a tRNA modification enzyme. SGI1 variants are mobilized specifically by conjugative plasmids of the incompatibility groups A and C (IncA and IncC). Using a comparative genomics approach based on genes conserved among members of the SGI1 group, we identified diverse integrative elements distantly related to SGI1 in several species of Vibrio, Aeromonas, Salmonella, Pokkaliibacter, and Escherichia. Unlike SGI1, these elements target two alternative chromosomal loci, the 5’ end of dusA and the 3’ end of yicC. Although they share many features with SGI1, they lack antibiotic resistance genes and carry alternative integration/excision modules. Functional characterization of IMEVchUSA3, a dusA-specific integrative element, revealed promoters that respond to AcaCD, the master activator of IncC plasmid transfer genes. Quantitative PCR and mating assays confirmed that IMEVchUSA3 excises from the chromosome and is mobilized by an IncC helper plasmid from Vibrio cholerae to Escherichia coli. IMEVchUSA3 encodes the AcaC homolog SgaC that associates with AcaD to form a hybrid activator complex AcaD/SgaC essential for its excision and mobilization. We identified the dusA-specific recombination directionality factor RdfN required for the integrase-mediated excision of dusA-specific elements from the chromosome. Like xis in SGI1, rdfN is under the control of an AcaCD-responsive promoter. Although the integration of IMEVchUSA3 disrupts dusA, it provides a new promoter sequence and restores the reading frame of dusA for proper expression of the tRNA-dihydrouridine synthase A. Phylogenetic analysis of the conserved proteins encoded by SGI1-like elements targeting dusA, yicC, and trmE gives a fresh perspective on the possible origin of SGI1 and its variants.Author summaryWe identified integrative elements distantly related to the Salmonella Genomic Island 1 (SGI1), a key vector of antibiotic resistance genes in Gammaproteobacteria. SGI1 and its variants reside at the 3’ end of trmE, share a large, highly conserved core of genes, and carry a complex integron that confers multidrug resistance phenotypes to their hosts. Unlike members of the SGI1 group, these novel genomic islands target the 5’ end dusA or the 3’ end of yicC, lack multidrug resistance genes, and seem much more diverse. We showed here that, like SGI1, these elements are mobilized by conjugative plasmids of the IncC group. Based on comparative genomics and functional analyses, we propose a hypothetical model of the evolution of SGI1 and its siblings from the progenitor of IncA and IncC conjugative plasmids via an intermediate dusA-specific integrative element through gene losses and gain of alternative integration/excision modules.
GOLPH3 and GOLPH3L are broad-spectrum COPI adaptors for sorting into intra-Golgi transport vesicles
Authors: Welch Lawrence G. , Peak-Chew Sew-Yeu , Begum Farida , Stevens Tim J. , Munro Sean 
Published: June 2021

AbstractGlycosylation is a diverse and abundant modification of proteins, lipids and RNA. The fidelity of glycosylation is, in part, assured by the correct compartmentalisation of Golgi-resident glycosylation enzymes within the Golgi stack. The COPI adaptor GOLPH3 has been shown to interact with the cytoplasmic tails of a subset of Golgi enzymes and direct their retention in the Golgi. However, other mechanisms of retention, and other roles for GOLPH3, have been proposed, and a comprehensive characterisation of the clientele of GOLPH3 and its paralogue GOLPH3L has been lacking. The role of GOLPH3 is of particular interest as it is frequently amplified in several solid tumour types. Here, we combine two orthogonal proteomic analyses to identify a diverse range of GOLPH3+3L clients and find that they act in a wide spectrum of glycosylation pathways, or have other roles in the Golgi. Using binding studies, bioinformatics and an in vivo Golgi retention assay, we show that GOLPH3+3L interact with the cytoplasmic tails of their clients through membrane-proximal positively-charged residues. Furthermore, deletion of GOLPH3+3L causes diverse defects in glycosylation. Thus, GOLPH3+3L are major COPI adaptors that impinge on most, if not all, of the glycosylation pathways of the Golgi.
Social experience and pheromone receptor activity reprogram behavioral switch and neuromodulatory gene expression in sensory neurons
Authors: Deanhardt Bryson , Duan Qichen , Du Chengcheng , Soeder Charles , Morlote Alec , Garg Deeya , Jones Corbin D. , Volkan Pelin Cayirlioglu 
Published: June 2021

AbstractSocial experience and pheromone signaling in olfactory neurons affect neuronal responses and male courtship behaviors in Drosophila. We previously showed that social experience and pheromone signaling modulate chromatin around behavioral switch gene fruitless, which encodes a transcription factor necessary and sufficient for male behaviors. Fruitless drives social experience dependent modulation of courtship behaviors and pheromone responses in sensory neurons, however, the molecular mechanisms underlying this neuromodulation remain less clear. To identify the molecular mechanisms driving social experience-dependent neuromodulation, we performed RNA-seq from antennal samples of mutants in pheromone receptors and fruitless, as well as grouped or isolated wild-type males. We found that loss of pheromone detection differentially alters the levels of fruitless exons suggesting changes in splicing patterns. In addition, many Fruitless target neuromodulatory genes, such as neurotransmitter receptors, ion channels, ion and membrane transporters, and odorant binding proteins are differentially regulated by social context and pheromone signaling. Recent studies showed that social experience and juvenile hormone signaling coregulate fru chromatin to modify pheromone responses in olfactory neurons. Interestingly, genes involved in juvenile hormone metabolism are also misregulated in different social contexts and mutant backgrounds. Our results suggest that modulation of neuronal activity and behaviors in response to social experience and pheromone signaling likely arise due to large-scale changes in transcriptional programs for neuromodulators downstream of behavioral switch gene function.