bluuebunny/crossref_metadata_2025_split huggingface dataset:
In situcell-surface conformation of the TCR-CD3 signaling complex
Authors: Natarajan Aswin , Wang Wenjuan , Flores Manuel Becerra , Li Tianqi , Shin Hye Won , Beesam Saikiran , Cardozo Timothy , Krogsgaard Michelle 
Published: February 2022

AbstractT cells play a vital role in adaptive immune responses to infections, inflammation and cancer and are dysregulated in autoimmunity. Antigen recognition by T cells – a key step in adaptive immune responses – is performed by the T cell receptor (TCR)-CD3 complex. The extracellular molecular organization of the individual CD3 subunits (CD3δε and CD3 γε) around the αβTCR is critical for T cell signaling. Here, we incorporated unnatural amino acid (UAA) photo-crosslinkers at specific mouse TCRα, TCRβ, CD3δ and CD3γ sites, based on previous mutagenesis, NMR spectroscopy and cryo-EM evidence, and crosslinking allowing us to identify nearby interacting CD3 or TCR subunits on the mammalian cell surface. Using this approach, we show that CD3γ and CD3ε, belonging to CD3γε heterodimer crosslinks to Cβ FG loop and Cβ G strand, respectively and CD3δ crosslinks to Cβ CC’ loop and Cα DE loop. Together with computational docking, we identify that inin situcell-surface conformation, the CD3 subunits exists in CD3ε’-CD3γ-CD3ε-CD3δ arrangement around the αβ TCR. This unconventional technique, which uses the native mammalian cell surface microenvironment, includes the plasma membrane and excludes random, artificial crosslinks, captures a dynamic, biologically relevant, cell-surface conformation of the TCR-CD3 complex, which is compatible with the reported static cryo-EM structure’s overall CD3 subunits arrangement, but with key differences at the TCR-CD3 interface, which may be critical for experiments in T cell model systems.
Allometric scaling of a superposition eye optimises sensitivity and acuity in large and small hawkmoths
Authors: Stöckl Anna , Grittner Rebecca , Taylor Gavin , Rau Christoph , Bodey Andrew J , Kelber Almut , Baird Emily 
Published: February 2022

AbstractAnimals vary widely in body size across and within species. This has consequences in large and small individuals for the function of organs and body parts. How these scale in relation to body size reveals evolutionary investment strategies, often resulting in trade-offs between functions. Eyes exemplify these trade-offs, as they are limited by their absolute size in two key performance features: sensitivity and spatial acuity. Previous studies of the 3D structure of apposition compound eyes, which are ideal models for allometric studies due to their size polymorphism, revealed that allometric scaling improves both local resolution and visual sensitivity in larger bumblebees (Taylor et al., 2019). Here, we build on the established methods and results to investigate allometric scaling in superposition compound eyes – the second prominent eye type in insects – for the first time. Our research highlights a surprising strategy to cope with the challenge of trading off sensitivity and spatial resolution in small eyes, as we show that the eyes of the hummingbird hawkmoth retain an optimal balance of these performance measures across all body sizes.
Phenome-wide association analysis of substance use disorders in a deeply phenotyped sample
Authors: Kember Rachel L. , Hartwell Emily E. , Xu Heng , Rotenberg James , Almasy Laura , Zhou Hang , Gelernter Joel , Kranzler Henry R. 
Published: February 2022

AbstractBackgroundSubstance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRS) and phenome-wide association studies (PheWAS) are useful in evaluating pleiotropic effects. The comparatively low prevalence of SUDs and lack of detailed information available in electronic health records limits their informativeness for such analyses.MethodsWe used the deeply-phenotyped Yale-Penn sample [(N=10,610; 46.3% African ancestry (AFR), 53.7% European ancestry (EUR)], recruited for genetic studies of substance dependence, to examine pleiotropy for 4 major substance-related traits: alcohol use disorder (AUD), opioid use disorder (OUD), smoking initiation (SMK), and lifetime cannabis use (CAN). The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA), a comprehensive psychiatric interview.ResultsIn AFR individuals PRS for AUD, and in EUR individuals PRS for AUD, OUD, and SMK, were associated with their respective primary DSM diagnoses. These PRS were also associated with additional phenotypes involving the same substance. PheWAS analyses of PRS in EUR individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in PheWAS analyses, such as family environment and early childhood experiences.ConclusionsSmaller, deeply-phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.
Grandparental Childcare During the Pandemic and Effects on Mental Health: Evidence From England
Authors: Di Gessa Giorgio , Bordone Valeria , Arpino Bruno 
Published: February 2022

AbstractObjectivesPolicies aiming at reducing rates of hospitalisation and death from COVID-19 encouraged older people to reduce physical interactions. For grandparents in England, this meant that provision of care for grandchildren was allowed only under very limited circumstances. Evidence also suggests that reduced face-to-face interactions took a toll on mental health during the pandemic. This study aims to investigate whether changes in grandchild care provision during the pandemic impacted grandparents’ mental health.MethodsUsing pre-pandemic data from Wave 9 (2018/19) and the second Covid-19 sub-study (November/December 2020) of the English Longitudinal Study of Ageing, we first describe changes in grandparenting since the start of the pandemic to then investigate, using regression models, associations between changes in grandparenting and mental health (depression, quality of life, life satisfaction) during the pandemic, while controlling for pre-pandemic levels of the outcome variables. Results: About 10% of grandparents stopped altogether to look after grandchildren during the pandemic, with 22% reporting an overall decrease in the amount of grandchild care provided and 20% an increase or similar levels. Compared to grandparents who mostly maintained unchanged their grandchild care provision, those who stopped altogether and those who mostly reduced the amount of grandchild care provided were more likely to report poorer mental health, even accounting for pre-pandemic health.DiscussionWhile measures to limit physical contact and shield older people were necessary to reduce the spread of COVID-19, policymakers should acknowledge potential adverse consequences for mental health among grandparents who experienced changes in their roles as grandchild caregivers.
Immune responses after twofold SARS-CoV-2 immunisation in elderly residents and Health Care Workers in nursing homes and homes with assisted living support - Proposal for a correlate of protection
Authors: Schiffner Julia , Eisemann Nora , Baltus Hannah , Jensen Sina , Wunderlich Katharina , Schüßeler Stefan , Eicker Charlotte , Teegen Bianca , Boniakowsky Doreen , Solbach Werner , Mischnik Alexander 
Published: February 2022

AbstractIn the present study, we were interested in the decline over time of anti SARS-CoV-2 antibodies and SARS-CoV-2 specific T-cell responses after two doses of mRNA vaccines in total and by age group and comorbidity. The second goal was to suggest an immunological correlate for protection on an individual basis and to describe the probability of protection over time after second vaccination.We analysed blood samples from 228 residents (median age 83.8 years) and from 273 Health Care Workers (HCW; median age 49.7 years) of five nursing homes and one home for the elderly with assisted living support. Participants had received two vaccinations. The blood samples were analysed for SARS-CoV-2 specific antibody and T-cell responses. We compared outcomes in the HCW and residents in the respective institutions. No breakthrough infections occurred during the study period. The initial immune responses in the younger participants were about 30 % higher than in the older ones. Over time, all parameters dropped continuously in all groups within the maximum observation period of 232 days. Comorbidities such as coronary heart disease or diabetes mellitus reduced the initial immune responses, regardless of age. In contrast to an almost linear decline in antibody levels, we observed that the interferon-gamma response remained at a constant level between about day 120 and 180, only to decline further thereafter.Based on our data, we propose on an individual level a correlate of protection: Persons who have a neutralizing capacity of 75 % (which would correspond to approx. 200 BAU/ml) and an interferon-gamma response above 200 mIU/ml should be considered to be protected resp. sufficiently immunized.
MTPpilot: an interactive software for visualization of NGS results in molecular tumor boards
Authors: Kahraman A. , Arnold F. M. , Hanimann J. , Nowak M. , Pauli C. , Britschgi C. , Moch H. , Zoche M. 
Published: February 2022

ABSTRACTComprehensive targeted Next Generation Sequencing (NGS) panels are routinely used in modern molecular cancer diagnostics. In molecular tumor boards the detected genomic alterations are often discussed to decide the next treatment options for the cancer patient. With the increasing size and complexity of NGS panels, the discussion of these results becomes increasingly complex, especially if they are reported in a text-based form, as it is the standard in current molecular pathology. We developed the Molecular Tumor Profiling pilot (MTPpilot) software to enable an efficient and quick analysis and visualization of complex NGS results, thanks to a combination of automated annotations and interactive tools. The software is tailored for the use at molecular tumor boards to aid clinical decision making. It is freely available as a web-application at https://www.mtppilot.org.
PENet: Continuous-Valued Pulmonary Edema Severity Prediction On Chest X-ray Using Siamese Convolutional Networks
Authors: Akbar Md Navid , Wang Xin , Erdoğmuş Deniz , Dalal Sandeep 
Published: February 2022

AbstractFor physicians to take rapid clinical decisions for patients with congestive heart failure, the assessment of pulmonary edema severity in chest radiographs is vital. While deep learning has been promising in detecting the presence or absence, or even discrete grades of severity, of such edema, prediction of the continuous-valued severity yet remains a challenge. Here, we propose PENet, a deep learning framework to assess the continuous spectrum of pulmonary edema severity from chest X-rays. We present different modes of implementing this network, and demonstrate that our best model outperforms that of earlier work (mean area under the curve of 0.91 over 0.87, for nine comparisons), while saving training data and computation.
Distinct Core Glycan and O-Glycoform Utilization of SARS-CoV-2 Omicron Variant Spike Protein RBD Revealed by Top-Down Mass Spectrometry
Authors: Roberts David S. , Mann Morgan , Li Brad H. , Kim Donguk , Brasier Allan R. , Jin Song , Ge Ying 
Published: February 2022

AbstractThe SARS-CoV-2 Omicron (B.1.1.529) variant possesses numerous spike (S) mutations particularly in the S receptor-binding domain (S-RBD) that significantly improve transmissibility and evasion of neutralizing antibodies. But exactly how the mutations in the Omicron variant enhance viral escape from immunological protection remains to be understood. The S-RBD remains the principal target for neutralizing antibodies and therapeutics, thus new structural insights into the Omicron S-RBD and characterization of the post-translational glycosylation changes can inform rational design of vaccines and therapeutics. Here we report the molecular variations and O-glycoform changes of the Omicron S-RBD variant as compared to wild-type (WA1/2020) and Delta (B.1.617.2) variants using high-resolution top-down mass spectrometry (MS). A novel O-glycosite (Thr376) unique to the Omicron variant is identified. Moreover, we have directly quantified the Core 1 and Core 2 O-glycan structures and characterized the O-glycoform structural heterogeneity of the three variants. Our findings reveal high resolution detail of Omicron O-glycoforms and their utilization to provide direct molecular evidence of proteoform alterations in the Omicron variant which could shed light on how this variant escapes immunological protection.
Disparities in Opioid-related Mortality Across United States Census Regions from 1999-2020
Authors: Addimulam Supriyanka , Gupta Swapnil , Mahalingam Sindhuja , Walia Namrata 
Published: February 2022

AbstractBackgroundOpioid-related mortality has been on a sharp rise in the decade. This study aims to provide insight into the difference in mortality between white and black population in various census regions of the United States between 1999-2020.MethodsThe data was extracted from multiple cause of death files from CDC Wonder database. The International Classification of Disease (ICD-10) codes used to extract data include F11 (mental and behavioral disorders due to use of opioids); T40.0 (Opium); T40.1 (Heroin); T40.2 (Other opioids); T40.3 (Methadone); T40.4 (Other synthetic narcotics). The regression analysis was conducted using Joinpoint statistical software.ResultsThe black population in the Midwest census region showed the highest age-adjusted mortality in the year 2020 (46.14 per 100,000). This was followed by the black (32.71 per 100,000) and white population (30.5 per 100,000) in the northeast census regions respectively. Overall, the opioid-related mortality followed a similar trend across all census regions. Except south census region where age-adjusted mortality was comparable between the black and white populations, blacks had higher opioid-related mortality in all other census regions.ConclusionThis study provides concise evidence of inequality in opioid-related deaths among various US census regions. Policy changes focused to certain regions are required to significantly address the underlying factors related to disparities in opioid-related mortality among the black population.
Profiling of the most reliable mutations from sequenced SARS-CoV-2 genomes scattered in Uzbekistan
Authors: Ayubov Mirzakamol S. , Buriev Zabardast T. , Mirzakhmedov Mukhammadjon K. , Yusupov Abdurakhmon N. , Usmanov Dilshod E. , Shermatov Shukhrat E. , Ubaydullaeva Khurshida A. , Abdurakhmonov Ibrokhim Y. 
Published: February 2022

AbstractDue to rapid mutations in the coronavirus genome over time and re-emergence of multiple novel variants of concerns (VOC), there is a continuous need for a periodic genome sequencing of SARS-CoV-2 genotypes of particular region. This is for on-time development of diagnostics, monitoring and therapeutic tools against virus in the global pandemics condition. Toward this goal, we have generated 18 high-quality whole-genome sequence data from 32 SARS-CoV-2 genotypes of PCR-positive COVID-19 patients, sampled from the Tashkent region of Uzbekistan. The nucleotide polymorphisms in the sequenced sample genomes were determined, including nonsynonymous (missense) and synonymous mutations in coding regions of coronavirus genome. Phylogenetic analysis grouped fourteen whole genome sample sequences (1, 2, 4, 5, 8, 10-15, 17, 32) into the G clade (or GR sub-clade) and four whole genome sample sequences (3, 6, 25, 27) into the S clade. A total of 128 mutations were identified, consisting of 45 shared and 83 unique mutations. Collectively, nucleotide changes represented one unique frameshift mutation, four upstream region mutations, six downstream region mutations, 50 synonymous mutations, and 67 missense mutations. The sequence data, presented herein, is the first coronavirus genomic sequence data from the Republic of Uzbekistan, which should contribute to enrich the global coronavirus sequence database, helping in future comparative studies. More importantly, the sequenced genomic data of coronavirus genotypes of this study should be useful for comparisons, diagnostics, monitoring, and therapeutics of COVID-19 disease in local and regional levels.
IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR in hepatocytes, the stroma and cancer cells
Authors: Widjaja Anissa A. , Ting Joyce Goh Wei , Viswanathan Sivakumar , Tan Jessie , Shekeran Shamini G , Carling David , Wen Lim Wei , Cook Stuart A. 
Published: February 2022

AbstractInterleukin 11 (IL11) stimulates stromal cell activation but also causes hepatocyte metabolic dysfunction. The mechanisms underlying these seemingly unrelated processes are not known. Here we report that IL11-stimulated ERK/P90RSK activity causes the sequential phosphorylation of LKB1 (STK11) at S325 and S428, leading to its inactivation. This leads to a reduction in AMPK activity whilst concomitantly activating mTOR in human fibroblasts, hepatic stellate cells, hepatocytes and cancer cells. In fibroblasts and hepatic stellate cells, IL11-mediated LKB1/AMPK inhibition causes myofibroblast transformation whereas in hepatocytes it inhibits autophagy and fatty acid oxidation and is toxic. Across cell types, the self-amplifying loop of autocrine IL11 activity was inhibited by AMPK activation with metformin, AICAR or 991. In mice on a western diet with fructose, anti-IL11 therapy or hepatocyte-specific deletion of Il11ra1 rescues LKB1/AMPK activity and reduces NASH. In contrast, restoration of IL11 signalling in hepatocytes of mice with global Il11ra1 deletion inactivates LKB1/AMPK and exacerbates NASH. These data show that LKB1, an important tumour suppressor and master kinase, is not constitutively active and identify the IL11/LKB1/AMPK/mTOR axis as a point of signalling convergence for epithelial homeostasis, fibrogenesis, immunometabolism and cancer.
Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole animal dual RNA-seq
Authors: Jim Kin Ki , Aprianto Rieza , Domenech Arnau , Kurushima Jun , van de Beek Diederik , Vandenbroucke-Grauls Christina M.J.E. , Bitter Wilbert , Veening Jan-Willem 
Published: February 2022

SUMMARYPneumolysin is a major virulence factor of Streptococcus pneumoniae that plays a key role in interaction with the host during invasive disease. How pneumolysin influences these dynamics between host and pathogen interaction during early phase of central nervous system infection in pneumococcal meningitis remains unclear. Using a whole animal in vivo dual RNA-seq approach, we identified pneumolysin-specific transcriptional responses in both S. pneumoniae and zebrafish (Danio rerio) during early pneumococcal meningitis. By functional enrichment analysis we identified host pathways known to be activated by pneumolysin, and discovered the importance of necroptosis for host survival. Inhibition of this pathway using the drugs necrostatin-5 or GSK’872 increased host mortality during pneumococcal meningitis. On the pathogen’s side, we find that pneumolysin-dependent competence activation is crucial for intra-host replication and virulence and that not all bacteria activate competence at the same time. Altogether, this study provides new insights into pneumolysin-specific transcriptional responses and identifies key pathways involved in pneumococcal meningitis.GRAPHICAL ABSTRACTHIGHLIGHTSPneumolysin-specific host and bacterial responses as identified by whole animal dual RNA-seq, available at https://veeninglab.com/dual-danioDiscovery of a functional necroptosis or necroptosis-like pathway in zebrafishHeterogeneity in competence development during infectionCompetence development is an important virulence determinant
Oligodendrocyte precursor cells engulf synaptic inputs in an experience- and microglia-dependent manner
Authors: Auguste Yohan S.S. , Ferro Austin , Dixon Jessica , Vrudhula Uma , Kahng Jessica , Nichitiu Anne-Sarah , Cheadle Lucas 
Published: February 2022

AbstractOligodendrocyte precursor cells (OPCs) are a highly proliferative class of non-neuronal progenitors that largely give rise to myelinating oligodendrocytes. Although OPCs persist across the lifespan, their functions beyond oligodendrogenesis remain to be fully characterized. Here, we show that OPCs contribute to neural circuit remodeling by internalizing presynaptic thalamocortical inputs in both the developing and adult mouse visual cortex. Inputs internalized by OPCs localize to lysosomal compartments, consistent with OPC engulfment of synapses occuring through phagocytosis. We further show that engulfment by OPCs is heightened during experience-dependent plasticity, and that this experience-dependent increase in engulfment requires microglia. These data identify a new function for OPCs beyond the generation of oligodendrocytes and reveal that distinct non-neuronal populations collaborate to modulate synaptic connectivity.
Estimating the net effect of functional traits on fitness across species and environments
Authors: Siefert Andrew , Laughlin Daniel C. 
Published: February 2022

ABSTRACTFunctional traits affect the demographic performance of individuals in their environment, leading to fitness differences that scale up to drive population dynamics and community assembly. Understanding the links between traits and fitness is therefore critical for predicting how populations and communities respond to environmental change. However, the net effects of traits on species fitness are largely unknown because we have lacked a framework for estimating fitness across multiple species and environments.We present a modeling framework that integrates trait effects on demographic performance over the life cycles of individuals to estimate the net effect of traits on species fitness. This approach involves 1) modeling trait effects on individual demographic rates (growth, survival, and recruitment) as multidimensional performance surfaces that vary with individual size and environment and 2) integrating these effects into a population model to project population growth rates (i.e., fitness) as a function of traits and environment. We illustrate our approach by estimating performance surfaces and fitness landscapes for trees across a temperature gradient in the eastern United States.Functional traits (wood density, specific leaf area, and maximum height) interacted with individual size and temperature to influence tree growth, survival, and recruitment rates, generating demographic trade-offs and shaping the contours of fitness landscapes. Tall tree species had high survival, growth, and fitness across the temperature gradient. Wood density and specific leaf area had interactive effects on demographic performance, resulting in fitness landscapes with multiple peaks.With this approach it is now possible to empirically estimate the net effect of traits on fitness, leading to improved understanding of the selective forces that drive community assembly and permitting generalizable predictions of population and community dynamics in changing environments.