bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precise blood proteome profiling in an undiagnosed population with COVID-19
Authors: Fredolini Claudia , Dodig-Crnković Tea , Bendes Annika , Dahl Leo , Dale Matilda , Mattsson Cecilia , Thomas Cecilia E , Beck Olof , Roxhed Niclas , Schwenk Jochen M 
Published: November 2021

AbstractSelf-sampled blood provided valuable information about the COVID-19 seroprevalence in the general population. To enable an even deeper understanding of pathophysiological processes following SARS-CoV-2 infections, 276 circulating proteins were quantified by proximity extension assays in dried blood spots (DBS). Samples from undiagnosed individuals collected during the first wave of the pandemic were selected based on their serological immune response and matched on self-reported symptoms. We stratified these as seropositive (IgM+IgG+;N= 41) or seronegative (IgM-IgG-;N= 37), and to represent the acute (IgM+IgG-;N= 26) and convalescent phases (IgM-IgG+;N= 40). This revealed proteins from a variety of clinical processes including inflammation and immune response (MBL2, MMP3, IL2RA, FCGR2A, CCL5), haemostasis (GP1BA, VWF), stress response (ANG), virus entry (SDC4) or nerve regeneration (CHL1). The presented approach complements clinical surveys and enables a deep molecular and population-wide analysis of COVID-19 from blood specimens collected outside a hospital setting.
Copy number heterogeneity identifies ER+ breast cancer patients with adverse outcome after adjuvant endocrine therapy
Authors: van den Bosch Tom , Rueda Oscar M , Caldas Carlos , Vermeulen Louis , Miedema Daniël M 
Published: November 2021

BackgroundEndocrine therapy forms the backbone of adjuvant treatment for estrogen-receptor positive (ER+) breast cancer. However, it remains unclear whether adjuvant treatment improves survival rates in low-risk patients. Low intra-tumor heterogeneity (ITH) has been shown to confer low-risk for recurrent disease. Here, it is studied if chromosomal copy number ITH (CNH) can identify low-risk ER+, lymph node-negative breast cancers patients who do not benefit from adjuvant endocrine therapy.MethodsLymph node-negative ER+ patients from the METABRIC dataset were retrospectively analyzed (n=708). CNH was determined from a single bulk copy number measurement for each patient. Patients were stratified by CNH score as low, medium or high. Overall survival (OS) was compared between patients that did, or did not receive adjuvant endocrine therapy per CNH group with Cox proportional-hazards models, using propensity score weights to correct for confounders.ResultsAdjuvant endocrine therapy improved the relapse free survival (RFS) for high-CNH/high-risk patients treatment (Hazard Ratio [HR] = 0.55, 95% Confidence Interval [CI] = 0.35 to 0.87), but not for low CNH/risk patients treatment (HR = 0.88, 95% CI = 0.50 to 1.55). For low-CNH/low-risk patients adjuvant endocrine therapy was associated with impaired OS (HR = 1.62, 95% CI = 1.10 to 2.40). Multivariable Cox analysis identified a significant interaction between CNH and endocrine therapy for OS (HR = 0.77, 95% CI = 0.62 to 0.96).ConclusionsThis retrospective study of lymph node-negative, ER+ breast cancer finds that patients identified as low-risk using CNH display reduced OS when treated with adjuvant endocrine therapy.
On The Dynamics of Interstate Diffusion of Firearm Violence and Impact of Firearm Regulations
Authors: Sen Swagatam , Sen Anindya , Liu Ye , Sen Bisakha 
Published: November 2021

AbstractObjectivesOur purpose was to test the impact of firearm regulations on the firearm violence flow across US state borders. Further we assessed the spatial variations in these impacts across different regions with the goal of identifying state-groups that are especially vulnerable to cross-border firearm violence.MethodsIncidence of firearm violence (2000-2017) has been modelled as an inhomogeneous diffusion process whose parameters depend on state firearm regulations. Firearm regulations measurement for a state accounted for all 14 law categories across 54 states since 1991 as per State Firearm Law Database. The effects of regulations and other covariates were estimated across all states.ResultsSix clusters of states were identified based on the variations of effects within and across those clusters. For 3 of these clusters the diffusive flow parameters were statistically significant. In all of these clusters the deterring effect of regulations on incidence and flow of crime was statistically significant.ConclusionThe clusters can be assigned to 5 descriptive categories based on their roles in the flow of firearm violence – Source states, Transitive states, Destination states, Isolated issue states and Stable. It was found that flow of firearm violence indeed does follow a diffusive process for most categories of states. It has also been recommended that while in-state regulations are important to curb firearm violence flowing into Destination states, they are not adequate unless regulatory stringency is also applied to neighboring Source and Transitive States.
MICU1 occludes MCU in the mitochondrial calcium uniporter complex
Authors: Tsai Chen-Wei , Van Keuren Anna , Bankston John , Ma Zhiwei , Tsai Ming-Feng 
Published: November 2021

AbstractThe mitochondrial calcium uniporter imports cytoplasmic Ca2+ into the mitochondrial matrix to regulate cell bioenergetics, Ca2+ signaling, and apoptosis. The uniporter contains the pore-forming MCU subunit, an EMRE protein that binds to MCU, and the regulatory MICU1/MICU2 subunits. Structural and biochemical studies have suggested that MICU1 gates MCU by blocking and unblocking the Ca2+ pore. However, mitoplast patch-clamp experiments argue that MICU1 does not block Ca2+ transport but instead potentiates MCU. To address this direct clash of proposed MICU1 function, we applied purified MICU1 to Ca2+-conducting MCU-EMRE subcomplexes in outside-out patches excised from Xenopus oocytes. MICU1 strongly inhibits Ca2+ currents, and the inhibition is abolished by mutating an MCU-interacting K126 residue in MICU1. Further experiments show that MICU1 block was not observed in mitoplasts because MICU1 dissociates from the uniporter complex. These results firmly establish that MICU1 shuts the uniporter in resting cellular conditions.
Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota
Authors: Jaunet-Lahary Titouan , Shimamura Tatsuro , Hayashi Masahiro , Nomura Norimichi , Hirasawa Kouta , Shimizu Tetsuya , Yamashita Masao , Kojima Keiichi , Sudo Yuki , Tamura Takashi , Iwanari Hiroko , Hamakubo Takao , Iwata So , Okazaki Kei-ichi , Hirai Teruhisa , Yamashita Atsuko 
Published: November 2021

AbstractOxalobacter formigenes is an oxalate-degrading bacterium in the gut microbiota that absorbs food-derived oxalate to use this as a carbon and energy source and thereby helps reduce the risk of kidney stone formation of the host animals 1–4. The bacterial oxalate transporter OxlT uptakes oxalate from the gut to bacterial cells and excrete formate as a degradation product, with a strict discrimination from other carboxylates that serve as nutrients 5–7. Nevertheless, the underlying mechanism remains unclear. Here, we present crystal structures of oxalate-bound and ligand-free OxlT in two different conformations, occluded and outward-facing states. The oxalate binding site contains two basic residues that form salt bridges with a dicarboxylate substrate while preventing the conformational switch to the occluded state without an acidic substrate, a ‘disallowed’ state for an antiporter 8, 9. The occluded ligand-binding pocket can accommodate oxalate but not larger dicarboxylates, such as metabolic intermediates. The permeation pathways from the binding pocket are completely blocked by extensive interdomain hydrophobic and ionic interactions. Nevertheless, a molecular dynamics simulation showed that a flip of a single side chain neighbouring the substrate is sufficient to trigger the gate opening. The OxlT structure indicates the underlying metabolic interactions enabling favourable symbiosis at a molecular level.
Artificial selection for predatory behavior results in dietary niche differentiation in an omnivorous mammal
Authors: Hämäläinen Anni , Kiljunen Mikko , Koskela Esa , Koteja Pawel , Mappes Tapio , Rajala Milla , Tiainen Katariina 
Published: November 2021

AbstractThe diet of an individual is a result of the availability of dietary items and the individual’s foraging skills and preferences. Behavioral differences may thus influence diet variation, but the evolvability of diet choice through behavioral evolution has not been studied. We used experimental evolution combined with a field enclosure experiment to test whether behavioral selection leads to dietary divergence. We analysed the individual dietary niche via stable isotope ratios of nitrogen (δ15N) and carbon (δ13C) in the hair of an omnivorous mammal, bank vole, from 4 lines selected for predatory behavior and 4 unselected control lines. Predatory voles had higher hair δ15N values than control voles, supporting our hypothesis that predatory voles would consume a higher trophic level diet (more animal vs. plant foods). This difference was significant in the early but not the late summer season. The δ13C values also indicated a seasonal change in the consumed plant matter and a difference in food sources among selection lines in the early summer. These results imply that environmental factors interact with evolved behavioral tendencies to determine dietary niche heterogeneity. Behavioral selection thus has potential to contribute to the evolution of diet choice and ultimately the species’ ecological niche breadth.
Marmoset Model for Mycobacterium avium Complex Pulmonary Disease
Authors: Peters Jay I , Maselli Diego Jose , Mangat Mandeep , Coalson Jacqueline J. , Hinojosa Ceci , Giavedoni Luis , Brown-Elliott Barbara A. , Chan Edward D. , Griffith David E. 
Published: November 2021

AbstractRationaleMycobacterium avium complex, is the most common nontuberculous mycobacterial respiratory pathogen in humans. Disease mechanisms are poorly understood due to the absence of a reliable animal model for M. avium complex pulmonary disease.ObjectiveAssess the susceptibility, immunologic and histopathologic responses of the common marmoset (Callithrix jacchus) to M. avium complex pulmonary infection.Methods7 adult female marmosets underwent endobronchial inoculation with 108 colony-forming units of M. intracellulare and were monitored for 30 or 60 days. Prior to infection, chest radiograph and serum cytokines were assessed; serum cytokines were also monitored weekly for 30 days. At sacrifice 30 days (3 animals) or 60 days (4 animals) after infection, chest radiograph, serum and bronchoalveolar lavage cytokines, histopathology, and cultures of the bronchoalveolar lavage, lungs, liver, and kidney were analyzed.Measurements and Main ResultsFive of seven animals (two at 30 days and three at 60 days of infection) had positive lung cultures for M. intracellulare. Extra-pulmonary cultures were positive in three animals. All animals appeared healthy throughout the study. All five animals with positive lung cultures had radiographic changes consistent with pneumonitis. At 30 days, those with M. intracellulare lung infection showed granulomatous inflammation while at 60 days there was less inflammatory change, but bronchiectasis was noted. The cytokine response in the bronchoalveolar lavage fluid was uniformly greater in the animals with positive M. intracellulare cultures than those without a productive infection with greater levels at 30-days compared to 60-days. Similarly, serum cytokines were more elevated in the animals that had positive M. intracellulare cultures compared to those without a productive infection, peaking 14-21 days after inoculation.ConclusionEndobronchial instillation of M. intracellulare resulted in pulmonary mycobacterial infection in marmosets with a differential immune response, radiographic and histopathologic abnormalities, and an indolent course consistent with M. avium complex lung infection in humans.
Oligogenic heterozygous inheritance of sperm abnormalities in mouse
Authors: Martinez Guillaume , Coutton Charles , Loeuillet Corinne , Cazin Caroline , Muroňová Jana , Boguenet Magalie , Lambert Emeline , Dhellemmes Magali , Chevalier Geneviève , Hograindleur Jean-Pascal , Vilpreux Charline , Neirijnck Yasmine , Kherraf Zine-Eddine , Escoffier Jessica , Nef Serge , Ray Pierre F. , Arnoult Christophe 
Published: November 2021

ABSTRACTMale infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects – the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.
Estimating the Mosquito Density in Guangzhou City, China
Authors: Li Meili , Zhang Xian , Ma Junling 
Published: November 2021

AbstractMosquito is a vector of many diseases. Predicting the trend of mosquito density is important for early warning and control of mosquito diseases. In this paper, we fit a discrete time mosquito model developed by Gong et al. in 2011, which considers the immature and adult stages, and weather dependent model parameters, to the Breteau Index and Bite Index data for Aedes aegypti in Guangzhou city, China in 2014, as well as the weather data for average temperature, precipitation, evaporation and daylight for the same period. We estimated the model parameters using the Markov Chain Monte-Carlo (MCMC) method. We find that many parameters are not identifiable. We revise and simplify the model so that the parameters of our new model are identifiable. Our results indicate that the model predicted mosquito prevalence agrees well with data. We then use the fitted parameter values against the Breteau Index and Bite Index data for Guangzhou city in 2017 and 2018, and show that the estimated parameter values are applicable for other seasons.
Molecular dynamics simulations reveal the selectivity mechanism of structurally similar agonists to TLR7 and TLR8
Authors: Wang Xiaoyu , Chen Yu , Zhang Steven , Deng Jinxia Nancy 
Published: November 2021

AbstractTLR7 and TLR8 are key members of the Toll-like receptor family, playing crucial roles in the signaling pathways of innate immunity, and thus become attractive therapeutic targets of many diseases including infections and cancer. Although TLR7 and TLR8 show a highly degree of sequence homology, their biological response to small molecule binding is very different. Aiming to understand the mechanism of selective profiles of small molecule modulators against TLR7 and TLR8, we carried out molecular dynamic simulations on three imidazoquinoline derivatives bound to the receptors separately. They are Resiquimod (R), Hybrid-2 (H), and Gardiquimod (G), selective agonists of TLR7 and TLR8. Our MD trajectories indicated that in the complex of TLR7-R and TLR7-G, the two chains forming the TLR7 dimer tended to remain “open” conformation, while the rest systems maintained in the closed format. The agonists R, H, and G developed conformational deviation mainly on the aliphatic tail. Furthermore, we attempted to quantify the selectivity between TLR7 and TLR8 by binding free energies via MM-GBSA method. It showed that the three selected modulators were more favorable for TLR7 than TLR8, and the ranking from the strongest to the weakest was H, R and G, aligning well with experiment data. In the TLR7, the flexible and hydrophobic aliphatic side chain of H has stronger van der Waals interactions with Val381 and Phe351 but only pick up interaction with one amino acid residue i.e. Tyr353 of TLR8. Unsurprisingly, the positively charged side chain of G has less favor interaction with Ile585 of TLR7 and Val573 of TLR8 explaining G is weak agonist in both TLR7 and TLR8. All three imidazoquinolines can form stable hydrogen bonds with Asp555 of TLR7 and the corresponding Asp543 of TLR8. In brief, the set of total 400ns MD studies sheds light on the potential selective mechanisms of agonists towards TLR7 and TLR8, indicating the van der Waals interaction as the driving force for the agonists binding, thus provides us insights for more potent and selective modulators to cooperate with the hydrophobic nature of the binding pocket.
Using OPM-MEG in contrasting magnetic environments
Authors: Hill Ryan M. , Devasagayam Jasen , Holmes Niall , Boto Elena , Shah Vishal , Osborne James , Safar Kristina , Worcester Frank , Mariani Christopher , Dawson Eliot , Woolger David , Bowtell Richard , Taylor Margot J. , Brookes Matthew J. 
Published: November 2021

ABSTRACTMagnetoencephalography (MEG) has been revolutionised in recent years by optically pumped magnetometers (OPMs). “OPM-MEG” offers higher sensitivity, better spatial resolution and lower cost than conventional instrumentation based on superconducting quantum interference devices (SQUIDS). Moreover, OPMs offer the possibility of motion robustness and lifespan compliance, dramatically expanding the range of MEG applications. However, OPM-MEG remains nascent technology; it places stringent requirements on magnetic shielding, and whilst a number of viable systems exist, most are custom made and there have been no cross-site investigations showing the reliability of data. In this paper, we undertake the first cross-site OPM-MEG comparison, using near identical commercial systems scanning the same participant. The two sites are deliberately contrasting, with different magnetic environments: a “green field” campus university site with an OPM-optimised shielded room (low interference) and a city centre hospital site with a “standard” (non-optimised) MSR (high interference). We show that despite a 25-fold difference in background field, and a 30-fold difference in low frequency interference, using dynamic field control and software-based suppression of interference we can generate comparable noise floors at both sites. In human data recorded during a visuo-motor task and a face processing paradigm, we were able to generate similar data, with source localisation showing that brain regions could be pinpointed with just ~10 mm spatial discrepancy and temporal correlations of > 80%. Overall, our study demonstrates that “plug- and-play” OPM-MEG systems exist and can be sited even in challenging magnetic environments.
Genetic coordination of sperm morphology and seminal fluid proteins promotes male reproductive success inDrosophila melanogaster
Authors: Galvin Jake , Larson Erica L. , Yedigarian Sevan , Rahman Mohammad , Borziak Kirill , DeNieu Michael , Manier Mollie K. 
Published: November 2021

AbstractSpermatozoal morphology is highly variable both among and within species and in ways that can significantly impact fertilization success. InDrosophila melanogaster, paternity success depends on sperm length of both competing males and length of the female’s primary sperm storage organ. We found that genes upregulated in long sperm testes are enriched for lncRNAs and seminal fluid proteins (Sfps). Transferred in seminal fluid to the female during mating, Sfps are secreted by the male accessory glands (AG) and affect female remating rate, physiology, and behavior with concomitant advantages for male reproductive success. Despite being upregulated in long sperm testes, they have no known function in testis tissue. We found that Sex Peptide and ovulin (Acp26Aa) knockouts resulted in shorter sperm, suggesting that Sfps may regulate sperm length during spermatogenesis. However, knockout of AG function did not affect sperm length, suggesting that AG expression has no influence on spermatogenic processes. We also found that long sperm males are better able to delay female remating, suggesting higher Sfp expression in AG. These results might suggest that long sperm males have a double advantage in sperm competition by both delaying female remating, likely through transfer of more Sfps, and by resisting sperm displacement. However, we also found that this extra advantage does not necessarily translate to more progeny or higher paternity success. Thus, we found that multiple components of the ejaculate coordinate to promote male reproductive success at different stages of reproduction, but the realized fitness advantages in sperm competition are uncertain.Significance StatementThe ejaculate is comprised of sperm produced in the testis and seminal fluid primarily produced in the male accessory glands (AG). These complementary components are both critical for male reproductive success, but they are largely considered to be functionally, genetically, and developmentally independent. In a quest to understand genetic mechanisms of sperm length variation, we found that genes upregulated in long sperm testes are enriched for lncRNAs and seminal fluid proteins (Sfps). Knockout of two Sfps, Sex Peptide and ovulin, results in shorter sperm, though knockout of AG function has no effect. Moreover, long sperm males delay female remating longer. These results suggest sophisticated testis-AG coordination that amplifies male reproductive success, with implications for evolutionary integration of sexually selected traits.
Relating spinal injury-induced neuropathic pain and spontaneous afferent activity to sleep and respiratory dysfunction
Authors: Idlett-Ali S , Kloefkorn H , Goolsby W , Hochman S 
Published: November 2021

ABSTRACTSpinal cord injury (SCI) can induce dysfunction in a multitude of neural circuits including those that lead to impaired sleep, respiratory dysfunction and neuropathic pain. We used a lower thoracic rodent contusion SCI model - known to develop mechanosensory stimulus hypersensitivity, and spontaneous activity in primary afferents that associates neuropathic pain - and paired this with new approaches that enabled chronic capture of three state sleep and respiration to characterize dysfunction and assess possible interrelations. Noncontact electric field sensors were embedded into home cages for noninvasive capture in naturally behaving mice of the temporal evolution of sleep and respiration changes for 6 weeks after SCI. Hindlimb mechanosensitivity was assessed weekly, and terminal experiments measured primary afferent spontaneous activity in situ from intact lumbar dorsal root ganglia (DRG). We observed that SCI led to increased spontaneous primary afferent activity (both firing rate and the number of spontaneously active DRGs) that correlated with reduced hindpaw mechanical sensitivity, increased respiratory rate variability, and increased sleep fragmentation. This is the first study to measure and link sleep dysfunction and variability in respiratory rate in a SCI model of neuropathic pain, and thereby provide broader insight into the magnitude of overall stress burden initiated by neural circuit dysfunction after SCI.