bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation and impact of polygenic hematological traits in monogenic sickle cell disease
Authors: Pincez Thomas , Lo Ken Sin , Pham Hung d’Alexandry d’Orengiani Anne-Laure , Garrett Melanie E. , Brugnara Carlo , Ashley-Koch Allison E. , Telen Marilyn J. , Galactéros Frédéric , Joly Philippe , Bartolucci Pablo , Lettre Guillaume 
Published: January 2022

ABSTRACTSeveral complications observed in sickle cell disease (SCD) are influenced by variation in hematological traits (HT), such as fetal hemoglobin (HbF) level and neutrophil count. Previous large-scale genome-wide association studies carried out in largely healthy individuals have identified 1000s of variants associated with HT, which have then been used to develop multi-ancestry polygenic trait scores (PTS). Here, we tested if these PTS associate with HT in SCD patients and can improve the prediction of SCD-related complications. In 2,056 SCD patients, we found that the PTS predicted less HT variance than in non-SCD African-ancestry individuals. This was particularly striking at the Duffy/DARC locus, where we observed an epistatic interaction between the SCD genotype and the Duffy null variant (rs2814778) that led to a two-fold weaker effect on neutrophil count. PTS for these routinely measured HT were not associated with complications in SCD. In contrast, we found that a simple PTS for HbF that includes only six variants explained a large fraction of the phenotypic variation (17.1-26.4%), associated with acute chest syndrome and stroke risk, and improved the prediction of vaso-occlusive crises. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 36% (P = 0.0008). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives.
Mucosal immunity against SARS-CoV-2 variants of concern including Omicron following vaccination
Authors: Tang Jinyi , Zeng Cong , Cox Thomas M. , Li Chaofan , Son Young Min , Cheon In Su , Wu Yue , Behl Supriya , Taylor Justin J. , Chakaraborty Rana , Johnson Aaron J. , Shiavo Dante N , Utz James P. , Reisenauer Janani S. , Midthun David E. , Mullon John J. , Edell Eric S. , Alameh Mohamad G. , Borish Larry , Kaplan Mark H. , Weissman Drew , Kern Ryan , Hu Haitao , Vassallo Robert , Liu Shan-Lu , Sun Jie 
Published: January 2022

AbstractSARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody (Ab) responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19 vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing Ab against D614G, Delta and Omicron in the BAL compared to COVID-19 convalescents, despite robust S-specific Ab responses in the blood. Further, mRNA vaccination induced significant circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using an animal immunization model, we demonstrate that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing Ab responses, especially against SARS-CoV-2 Omicron; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing Ab response, not only against the ancestral virus but also the Omicron variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during re-infection, but offer limited protection against breakthrough infection, especially by Omicron. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by Omicron and future variants.
Projected health impact of post-discharge malaria chemoprevention among children with severe malarial anaemia in Africa
Authors: Okell Lucy C , Kwambai Titus K. , Dhabangi Aggrey , Khairallah Carole , Nkosi-Gondwe Thandile , Opoka Robert , Mousa Andria , Kühl Melf-Jakob , Lucas Tim C. D. , Idro Richard , Weiss Daniel J. , Cairns Matthew , ter Kuile Feiko O , Phiri Kamija , Robberstad Bjarne , Mori Amani Thomas 
Published: January 2022

AbstractChildren recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0-5 year-old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods. We then modelled the potential impact of PDMC across malaria-endemic African countries. In the 19 highest-burden countries, we estimate that only 2-5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC, 37,000 (range 16,000-84,000) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 18-29% of all SMA episodes in higher transmission settings.
Estimating the Effects of Legalizing Recreational Cannabis on Newly Incident Cannabis Use
Authors: Montgomery Barrett Wallace , Roberts Meaghan H. , Margerison Claire E. , Anthony James C. 
Published: January 2022

AbstractLiberalized state-level recreational cannabis policies in the United States (US) fostered important policy evaluations with a focus on epidemiological parameters such as proportions [e.g., active cannabis use prevalence; cannabis use disorder (CUD) prevalence]. This cannabis policy evaluation project adds novel evidence on a neglected parameter – namely, estimated occurrence of newly incident cannabis use for underage (<21 years) versus older adults. The project’s study populations were specified to yield nationally representative estimates for all 51 major US jurisdictions, with probability sample totals of 819,543 non-institutionalized US civilian residents between 2008 and 2019. Standardized items to measure cannabis onsets are from audio computer-assisted self-interviews. Policy effect estimates are from event study difference-in-difference (DiD) models that allow for causal inference when policy implementation is staggered. The evidence indicates no policy-associated changes in the occurrence of newly incident cannabis onsets for underage persons, but an increased occurrence of newly onset cannabis use among older adults (i.e., >21 years). We offer a tentative conclusion of public health importance: Legalized cannabis retail sales might be followed by the increased occurrence of cannabis onsets for older adults, but not for underage persons who cannot buy cannabis products in a retail outlet. Cannabis policy research does not yet qualify as a mature science. We argue that modeling newly incident cannabis use might be more informative than the modeling of prevalences when evaluating policy effects and provide evidence of the advantages of the event study model over regression methods that seek to adjust for confounding factors.
Neanderthals did not likely consume Physcomitrium patens – a model moss species
Authors: Haas Fabian B. , Eisenhofer Raphael , Schreiber Mona , Weyrich Laura S. , Rensing Stefan A. 
Published: January 2022

AbstractThis manuscript is discussing the method of Weyrich et al., 2017, “Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus”. When studying the dietary profile of a Neanderthal specimen from El Sidrón cave (Spain) by sequencing ancient DNA present in calcified dental plaque (calculus) the authors identified a wide-range of potential food sources, including woolly rhinoceros, mushrooms, pine nuts, and moss – namely the less-than-abundant model species Physcomitrium patens. We doubted that Neanderthals were actually eating P. patens. By analyzing the ancient DNA reads using different mapping methods, we show likely a misinterpretation based on the previously used methods. The probability of Neanderthals eating P. patens is the same as eating rice or tomato. However, neither crop was grown in Europe at the time Neanderthals thrived.
A chromosome-level, fully phased genome assembly of the oat crown rust fungus Puccinia coronata f. sp. avenae: a resource to enable comparative genomics in the cereal rusts
Authors: Henningsen Eva C. , Hewitt Tim , Dugyala Sheshanka , Nazareno Eric S. , Gilbert Erin , Li Feng , Kianian Shahryar F. , Steffenson Brian J. , Dodds Peter N. , Sperschneider Jana , Figueroa Melania 
Published: January 2022

AbstractAdvances in sequencing technologies as well as development of algorithms and workflows have made it possible to generate fully phased genome references for organisms with non-haploid genomes such as dikaryotic rust fungi. To enable discovery of pathogen effectors and further our understanding of virulence evolution, we generated a chromosome-scale assembly for each of the two nuclear genomes of the oat crown rust pathogen, Puccinia coronata f. sp. avenae (Pca). This resource complements two previous released partially phased genome references of Pca, which display virulence traits absent in the isolate of historic race 203 (isolate Pca203) which was selected for this genome project. A fully phased, chromosome-level reference for Pca203 was generated using PacBio reads and Hi-C data and a recently developed pipeline named NuclearPhaser for phase assignment of contigs and phase switch correction. With 18 chromosomes in each haplotype and a total size of 208.10 Mbp, Pca203 has the same number of chromosomes as other cereal rust fungi such as Puccinia graminis f. sp. tritici and Puccinia triticina, the causal agents of wheat stem rust and wheat leaf rust, respectively. The Pca203 reference marks the third fully-phased chromosome-level assembly of a cereal rust to date. Here, we demonstrate that the chromosomes of these three Puccinia species are syntenous and that chromosomal size variations are primarily due to differences in repeat element content.
Temporal Optimization of Radiation Therapy to Heterogeneous Tumour Populations and Cancer Stem Cells
Authors: Meaney Cameron , Kohandel Mohammad , Novruzi Arian 
Published: January 2022

AbstractExternal beam radiation therapy is a key part of modern cancer treatments which uses high doses of radiation to destroy tumour cells. Despite its widespread usage and extensive study in theoretical, experimental, and clinical works, many questions still remain about how best to administer it. Many mathematical studies have examined optimal scheduling of radiotherapy, and most come to similar conclusions. Importantly though, these studies generally assume intratumoral homogeneity. But in recent years, it has become clear that tumours are not homogeneous masses of cancerous cells, but wildly heterogeneous masses with various subpopulations which grow and respond to treatment differently. One subpopulation of particular importance is cancer stem cells (CSCs) which are known to exhibit higher radioresistence compared with non-CSCs. Knowledge of these differences between cell types could theoretically lead to changes in optimal treatment scheduling. Only a few studies have examined this question, and interestingly, they arrive at apparent conflicting results. However, an understanding of their assumptions reveals a key difference which leads to their differing conclusions.In this paper, we generalize the problem of temporal optimization of dose distribution of radiation therapy to a two cell type model. We do so by creating a mathematical model and a numerical optimization algorithm to find the distribution of dose which leads to optimal cell kill. We then create a data set of optimization solutions and use data analysis tools to learn the relationships between model parameters and the qualitative behaviour of optimization results. Analysis of the model and discussion of biological importance are provided throughout. We find that the key factor in predicting the behaviour of the optimal distribution of radiation is the ratio between the radiosensitivities of the present cell types. These results can provide guidance for treatment in cases where clinicians have knowledge of tumour heterogeneity and of the abundance of CSCs.
How to use transcriptomic data for game-theoretic modeling of treatment-induced resistance in cancer cells? A case study in patient-derived glioblastoma organoids
Authors: Spekking Louise , Lohk Christer , Jung Weronika , Verduin Maikel , Azimi Sepinoud , Hubert Christopher , Vooijs Marc , Cavill Rachel , Staňková Kateřina 
Published: January 2022

AbstractGame theory is a powerful tool to model strategic decision making, but also interactions within Darwinian biological systems, such as cancer. As such, in the past decades, game-theoretical models have helped to understand cancer, its response to various treatments, and to design better therapies. However, to fully utilize the potential of game-theoretical modelling in designing better anti-cancer therapies, we need more information on cancer population (ecological) and strategy (evolutionary) dynamics in response to treatment for each patient and their tumors. Here we explore how transcriptomics data can be utilized as an input of game-theoretical models for predicting evolutionary response to irradiation in patient-derived glioblastoma organoids. For that purpose, we utilize both supervised and unsupervised machine learning methods to identify relevant cancer cell types and how their proportions change over time in the organoids. We then fit these proportions to the replicator dynamics, the most common evolutionary game dynamics, to predict both transient evolutionary dynamics and evolutionary stable strategy (ESS) cell proportions. Our predictions in glioblastoma organoids suggest that hypoxia is the most important factor in identifying short-term response to irradiation, while this seems much less relevant for the long-term response corresponding to the ESSs. Further, we conclude that supervised methods are the best way to estimate cancer evolutionary dynamics when therapy resistance is a qualitative evolutionary trait. We believe that our methodology can help in designing better therapies through testing evolutionary responses in patient-derived organoids, while in parallel the ecological response can be tracked through serum biomarkers and imaging in the corresponding patients.
A Statistical Physics Approach for Disease Module Detection
Authors: Wang Xu-Wen , Qiao Dandi , Cho Michael , DeMeo Dawn L. , Silverman Edwin K. , Liu Yang-Yu 
Published: January 2022

ABSTRACTExtensive evidence indicates that the pathobiological processes of a complex disease are associated with perturbation within specific disease neighborhoods of the human protein-protein interaction (PPI) network (a.k.a. the interactome), often referred to as the disease module. Many computational methods have been developed to integrate the interactome and omics profiles to extract context-dependent disease modules. Yet, existing methods all have fundamental limitations in terms of rigor and/or efficiency. Here, we developed a statistical physics approach based on the random-field Ising model (RFIM) for disease module detection, which is both mathematically rigorous and computationally efficient. We applied our RFIM approach with genome-wide association studies (GWAS) of six complex diseases to examine its performance for disease module detection. We found that our RFIM approach outperforms existing methods in terms of computational efficiency, connectivity of disease modules, and robustness to the interactome incompleteness.
Role of RIGI, MDA5 and interferon alpha of duck in Duck Plague infection – a novel report
Authors: Pal Subhomoy , Banerjee Samiddha , Pal Abantika , Kalita Dhruba Jyoti , Batabyal Subhasis , Debnath Manti , Chakraborty Argha , Mondal Gourhari , Roy Barun , Chatterjee Paresh Nath , Chatterjee Jayanta Kumar , Pal Aruna 
Published: January 2022

AbstractDuck Plague (DP) or Duck viral enteritis is an acute contagious and highly fatal disease in water fowl commonly caused by Anatidalphavirus-1 belonging from Herpesviridae family and contains double stranded DNA as genetic material. Pathogen associated molecular pattern (PAMP)s when identified by Pathogen Recognition Receptor (PRR)s acts as effective immunity system action against the pathogen. Melanoma Differentiation-Associated protein 5 (MDA5) and Retionic Acid Inducible Gene I (RIG1) are protein sensor commonly sense for viral double stranded RNA and helps for pro-inflammatory cytokine expression. Gut Associated Lymphoid Tissue (GALT)s have important role in immune response. The current study depicts the important role of three important immune response genes as RIGI, MDA5 and INFalpha in duck plague infestation for the first time. In silico studies followed by differential mRNA expression of RIG1, MDA5 and INFalpha was employed to detect effectiveness of gut associated immune responsiveness in liver, where kupfer cells are the major immune response cells. This was further confirmed through histological section of liver, kupfer cell and immunohistochemistry. This will be helpful to identify molecular mechanism of host innate immunity through duck plague virus infection in indigenous duck. This information may be helful for production of duck with the inherent resistance against duck plague virus infection through suitable biotechnological approaches as gene editing.Due to this inherent nature of better immunity in terms of resistance to other common avian diseases, duck will evolve as one of the major sustainable poultry species.The current study explores the scope to study host immunity against herpes virus in animal model.
Serum proteomics identifies immune pathways and candidate biomarkers of coronavirus infection in wild vampire bats
Authors: Becker Daniel J. , Lei Guang-Sheng , Janech Michael G. , Brand Alison M. , Fenton M. Brock , Simmons Nancy B. , Relich Ryan F. , Neely Benjamin A. 
Published: January 2022

AbstractThe apparent ability of bats to harbor many virulent viruses without showing disease is likely driven by distinct immune responses that coevolved with mammalian flight and the exceptional longevity of this order. Yet our understanding of the immune mechanisms of viral tolerance is restricted to a small number of bat–virus relationships and remains poor for coronaviruses (CoVs), despite their relevance to human health. Proteomics holds particular promise for illuminating the immune factors involved in bat responses to infection, because it can accommodate especially low sample volumes (e.g., sera) and thus can be applied to both large and small bat species as well as in longitudinal studies where lethal sampling is necessarily limited. Further, as the serum proteome includes proteins secreted from not only blood cells but also proximal organs, it provides a more general characterization of immune proteins. Here, we expand our recent work on the serum proteome of wild vampire bats (Desmodus rotundus) to better understand CoV pathogenesis. Across 19 bats sampled in 2019 in northern Belize with available sera, we detected CoVs in oral or rectal swabs from four individuals (21.1% positivity). Phylogenetic analyses identified all vampire bat sequences as novel α-CoVs most closely related to known human CoVs. Across 586 identified serum proteins, we found no strong differences in protein composition nor abundance between uninfected and infected bats. However, receiver operating characteristic curve analyses identified seven to 32 candidate biomarkers of CoV infection, including AHSG, C4A, F12, GPI, DSG2, GSTO1, and RNH1. Enrichment analyses using these protein classifiers identified downregulation of complement, regulation of proteolysis, immune effector processes, and humoral immunity in CoV-infected bats alongside upregulation of neutrophil immunity, overall granulocyte activation, myeloid cell responses, and glutathione processes. Such results denote a mostly cellular immune response of vampire bats to CoV infection and identify putative biomarkers that could provide new insights into CoV pathogenesis in wild and experimental populations. More broadly, applying a similar proteomic approach across diverse bat species and to distinct life history stages in target species could improve our understanding of the immune mechanisms by which wild bats tolerate viruses.
Functional and evolutionary significance of unknown genes from uncultivated taxa
Authors: Rodríguez del Río Álvaro , Giner-Lamia Joaquín , Cantalapiedra Carlos P. , Botas Jorge , Deng Ziqi , Hernández-Plaza Ana , Paoli Lucas , Schmidt Thomas S.B. , Sunagawa Shinichi , Bork Peer , Coelho Luis Pedro , Huerta-Cepas Jaime 
Published: January 2022

AbstractMost microbes on our planet remain uncultured and poorly studied. Recent efforts to catalog their genetic diversity have revealed that a significant fraction of the observed microbial genes are functional and evolutionary untraceable, lacking homologs in reference databases. Despite their potential biological value, these apparently unrelated orphan genes from uncultivated taxa have been routinely discarded in metagenomics surveys. Here, we analyzed a global multi-habitat dataset covering 151,697 medium and high-quality metagenome assembled genomes (MAGs), 5,969 single-amplified genomes (SAGs), and 19,642 reference genomes, and identified 413,335 highly curated novel protein families under strong purifying selection out of previously considered orphan genes. These new protein families, representing a three-fold increase over the total number of prokaryotic orthologous groups described to date, spread out across the prokaryote phylogeny, can span multiple habitats, and are notably overrepresented in recently discovered taxa. By genomic context analysis, we pinpointed thousands of unknown protein families to phylogenetically conserved operons linked to energy production, xenobiotic metabolism and microbial resistance. Most remarkably, we found 980 previously neglected protein families that can accurately distinguish entire uncultivated phyla, classes, and orders, likely representing synapomorphic traits that fostered their divergence. The systematic curation and evolutionary analysis of the unique genetic repertoire of uncultivated taxa opens new avenues for understanding the biology and ecological roles of poorly explored lineages at a global scale.