bluuebunny/crossref_metadata_2025_split huggingface dataset:
A panoptic segmentation approach for tumor-infiltrating lymphocyte assessment: development of the MuTILs model and PanopTILs dataset
Authors: Liu Shangke , Amgad Mohamed , Rathore Muhammad A. , Salgado Roberto , Cooper Lee A.D. 
Published: January 2022

AbstractTumor-Infiltrating Lymphocytes (TILs) have strong prognostic and predictive value in breast cancer, but their visual assessment is subjective. To improve reproducibility, the International Immuno-oncology Working Group recently released recommendations for the computational assessment of TILs that build on visual scoring guidelines. However, existing resources do not adequately address these recommendations due to the lack of annotation datasets that enable joint, panoptic segmentation of tissue regions and cells. Moreover, existing deep-learning methods focus entirely on either tissue segmentation or cell nuclei detection, which complicates the process of TILs assessment by necessitating the use of multiple models and reconciling inconsistent predictions. We introducePanopTILs, a region and cell-level annotation dataset containing 814,886 nuclei from 151 patients, openly accessible at: sites.google.com/view/panoptils. Using PanopTILs we developedMuTILs, a neural network optimized for assessing TILs in accordance with clinical recommendations. MuTILs is a concept bottleneck model designed to be interpretable and to encourage sensible predictions at multiple resolutions. Using a rigorous internal-external cross-validation procedure, MuTILs achieves an AUROC of 0.93 for lymphocyte detection and a DICE coefficient of 0.81 for tumor-associated stroma segmentation. Our computational score closely matched visual scores from 2 pathologists (Spearman R=0.58-0.61, p<0.001). Moreover, computational TILs scores had a higher prognostic value than visual scores, independent of TNM stage and patient age. In conclusion, we introduce a comprehensive open data resource and a novel modeling approach for detailed mapping of the breast tumor microenvironment.
Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study
Authors: Howe Laurence J , Rasheed Humaira , Jones Paul R , Boomsma Dorret I , Evans David M , Giannelis Alexandros , Hayward Caroline , Hopper John L , Hughes Amanda , Lahtinen Hannu , Li Shuai , Lind Penelope A , Martin Nicholas G , Martikainen Pekka , Medland Sarah E , Morris Tim T , Nivard Michel G , Pingault Jean-Baptiste , Silventoinen Karri , Smith Jennifer A , Willoughby Emily A , Wilson James F ,   Within Family Consortium, Olav Åsvold Bjørn , Næss Øyvind E , Smith George Davey , Kaprio Jaakko , Brumpton Ben , Davies Neil M 
Published: January 2022

AbstractPrevious Mendelian randomization (MR) studies using population samples (population-MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. Mendelian randomization using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis.Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72,932 siblings from UK Biobank and the Norwegian HUNT study and summary-level data from a within-sibship Genome-wide Association Study including over 140,000 individuals.Both population and within-sibship MR estimates provided evidence that educational attainment influences BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independent of potential demographic and family-level confounders.
XTRA Study protocol: eXploring medical sTudents’ caReer reAdiness - A cross sectional study in the UK
Authors: Godoi Amanda , McDade-Kumar Mia , Virk Farazi , Casteleyn Charlotte , Marei Omar , Yang Ting , Moussa Ahmed , Aman Kashif , Byrne Matthew H V , Babu Priya Rose , Trikha Sanya , Bamdad Kiana , Tombs Michal 
Published: January 2022

AbstractBackground and objectivesProfessional and career enhancing opportunities are essential for developing skills required for a successful career in medicine. Research to date has mainly focused on the extent to which medical schools prepare students for clinical work as junior doctors. However, there remains a need to ascertain how students prepare for their career and what facilitates or hinders learning regarding careers in medicine. The purpose of the XTRA study is to examine career readiness of medical students at UK universities and the support they receive during their studies regarding career planning.MethodsThe eXploring medical sTudents’ caReer reAdiness (XTRA) study is a national cross sectional study of all medical students enrolled at a UK medical school. Data collection will occur via a secure online survey designed as a training need analysis based on the principles of Super’s theory (Super, 1953) of career development. A snowball sampling strategy will be used to recruit participants via social media and networks. Results will be analysed using quantitative analysis and thematic analysis to identify themes in qualitative responses. The primary outcome is to understand the perspective of current medical students on how well prepared they are about entering their careers in healthcare.ConclusionsWe anticipate that findings from this study will help identify career readiness of medical students to facilitate the development of career development programmes and resources to ensure medical students are well equipped for their future careers.
In vivo single-cell profiling of lncRNAs during Ebola virus infection
Authors: Santus Luisa , García-Pérez Raquel , Sopena-Rios Maria , Lin Aaron E , Adams Gordon C , Barnes Kayla G , Siddle Katherine J , Wohl Shirlee , Reverter Ferran , Rinn John L , Bennett Richard S , Hensley Lisa E , Sabeti Pardis C , Melé Marta 
Published: January 2022

AbstractLong non-coding RNAs (lncRNAs) are pivotal mediators of systemic immune response to viral infection, yet most studies concerning their expression and functions upon immune stimulation are limited to in vitro bulk cell populations. This strongly constrains our understanding of how lncRNA expression varies at single-cell resolution, and how their cell-type specific immune regulatory roles may differ compared to protein-coding genes. Here, we perform the first in-depth characterization of lncRNA expression variation at single-cell resolution during Ebola virus (EBOV) infection in vivo. Using bulk RNA-sequencing from 119 samples and 12 tissue types, we significantly expand the current macaque lncRNA annotation. We then profile lncRNA expression variation in immune circulating single-cells during EBOV infection and find that lncRNAs’ expression in fewer cells is a major differentiating factor from their protein-coding gene counterparts. Upon EBOV infection, lncRNAs present dynamic and mostly cell-type specific changes in their expression profiles especially in monocytes, the main cell type targeted by EBOV. Such changes are associated with gene regulatory modules related to important innate immune responses such as interferon response and purine metabolism. Within infected cells, several lncRNAs have positively and negatively correlated expression with viral load, suggesting that expression of some of these lncRNAs might be directly hijacked by EBOV to attack host cells. This study provides novel insights into the roles that lncRNAs play in the host response to acute viral infection and paves the way for future lncRNA studies at single-cell resolution.
The SARS-CoV-2 Omicron (B.1.1.529) variant exhibits altered pathogenicity, transmissibility, and fitness in the golden Syrian hamster model
Authors: Yuan Shuofeng , Ye Zi-Wei , Liang Ronghui , Tang Kaiming , Zhang Anna Jinxia , Lu Gang , Ong Chon Phin , Poon Vincent Kwok-Man , Chan Chris Chung-Sing , Mok Bobo Wing-Yee , Qin Zhenzhi , Xie Yubin , Sun Haoran , Tsang Jessica Oi-Ling , Yuen Terrence Tsz-Tai , Chik Kenn Ka-Heng , Chan Chris Chun-Yiu , Cai Jian-Piao , Luo Cuiting , Lu Lu , Yip Cyril Chik-Yan , Chu Hin , To Kelvin Kai-Wang , Chen Honglin , Jin Dong-Yan , Yuen Kwok-Yung , Chan Jasper Fuk-Woo 
Published: January 2022

ABSTRACTThe newly emerging SARS-CoV-2 Omicron (B.1.1.529) variant first identified in South Africa in November 2021 is characterized by an unusual number of amino acid mutations in its spike that renders existing vaccines and therapeutic monoclonal antibodies dramatically less effective. The in vivo pathogenicity, transmissibility, and fitness of this new Variant of Concerns are unknown. We investigated these virological attributes of the Omicron variant in comparison with those of the currently dominant Delta (B.1.617.2) variant in the golden Syrian hamster COVID-19 model. Omicron-infected hamsters developed significantly less body weight losses, clinical scores, respiratory tract viral burdens, cytokine/chemokine dysregulation, and tissue damages than Delta-infected hamsters. The Omicron and Delta variant were both highly transmissible (100% vs 100%) via contact transmission. Importantly, the Omicron variant consistently demonstrated about 10-20% higher transmissibility than the already-highly transmissible Delta variant in repeated non-contact transmission studies (overall: 30/36 vs 24/36, 83.3% vs 66.7%). The Delta variant displayed higher fitness advantage than the Omicron variant without selection pressure in both in vitro and in vivo competition models. However, this scenario drastically changed once immune selection pressure with neutralizing antibodies active against the Delta variant but poorly active against the Omicron variant were introduced, with the Omicron variant significantly outcompeting the Delta variant. Taken together, our findings demonstrated that while the Omicron variant is less pathogenic than the Delta variant, it is highly transmissible and can outcompete the Delta variant under immune selection pressure. Next-generation vaccines and antivirals effective against this new VOC are urgently needed.One Sentence SummaryThe novel SARS-CoV-2 Omicron variant, though less pathogenic, is highly transmissible and outcompetes the Delta variant under immune selection pressure in the golden Syrian hamster COVID-19 model.
Systematic analysis of human antibody response to ebolavirus glycoprotein reveals high prevalence of neutralizing public clonotypes
Authors: Chen Elaine C. , Gilchuk Pavlo , Zost Seth J. , Ilinykh Philipp A. , Binshtein Elad , Huang Kai , Myers Luke , Bonissone Stefano , Day Samuel , Kona Chandrahaas R. , Trivette Andrew , Reidy Joseph X. , Sutton Rachel E. , Gainza Christopher , Monroig Summer , Davidson Edgar , Saphire Erica Ollmann , Doranz Benjamin J. , Castellana Natalie , Bukreyev Alexander , Carnahan Robert H. , Crowe James E. 
Published: January 2022

SUMMARYUnderstanding the human antibody response to emerging viral pathogens is key to epidemic preparedness. As the size of the B cell response to a pathogenic virus protective antigen is undefined, we performed deep paired heavy and light chain sequencing in EBOV-GP specific memory B cells, allowing analysis of the ebolavirus-specific antibody repertoire both genetically and functionally. This approach facilitated investigation of the molecular and genetic basis for evolution of cross-reactive antibodies by elucidating germline-encoded properties of antibodies to EBOV and identification of the overlap between antibodies in the memory B-cell and serum repertoire. We identified 73 public clonotypes to EBOV, 20% of which encoded antibodies with neutralization activity and capacity to protect in vivo. This comprehensive analysis of the public and private antibody repertoire provides insight into the molecular basis of the humoral immune response to EBOV-GP, which informs vaccine design of new vaccines and improved therapeutics.
Staphylococcus aureus does not synthesize arginine from proline under physiological conditions
Authors: Jeong Bohyun , Shah Majid Ali , Roh Eunjung , Kim Kyeongkyu , Park Indal , Bae Taeok 
Published: January 2022

AbstractThe Gram-positive pathogen Staphylococcus aureus is the only bacterium known to synthesize arginine from proline via the arginine-proline interconversion pathway, despite having genes for the well-conserved glutamate pathway. Since the proline-arginine interconversion pathway is repressed by CcpA-mediated carbon catabolite repression (CCR), CCR has been attributed to the arginine auxotrophy of S. aureus. Using ribose as a secondary carbon source, here, we demonstrate that S. aureus arginine auxotrophy is not due to CCR but due to the inadequate concentration of proline degradation product. Proline is degraded by proline dehydrogenase (PutA) into pyrroline-5-carboxylate (P5C). Although the PutA expression was fully induced by ribose, the P5C concentration remained insufficient to support arginine synthesis because P5C was constantly consumed by the P5C reductase ProC. When the P5C concentration was artificially increased by either PutA overexpression or proC-deletion, S. aureus could synthesize arginine from proline regardless of carbon source. In contrast, when the P5C concentration was reduced by overexpression of proC, it inhibited the growth of the ccpA-deletion mutant without arginine. Intriguingly, the ectopic expression of the glutamate pathway enzymes converted S. aureus into arginine prototroph. In an animal experiment, the arginine-proline interconversion pathway was not required for the survival of S. aureus. Based on these results, we concluded that S. aureus does not synthesize arginine from proline under physiological conditions. We also propose that arginine auxotrophy of S. aureus is not due to the CcpA-mediated CCR but due to the inactivity of the conserved glutamate pathway.ImportanceStaphylococcus aureus is a versatile Gram-positive human pathogen infecting various human organs. The bacterium’s versatility is partly due to efficient metabolic regulation via the carbon catabolite repression system (CCR). S. aureus is known to interconvert proline and arginine, and CCR represses the synthesis of both amino acids. However, when CCR is released by a non-preferred carbon source, S. aureus can synthesize proline but not arginine. In this study, we show that, in S. aureus, the intracellular concentration of pyrroline-5-carboxylate (P5C), the degradation product of proline and the substrate of proline synthesis, is too low to synthesize arginine from proline. These results call into question the notion that S. aureus synthesizes arginine from proline.
In vivo growth of Staphylococcus lugdunensis is facilitated by the concerted function of heme and non-heme iron acquisition mechanisms
Authors: Flannagan Ronald S. , Brozyna Jeremy R. , Kumar Brijesh , Adolf Lea A. , Power Jeffrey John , Heilbronner Simon , Heinrichs David E. 
Published: January 2022

AbstractAcquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Here we show that S. lugdunensis utilizes diverse genome encoded iron acquisition mechanisms to satisfy its need for this nutrient. Indeed, S. lugdunensis can usurp hydroxamate siderophores, and staphyloferrin A and B from S. aureus, using the fhuC ATPase-encoding gene. Acquisition of catechol siderophores and catecholamine stress hormones necessitates the presence of the sst-1 transporter-encoding locus, but not the sst-2 locus. Iron-dependent growth in acidic culture conditions necessitates the feoAB locus. Heme iron is acquired via expression of the iron-regulated surface determinant (isd) locus. During systemic infection of mice we demonstrate that while S. lugdunensis does not cause overt illness, it does colonize and proliferate to high numbers in the kidneys. By combining mutations in the various iron acquisition loci, we further demonstrate that only a strain mutated for all of isd, fhuC, sst-1, and feo, versus combination mutants carrying wild type copies of any one of those loci, was attenuated in its ability to proliferate to high numbers in kidneys. Taken together our data reveal that S. lugdunensis requires a repertoire of both heme and non-heme iron acquisition mechanisms to proliferate during systemic infection of mammals.ImportanceAcquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Owing to an inability to synthesize siderophores, growth of S. lugdunensis is dramatically impaired in the presence of transferrin or serum, yet S. lugdunensis nonetheless uses several other genome-encoded iron acquisition mechanisms, in concert, to proliferate within the mammalian host. Therefore, the development of interventions that target bacterial iron acquisition systems should consider the overlapping function of distinct metal acquisition strategies deployed by bacterial pathogens.
People with HIV Have Higher Risk of COVID-19 Diagnosis but Similar Outcomes than the General Population
Authors: Tang Michael E , Gaufin Thaidra , Anson Ryan , Zhu Wenhong , Mathews William C , Cachay Edward R 
Published: January 2022

AbstractBackgroundWe investigated the effect of HIV on COVID-19 outcomes with attention to selection bias due to differential testing and to comorbidity burden.MethodsRetrospective cohort analysis using four hierarchical outcomes: positive SARS-CoV-2 test, COVID-19 hospitalization, intensive care unit (ICU) admission, and hospital mortality. The effect of HIV status was assessed using traditional covariate-adjusted, inverse probability weighted (IPW) analysis based on covariate distributions for testing bias (testing IPWs), HIV infection status (HIV IPWs), and combined models. Among PWH, we evaluated whether CD4 count and HIV plasma viral load (pVL) discriminated between those who did or did not develop study outcomes using receiver operating characteristic analysis.ResultsBetween March and November 2020, 63,319 people were receiving primary care services at UCSD, of whom 4,017 were people living with HIV (PWH). PWH had 2.1 times the odds of a positive SARS-CoV-2 test compared to those without HIV after weighting for potential testing bias, comorbidity burden, and HIV-IPW (95% CI 1.6-2.8). Relative to persons without HIV, PWH did not have an increased rate of COVID-19 hospitalization after controlling for comorbidities and testing bias [adjusted incidence rate ratio (aIRR): 0.5, 95% CI: 0.1 – 1.4]. PWH had neither a different rate of ICU admission (aIRR:1.08, 95% CI; 0.31 – 3.80) nor in-hospital death (aIRR:0.92, 95% CI; 0.08 – 10.94) in any examined model. Neither CD4 count nor pVL predicted any of the hierarchical outcomes among PWH.ConclusionsPWH have a higher risk of COVID-19 diagnosis but similar outcomes compared to those without HIV.Summary pointAfter considering the effects of potential bias due to differential testing, comorbidities, and other patient characteristics, people with HIV had an increased rate of SARS-CoV-2 positivity and similar rates of hospitalization, ICU admission, and death.
Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population
Authors: Zaghlool Shaza B. , Halama Anna , Stephan Nisha , Thangam Manonanthini , Ahlqvist Emma , Albagha Omar M. E. , Abou⍰Samra Abdul Badi , Suhre Karsten 
Published: January 2022

ABSTRACTBackgroundType 2 diabetes (T2D) has a heterogeneous etiology which is increasingly recognized to influence the risk of complications and choice of treatment. A data driven cluster analysis in four separate European populations of patients with type 2 diabetes identified four subtypes of severe insulin dependent (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) (Ahlqvist et al., Lancet Diabetes Endocrinology, 2018). Our aim was to extend this classification to the Arab population of Qatar and characterize the biological processes that differentiate these subtypes in relation to metabolomic and proteomic signatures.MethodsThe Ahlqvist et al. subtype clustering approach was applied to 631 individuals with T2D from the Qatar Biobank (QBB) and validated in an independent set of 420 participants from the same population. The association between blood metabolites (n=1,159) and protein levels (n=1,305) with each cluster were established.FindingsThe four subtypes of T2D were reproduced and validated in the population of Qatar. Cluster-specific metabolomic and proteomic associations revealed subtype-specific molecular processes. Activation of the complement system with many features of autoimmune diabetes and reduced 1,5-anhydroglucitol (1,5-AG) characterized SIDD, with evidence of impaired insulin signaling in SIRD, elevated leptin and fatty acid binding protein in MOD, whilst MARD appeared to be the healthiest subgroup.InterpretationWe have replicated the four T2D clusters in an Arab population and identified distinct metabolic and proteomic signatures, providing insights into underlying etiology with the potential to deploy subtype-specific treatment options.
Immunity in Omicron SARS-CoV-2 breakthrough COVID-19 in vaccinated adults
Authors: Kared Hassen , Wolf Asia-Sophia , Alirezaylavasani Amin , Ravussin Anthony , Solum Guri , Tran Trung The , Lund-Johansen Fridtjof , Vaage John Torgils , Nissen-Meyer Lise Sofie , Nygaard Unni C. , Hungnes Olav , Robertson Anna H , Næss Lisbeth Meyer , Trogstad Lill , Magnus Per , Munthe Ludvig A , Mjaaland Siri 
Published: January 2022

AbstractThe new SARS-CoV-2 variant of concern (VOC) Omicron has more than 30 mutations in the receptor binding domain (RBD) of the Spike protein enabling viral escape from antibodies in vaccinated individuals and increased transmissibility1-6. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a superspreader event had robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergentde novoT cell response to non-Spike antigens. We compared cases from a Christmas party where 81 of 110 (74%) developed Omicron breakthrough COVID-197, with Delta breakthrough cases and vaccinated non-infected controls. Omicron cases had significantly increased activated SARS-CoV-2 wild type Spike-specific (vaccine) cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, activated anti-Spike plasmablasts and anti-RBD memory B cells compared to controls. Omicron cases had significantly increasedde novomemory T cell responses to non-Spike viral antigens compared to Delta breakthrough cases demonstrating development of broad immunity. The rapid release of Spike and RBD-specific IgG+B cell plasmablasts and memory B cells into circulation suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity.