bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2 infection risk among unvaccinated is negatively associated with community-level vaccination rates
Authors: Milman Oren , Yelin Idan , Aharony Noga , Katz Rachel , Herzel Esma , Ben-Tov Amir , Kuint Jacob , Gazit Sivan , Chodick Gabriel , Patalon Tal , Kishony Roy 
Published: March 2021

AbstractMass vaccination has the potential to curb the current COVID-19 pandemic by protecting vaccinees from the disease and possibly lowering the chance of transmission to unvaccinated individuals. The high effectiveness of the widely-administered BNT162b vaccine in preventing not only the disease but also infection suggests a potential for a population-level effect, critical for disease eradication. However, this putative effect is difficult to observe, especially in light of highly fluctuating spatio-temporal epidemic dynamics. Here, analyzing vaccination records and test results collected during a rapid vaccine rollout for a large population from 223 geographically defined communities, we find that the rates of vaccination in each community are highly correlated with a later decline in infections among a cohort of under 16 years old which are unvaccinated. These results provide observational evidence that vaccination not only protects individual vaccinees but also provides cross-protection to unvaccinated individuals in the community.
Proteasome autophagy is specifically regulated and requires factors dispensible for general autophagy
Authors: Waite Kenrick A. , Burris Alicia , Vontz Gabrielle , Lang Angelica , Roelofs Jeroen 
Published: March 2021

ABSTRACTChanging physiological conditions can increase the need for protein degradative capacity in eukaryotic cells. Both the ubiquitin-proteasome system and autophagy contribute to protein degradation. However, proteasomes are also an autophagy substrate. Thus, these processes must be differentially regulated depending on the physiological conditions presented. The signals and molecular mechanisms that govern proteasome autophagy are only partly elucidated. Our data indicate that chemical inhibition of TORC1 with rapamycin induces a bi-phasic response where proteasome levels are upregulated followed by an autophagy-dependent reduction. Surprisingly, several conditions that result in inhibited TORC1 exclusively induce proteasome autophagy (i.e. without any proteasome upregulation), suggesting a convergence of signals upstream of proteasome autophagy under different physiological conditions. Indeed, several conditions that activate general autophagy did not induce proteasome autophagy further distinguishing between proteasome autophagy and general autophagy. Consistent with this, we found that Atg11, the receptor for selective autophagy, and the map kinases Mpk1, Mkk1, and Mkk2, all play a role in autophagy of proteasomes, while they are dispensible for general autophagy. In all, our data provide new insights into the molecular regulation of proteasome autophagy by demonstrating that these complexes are specifically regulated under different autophagy inducing conditions.
NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions
Authors: Kim Jung Ho , Hong Jeong Hoon , Choi Yoon-La , Lee Ji Ae , Seo Mi-kyoung , Lee Mi-Sook , An Sung Bin , Sung Min Jung , Cho Nam-Yun , Kim Sung-Su , Shin Young Kee , Kim Sangwoo , Kang Gyeong Hoon 
Published: March 2021

ABSTRACTBackgroundNTRK fusions are emerging tissue-agnostic drug targets in malignancies including colorectal cancers (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated.MethodsPan-TRK expression was assessed by immunohistochemistry in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs (133 microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)) and 565 premalignant colorectal lesions (300 serrated lesions and 265 conventional adenomas). TRK-positive cases were subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements.ResultsTRK positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) sporadic MSI-high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) SSLs. The 11 TRK-positive MSI-high CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, KRAS/BRAF wild-type, and NTRK1 or NTRK3 fusion (TPM3-NTRK1, TPR-NTRK1, LMNA-NTRK1, SFPQ-NTRK1, ETV6-NTRK3, or EML4-NTRK3). Both NTRK1 or NTRK3 rearrangement and KRAS/BRAF wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK overexpression and early dysplastic changes are occasionally co-localized in the crypt base area of SSLs. Age-related occurrence patterns suggest that the progression interval from NTRK-rearranged SSLs to CRCs may be shorter than from BRAF-mutated SSLs to CRCs.ConclusionNTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without KRAS/BRAF mutations prior to full occurrence of MSI-high/CIMP-high.
Six-month pulmonary impairment after severe COVID-19: a prospective, multicenter follow-up study
Authors: Faverio Paola , Luppi Fabrizio , Rebora Paola , Busnelli Sara , Stainer Anna , Catalano Martina , Parachini Luca , Monzani Anna , Galimberti Stefania , Bini Francesco , Bodini Bruno Dino , Betti Monia , Giacomi Federica De , Scarpazza Paolo , Oggionni Elisa , Scartabellati Alessandro , Bilucaglia Luca , Ceruti Paolo , Modina Denise , Harari Sergio , Caminati Antonella , Valsecchi Maria Grazia , Bellani Giacomo , Foti Giuseppe , Pesci Alberto 
Published: March 2021

AbstractBackground and objectiveLong-term pulmonary sequelae following SARS-CoV-2 pneumonia are not yet confirmed, however preliminary observations suggests a possible relevant clinical, functional and radiological impairment. The aim of this study was to identify and characterise pulmonary sequelae caused by SARS-CoV-2 pneumonia at 6-month follow-up.MethodsIn this multicenter, prospective, observational cohort study, patients hospitalised for SARS-CoV-2 pneumonia and without prior diagnosis of structural lung diseases were stratified by maximum ventilatory support (“oxygen only”, “continuous positive airway pressure (CPAP)” and “invasive mechanical ventilation (IMV)”) and followed up at 6 months from discharge. Pulmonary function tests and diffusion capacity for carbon monoxide (DLCO), 6 minutes walking test, chest X-ray, physical exam and modified Medical Research Council (mMRC) dyspnoea score were collected.ResultsBetween March and June 2020, 312 patients were enrolled (83, 27% women; median [IQR] age 61.1 [53.4,69.3] years). The parameters that showed the highest rate of impairment were DLCO and chest-X-ray, in 46% and 25% of patients, respectively. However, only a minority of patients reported dyspnoea (31%), defined as mMRC ≥ 1, or showed a restrictive ventilatory defects (9%). In the logistic regression model, having asthma as comorbidity was associated with DLCO impairment at follow-up, while prophylactic heparin administration during hospitalisation appeared as a protective factor. Need for invasive ventilatory support during hospitalisation was associated with chest imaging abnormalities.ConclusionDLCO and radiological assessment appear to be the most sensitive tools to monitor patients with COVID-19 during follow-up. Future studies with longer follow-up are warranted to better understand pulmonary sequelae.Summary at a glanceDLCO and radiological assessment are the most sensitive tools to monitor COVID-19 patients at 6-month follow-up. Invasive ventilatory support is a risk factor for detection of radiological abnormalities, but not for DLCO impairment, at follow-up. Whileuse of prophylactic heparin acts as a protective factor on the development of DLCOimpairment.
Development and validation of the RCOS prognostic index: a bedside multivariable logistic regression model to predict hypoxaemia or death in patients with SARS-CoV-2 infection
Authors: Alvarez-Uria Gerardo , Gandra Sumanth , Gurram Venkata R , Reddy Raghu P , Midde Manoranjan , Kumar Praveen , Arce Ketty E 
Published: March 2021

AbstractPrevious COVID-19 prognostic models have been developed in hospital settings, and are not applicable to COVID-19 cases in the general population. There is an urgent need for prognostic scores aimed to identify patients at high risk of complications at the time of COVID-19 diagnosis. The RDT COVID-19 Observational Study (RCOS) collected clinical data from patients with COVID-19 admitted regardless of the severity of their symptoms in a general hospital in India. We aimed to develop and validate a simple bedside prognostic score to predict the risk of hypoxaemia or death.4035 patients were included in the development cohort and 2046 in the validation cohort. The primary outcome occurred in 961 (23.8%) and 548 (26.8%) patients in the development and validation cohorts, respectively. The final model included 12 variables: age, systolic blood pressure, heart rate, respiratory rate, aspartate transaminase, lactate dehydrogenase, urea, C-reactive protein, sodium, lymphocyte count, neutrophil count and neutrophil/lymphocyte ratio. In the validation cohort, the area under the receiver operating characteristic curve (AUROCC) was 0.907 (95% CI, 0.892-0.922) and the Brier Score was 0.098. The decision curve analysis showed good clinical utility in hypothetical scenarios where admission of patients was decided according to the prognostic index. When the prognostic index was used to predict mortality in the validation cohort, the AUROCC was 0.947 (95% CI, 0.925-0.97) and the Brier score was 0.0188.If our results are validated in other settings, the RCOS prognostic index could help improve the decision making in the current COVID-19 pandemic, especially in resource limited-settings.
Identification of candidate genes for self-compatibility in perennial ryegrass (Lolium perenneL.)
Authors: Cropano Claudio , Manzanares Chloé , Yates Steven , Copetti Dario , Do Canto Javier , Lübberstedt Thomas , Koch Michael , Studer Bruno 
Published: March 2021

AbstractSelf-incompatibility (SI) is a genetic mechanism preventing self-pollination in approximately 40% of plant species. Two multiallelic loci, calledSandZ, control the gametophytic SI system of the grass family (Poaceae), which contains all major forage grasses. Loci independent fromSandZhave been reported to disrupt SI and lead to self-compatibility (SC). A locus causing SC in perennial ryegrass (Lolium perenneL.) was previously mapped on linkage group (LG) 5 in a F2population segregating for SC. Using a subset of the same population (n=68), we first performed low-resolution quantitative trait locus (QTL) mapping to exclude the presence of additional, previously undetected contributors to SC. The previously reported QTL on LG 5 explained 38.4% of the phenotypic variation, and no significant contribution from other genomic regions was found. This was verified by the presence of significantly distorted markers in the region overlapping with the QTL. Second, we fine mapped the QTL to 0.26 cM using additional 2,056 plants and 23 novel sequence-based markers. Using an Italian ryegrass (Lolium multiflorumLam.) genome assembly as reference, the markers flanking SC were estimated to span a ~3 Mb region encoding for 57 predicted genes. Among these, seven genes were proposed as relevant candidate genes based on their annotation and function described in previous studies. Our work is a step forward to identify SC genes in forage grasses and provides diagnostic markers for marker-assisted introgression of SC into elite germplasm.Key messageA previously reported QTL conferring self-compatibility to perennial ryegrass was fine mapped to a 0.26 cM locus, corresponding to an estimated ~ 3 Mb physical region containing 57 predicted protein-encoding genes.
Evolutionary trade-offs at the ArabidopsisWRR4Aresistance locus underpin alternateAlbugocandida recognition specificities
Authors: Castel Baptiste , Fairhead Sebastian , Furzer Oliver J. , Redkar Amey , Wang Shanshan , Cevik Volkan , Holub Eric B. , Jones Jonathan D. G. 
Published: March 2021

SummaryThe oomyceteAlbugo candidacauses white rust of Brassicaceae, including vegetable and oilseed crops, and wild relatives such asArabidopsis thaliana. NovelWhite Rust Resistance(WRR)-genes from Arabidopsis enable new insights into plant/parasite co-evolution.WRR4Afrom Arabidopsis accession Col-0 provides resistance to many but not all white rust races, and encodes a nucleotide-binding (NB), leucine-rich repeat (LRR) (NLR) immune receptor protein. Col-0WRR4Aresistance is broken by a Col-0-virulent isolate ofA. candidarace 4 (AcEx1). We identified an allele ofWRR4Ain Arabidopsis accession Oy-0 and other accessions that confers full resistance to AcEx1.WRR4AOy-0carries a C-terminal extension required for recognition of AcEx1, but reduces recognition of several effectors recognized by theWRR4ACol-0allele.WRR4AOy-0confers full resistance to AcEx1 when expressed as a transgene in the oilseed cropCamelina sativa.SignificanceA C-terminal extension in an allele of the Arabidopsis resistance-protein WRR4A changes effector recognition specificity, enabling theWRR4AOy-0allele to confer immunity toAlbugo candidaraces that overcome theWRR4ACol-0allele. This resistance can be transferred to the oil-producing cropCamelina sativa.Graphical abstract
Shared and unique properties of place cells in anterior cingulate cortex and hippocampus
Authors: Bota Ayaka , Goto Akihiro , Tsukamoto Suzune , Schmidt Alexander , Wolf Fred , Luchetti Alessandro , Nakai Junichi , Hirase Hajime , Hayashi Yasunori 
Published: March 2021

AbstractIn the brain, spatial information is represented by neurons that fire when an animal is at specific locations, including place cells in hippocampus and grid cells in entorhinal cortex. But how this information is processed in downstream brain regions still remains elusive. Using chronic Ca2+imaging, we examined the activity of neurons in anterior cingulate cortex (ACC), a brain region implicated in memory consolidation, and found neurons that fire in a manner consistent with the properties of place cells. While the ACC place cells showed stability, location and context specificity similar to the hippocampal counterparts, they also have unique properties. Unlike hippocampal place cells that immediately formed upon exposure to a novel environment, ACC place cells increased over days. Also, ACC place cells tend to have additional place fields whereas typical hippocampal place cells have only one. Hippocampal activity is required for the formation of ACC place cells, but once they are established, hippocampal inactivation did not have any impact on ACC place cell firing. We thus identified features of ACC place cells that carry spatial information in a unique fashion.
Single-cell analysis of the human pancreas in type 2 diabetes using multi-spectral imaging mass cytometry
Authors: Wu Minghui , Lee Michelle Y.Y. , Traum Daniel , Schug Jonathan , Kusmartseva Irina , Atkinson Mark A. ,   HPAP Consortium, Kaestner Klaus H. 
Published: March 2021

SUMMARYType 2 diabetes mellitus (T2D) is a chronic age-related disorder characterized by hyperglycemia due to the failure of pancreatic beta cells to compensate for increased insulin demand, typically associated with peripheral insulin resistance. However, despite decades of research, the pathogenic mechanisms underlying T2D remain poorly defined. Imaging mass cytometry (IMC) enables multiplexed assessment of the abundance and subcellular localization of multiple proteins on the same tissue section. Herein, we utilized IMC with a panel of 34 antibodies to quantify key markers of pancreatic exocrine, islet, and immune cells as well as stromal components. We employed this panel to analyze over 2.1 million cells from 16 pancreata obtained from donors with T2D and 13 pancreata from age similar non-diabetic controls. In the T2D pancreata, we observed significant alterations in islet architecture, endocrine cell composition, and surprisingly immune cell constituents. Thus, both HLA-DR positive CD8 T cells and macrophages were enriched intra-islet in the T2D pancreas. These efforts demonstrate the utility of IMC to investigate complex events at the cellular level in order to provide new insights into the pathophysiology of T2D.
Dietary cardenolides enhance growth and change the direction of the fecundity-longevity trade-off in milkweed bugs (Heteroptera: Lygaeinae)
Authors: Pokharel Prayan , Steppuhn Anke , Petschenka Georg 
Published: March 2021

AbstractSequestration, i.e., the accumulation of plant toxins into body tissues for defence, is primarily observed in specialised insects. Sequestration was frequently predicted to incur a physiological cost mediated by increased exposure to plant toxins and may require resistance traits different from those of non-sequestering insects. Alternatively, sequestering species could experience a cost in the absence of toxins due to selection on physiological homeostasis under permanent exposure of sequestered toxins in body tissues.Milkweed bugs (Heteroptera: Lygaeinae) sequester high amounts of plant-derived cardenolides. Although being potent inhibitors of the ubiquitous animal enzyme Na+/K+-ATPase, milkweed bugs can tolerate cardenolides by means of resistant Na+/K+-ATPases. Both adaptations, resistance and sequestration, are ancestral traits shared by most species of the Lygaeinae.Using four milkweed bug species and the related European firebug (Pyrrhocoris apterus) showing different combinations of the traits ‘cardenolide resistance’ and ‘cardenolide sequestration’, we set out to test how the two traits affect larval growth upon exposure to dietary cardenolides in an artificial diet system. While cardenolides impaired the growth ofP. apterusnymphs neither possessing a resistant Na+/K+-ATPase nor sequestering cardenolides, growth was not affected in the non-sequestering milkweed bugArocatus longiceps, which possesses a resistant Na+/K+-ATPase. Remarkably, cardenolides increased growth in the sequestering dietary specialistsCaenocoris neriiandOncopeltus fasciatusbut not in the sequestering dietary generalistSpilostethus pandurus, which all possess a resistant Na+/K+-ATPase.We then assessed the effect of dietary cardenolides on additional life history parameters, including developmental speed, the longevity of adults, and reproductive success inO. fasciatus. Remarkably, nymphs under cardenolide exposure developed substantially faster and lived longer as adults. However, fecundity of adults was reduced when maintained on cardenolide-containing diet for their entire life-time but not when adults were transferred to non-toxic sunflower seeds.We speculate that the resistant Na+/K+-ATPase of milkweed bugs is selected for working optimally in a ‘toxic environment’, i.e. when sequestered cardenolides are stored in the body tissues. Contrary to the assumption that toxins sequestered for defence produce a physiological burden, our data suggest that they can even increase fitness in specialised insects.
Modeling pulsed evolution and time-independent variation improves the confidence level of ancestral and hidden state predictions in continuous traits
Authors: Gao Yingnan , Wu Martin 
Published: March 2021

AbstractAncestral state reconstruction is a fundamental tool for studying trait evolution. It is also very useful for predicting the unknown trait values (hidden states) of extant species. A well-known problem in ancestral and hidden state predictions is that the uncertainty associated with predictions can be so large that predictions themselves are of little use. Therefore, for meaningful interpretation of predicted traits and hypothesis testing, it is prudent to accurately assess the uncertainty of the predictions. Commonly used Brownian motion (BM) model fails to capture the complexity of tempo and mode of trait evolution in nature, making predictions under the BM model vulnerable to lack-of-fit errors from model misspecification. Using simulations and empirical data (bacterial genomic traits and vertebrate body size), we show that the presence of pulsed evolution and time-independent variation significantly undermines the confidence level of continuous traits predicted under the BM model. The residual Z-scores are neither homoscedastic nor normally distributed. Consequently, the 95% confidence intervals of predicted traits are so unreliable that the actual coverage probability ranges from 29% (strongly permissive) to 100% (strongly conservative). To remedy the model misspecification problem, we develop RasperGade that accounts for both pulsed evolution and time-independent variation. When applied to simulated and empirical data, RasperGade outperforms commonly used tools such asape. It restores the normality and homoscedasticity of the Z-score distributions. Accordingly, RasperGade greatly improves the reliability of confidence intervals of predictions and reduces the deviation of their actual coverage probabilities from the 95% expectation by as much as 99%.
An interpretable meta-clustering framework for single-cell RNA-Seq data integration and evaluation
Authors: Hu Zhiyuan , Ahmed Ahmed A. , Yau Christopher 
Published: March 2021

AbstractSingle-cell RNA sequencing (scRNA-Seq) datasets that are produced from clinical samples are often confounded by batch effects and inter-patient variability. Existing batch effect removal methods typically require strong assumptions on the composition of cell populations being near identical across patients. Here we present a novel meta-clustering workflow, CIDER, based on inter-group similarity measures. We demonstrate that CIDER outperforms other scRNA-Seq clustering methods and integration approaches in both simulated and real datasets. Moreover, we show that CIDER can be used to assess the biological correctness of integration in real datasets, while it does not require the existence of prior cellular annotations.
Identification of neural progenitor cells and their progeny reveals long distance migration in the developing octopus brain
Authors: Deryckere Astrid , Styfhals Ruth , Elagoz Ali Murat , Maes Gregory E. , Seuntjens Eve 
Published: March 2021

AbstractCephalopods have evolved nervous systems that parallel the complexity of mammalian brains in terms of neuronal numbers and richness in behavioral output. How the cephalopod brain develops has only been described at the morphological level, and it remains unclear where the progenitor cells are located and what molecular factors drive neurogenesis. Using histological techniques, we located dividing cells, neural progenitors and postmitotic neurons inOctopus vulgarisembryos. Our results indicate that progenitors are located outside the central brain cords in the lateral lips adjacent to the eyes, suggesting that newly formed neurons migrate into the cords. Lineage tracing experiments then showed that progenitors, depending on their location in the lateral lips, generate neurons for the different lobes. The finding that octopus newborn neurons migrate over long distances is reminiscent of vertebrate neurogenesis and suggests it might be a fundamental strategy for large brain development.