bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIRDMAn: A Bayesian differential abundance framework that enables robust inference of host-microbe associations
Authors: Rahman Gibraan , Morton James T. , Martino Cameron , Sepich-Poore Gregory D. , Allaband Celeste , Guccione Caitlin , Chen Yang , Hakim Daniel , Estaki Mehrbod , Knight Rob 
Published: February 2023

AbstractQuantifying the differential abundance (DA) of specific taxa among experimental groups in microbiome studies is challenging due to data characteristics (e.g., compositionality, sparsity) and specific study designs (e.g., repeated measures, meta-analysis, cross-over). Here we present BIRDMAn (BayesianInferentialRegression forDifferentialMicrobiomeAnalysis), a flexible DA method that can account for microbiome data characteristics and diverse experimental designs. Simulations show that BIRDMAn models are robust to uneven sequencing depth and provide a >20-fold improvement in statistical power over existing methods. We then use BIRDMAn to identify antibiotic-mediated perturbations undetected by other DA methods due to subject-level heterogeneity. Finally, we demonstrate how BIRDMAn can construct state-of-the-art cancer-type classifiers using The Cancer Genome Atlas (TCGA) dataset, with substantial accuracy improvements over random forests and existing DA tools across multiple sequencing centers. Collectively, BIRDMAn extracts more informative biological signals while accounting for study-specific experimental conditions than existing approaches.
Effects of IL2/anti-IL2 antibody complex on chikungunya virus-induced arthritis in a mouse model
Authors: Tritsch Sarah R. , Porzucek Abigail J. , Schwartz Arnold M. , Proctor Abigale M. , Amdur Richard , Latham Patricia S. , Simon Gary L. , Mores Christopher N. , Chang Aileen Y. 
Published: February 2023

AbstractChikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of IL-2, an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, effector (Teff) T cells, and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the IL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one.
Organism-Wide Analysis of Sepsis Reveals Mechanisms of Systemic Inflammation
Authors: Takahama Michihiro , Patil Ashwini , Johnson Katherine , Cipurko Denis , Miki Yoshimi , Taketomi Yoshitaka , Carbonetto Peter , Plaster Madison , Richey Gabriella , Pandey Surya , Cheronis Katerina , Ueda Tatsuki , Gruenbaum Adam , Dudek Steven M. , Stephens Matthew , Murakami Makoto , Chevrier Nicolas 
Published: February 2023

SUMMARYSepsis is a systemic response to infection with life-threatening consequences. Our understanding of the impact of sepsis across organs of the body is rudimentary. Here, using mouse models of sepsis, we generate a dynamic, organism-wide map of the pathogenesis of the disease, revealing the spatiotemporal patterns of the effects of sepsis across tissues. These data revealed two interorgan mechanisms key in sepsis. First, we discover a simplifying principle in the systemic behavior of the cytokine network during sepsis, whereby a hierarchical cytokine circuit arising from the pairwise effects of TNF plus IL-18, IFN-γ, or IL-1β explains half of all the cellular effects of sepsis on 195 cell types across 9 organs. Second, we find that the secreted phospholipase PLA2G5 mediates hemolysis in blood, contributing to organ failure during sepsis. These results provide fundamental insights to help build a unifying mechanistic framework for the pathophysiological effects of sepsis on the body.
Ecological and life-history traits and their relationship with West Nile virus and Saint Louis Encephalitis virus exposure risk
Authors: Giayetto O. , Mansilla A.P. , Nazar F.N. , Diaz A. 
Published: February 2023

AbstractHost life-history traits can influence host-vector encounter rates, and so differentially determine the exposure risk of bird species. This modulation of host-virus encounters’ dynamics is especially important when facing “generalist” arboviruses like West Nile virus (WNV) and Saint Louis Encephalitis virus (SLEV). Using prevalence data collected by our laboratory since 2004, we tested several hypothesis that included birds’ ecological and life-history traits to determine which traits were better predictors of birds’ exposure risk to these arboviruses. By means of information-theoretic procedures and generalized mixed linear models, we observed that body mass was an important trait when predicting birds’ exposure risk to WNV and SLEV and migratory status significantly influenced birds’ exposure risk only to WNV. Our study highlights important traits to consider when studying the transmission system of these arboviruses, being useful to focus resources when characterizing viral transmission networks and discuss the repercussions of these traits over birds’ immune function throughout the pace of life syndrome and trade-offs theory.
Premature Aging and Reduced Cancer Incidence Associated with Near-Complete Body-WideMycInactivation
Authors: Wang Huabo , Lu Jie , Stevens Taylor , Roberts Alexander , Mandel Jordan , Avula Raghunandan , Ma Bingwei , Wu Yijen , Wang Jinglin , Van’t Land Clinton , Finkel Toren , Vockley Jerry E. , Airik Merlin , Airik Rannar , Muzumdar Radhika , Gong Zhenwei , Torbenson Michel S. , Prochownik Edward V. 
Published: February 2023

SummaryMYCproto-oncogene dysregulation alters metabolism, translation and other functions in ways that support tumor induction and maintenance. AlthoughMyc+/-mice are healthier and longer-lived than control mice, the long-term ramifications of more completeMycloss remain unknown. We now describe the chronic consequences of body-wideMycinactivation initiated postnatally. “MycKO” mice acquire numerous features of premature aging including altered body composition and habitus, metabolic dysfunction, hepatic steatosis and the dysregulation of numerous gene sets involved in functions that normally deteriorate with aging. Yet,MycKO mice have extended life spans that correlate with a 3-4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also down-regulate Myc and gradually deregulate many of the same Myc target gene sets that are dysregulated inMycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc and its target genes and can be genetically separated.
MicroRNA-221/222-expression in HSC and MPP safeguards their quiescence and multipotency by downregulating stress-independent and dependent expression of IEG and of several myelo/granulopoiesis-enhancing target genes
Authors: Jani Peter K. , Petkau Georg , Kawano Yohei , Klemm Uwe , Guerra Gabriela Maria , Heinz Gitta Anne , Heinrich Frederik , Durek Pawel , Mashreghi Mir-Farzin , Melchers Fritz 
Published: February 2023

ABSTRACTThe microRNA cluster-221/222 is expressed in hematopoietic stem cells (HSC) and multipotent progenitors (MPP). To study its function in hematopoiesis, we generated mice, in which this cluster is selectively deleted by Vav-cre in HSC and, thus, in all hematopoietic cells. Fluorescence-activated cell sorting analyses of the lineage-negative HSC and MPP compartments in bone marrow at unperturbed, steady state hematopoiesis detect strong activation of HSC to MPP, as well as increased granulocytes in the periphery, induced by miR-221/222-deficiency. Short-term social stress on mice also activates HSC to MPP, but the time of stress is too short to detect further increases in granulocyte numbers. Single cell deep mRNA sequencing identifies Fos as direct, and Jun as well as six other immediate early genes (IEG) as indirect targets of miR-221/222 at unperturbed hematopoiesis. Three of these IEG - Klf6, Nr4a1 and Zfp36 - have previously been found to influence myelo/granulopoiesis. Short stress induces higher levels of the same, and an even larger number of IEGs, now also in MPP, indicating, that stress and miR-221/222 both activate HSC to MPP by IEG upregulation in perturbed hematopoiesis. Furthermore, combined stress and miR-221/222-deficiency rapidly increase numbers of myelo/granulocyte progenitors (MEP, GMP) in bone marrow. Additional indirect miR-221/222-targets become detectable in MPP, of which H3f3b has previously been found to influence myelopoiesis. In serial transplantations, miR-221/222-deficient HSC retain their capacity to home to, and become resident in bone marrow, but they loose their lymphopoietic capacities, thus their multipotency. Our results suggest, that miR-221/222-expression in HSC and MPP safeguards their quiescence and multipotency by downregulating the expression of IEG and of myelo/granulopoiesis-enhancing target genes. Since miR-221/222 is also expressed in human HSC and MPP, its expression should improve clinical settings of human bone marrow transplantations.
HLAin isolated REM sleep behavior disorder and Lewy body dementia
Authors: Yu Eric , Krohn Lynne , Ruskey Jennifer A. , Asayesh Farnaz , Spiegelman Dan , Shah Zalak , Chia Ruth , Arnulf Isabelle , Hu Michele T.M. , Montplaisir Jacques Y. , Gagnon Jean-François , Desautels Alex , Dauvilliers Yves , Gigli Gian Luigi , Valente Mariarosaria , Janes Francesco , Bernardini Andrea , Högl Birgit , Stefani Ambra , Ibrahim Abubaker , Heidbreder Anna , Sonka Karel , Dusek Petr , Kemlink David , Oertel Wolfgang , Janzen Annette , Plazzi Giuseppe , Antelmi Elena , Figorilli Michela , Puligheddu Monica , Mollenhauer Brit , Trenkwalder Claudia , Sixel-Döring Friederike , Cochen De Cock Valérie , Ferini-Strambi Luigi , Dijkstra Femke , Viaene Mineke , Abril Beatriz , Boeve Bradley F. , Rouleau Guy A. , Postuma Ronald B. , Scholz Sonja W. ,   the International LBD Genomics Consortium, Gan-Or Ziv 
Published: February 2023

AbstractBackground and ObjectivesIsolated/idiopathic REM sleep behavior disorder (iRBD) and Lewy body dementia (LBD) are synucleinopathies that have partial genetic overlap with Parkinson’s disease (PD). Previous studies have shown that neuroinflammation plays a substantial role in these disorders. In PD, specific residues of the human leukocyte antigen (HLA) were suggested to be associated with a protective effect. This study examined whether theHLAlocus plays a similar role in iRBD, LBD and PD.MethodsWe performed HLA imputation on iRBD genotyping data (1,072 patients and 9,505 controls) and LBD whole-genome sequencing (2,604 patients and 4,032 controls) using the multi-ethnic HLA reference panel v2 from the Michigan Imputation Server. Using logistic regression, we tested the association of HLA alleles, amino acids and haplotypes with disease susceptibility. We included age, sex and the top 10 principal components as covariates. We also performed an omnibus test to examine which HLA residue positions explain the most variance.ResultsIn iRBD,HLA-DRB1*11:01 was the only allele passing FDR correction (OR=1.57, 95% CI=1.27-1.93,p=2.70e-05). We also discovered associations between iRBD andHLA-DRB170D (OR=1.26, 95%CI=1.12-1.41,p=8.76e-05), 70Q (OR=0.81, 95% CI=0.72-0.91,p=3.65e-04) and 71R (OR=1.21, 95% CI=1.08-1.35,p=1.35e-03). InHLA-DRB1, position 71 (pomnibus=0.00102) and 70 (pomnibus=0.00125) were associated with iRBD. We found no association in LBD.DiscussionThis study identified an association betweenHLA-DRB111:01 and iRBD, distinct from the previously reported association in PD. Therefore, theHLAlocus may play different roles across synucleinopathies. Additional studies are required better to understand HLA’s role in iRBD and LBD.
Road networks to explore COVID-19 infection
Authors: Uddin Shahadat , Khan Arif , Lu Haohui , Zhou Fangyu , Karim Shakir , Hajati Farshid , Moni Mohammad Ali 
Published: February 2023

AbstractCOVID-19 pandemic triggered an unprecedented level of restrictive measures globally. Most countries resorted to lockdowns at some point to buy the much-needed time for flattening the curve and scaling up vaccination and treatment capacity. Although lockdowns, social distancing and business closures generally slowed down the case growth, there is a growing concern about the social, economic and psychological impact of these restrictions, especially on the disadvantaged and poorer part of society. While we are all in this together, these segments are often taking the heavier toll of the pandemic and facing harsher restrictions or getting blamed for community transmission. This study tries to explore this perspective using quantitative analysis and network theory. The research is set in the context of the latest delta and omicron outbreaks in the Greater Sydney area, Australia, during late 2021. We first try to model how the local road networks between the neighbouring suburbs (i.e., neighbourhood measure) and current infection count affect the case growth and how they differ between delta and omicron variants. We use a geographic information system, population and infection data to measure - road connections, mobility and transmission probability across the suburbs. We then looked at three socio-demographic variables – age, education and income and explored how they moderate independent and dependent variables (infection rates and neighbourhood measures). The result shows strong model performance to predict infection rate based on neighbourhood road connection. However, apart from age in the delta variant’s context, the other two variables – income and education level do not seem to moderate the relation between infection rate and neighbourhood measure. The results indicate that suburbs with a more socio- economically disadvantaged population do not necessarily contribute to more community transmission. The study findings could be potentially helpful for stakeholders in tailoring any health decision for future pandemics.
Standardization of a High-Fidelity Postpartum Hemorrhage Simulation Scenario Across Two Geographically Separated Campuses
Authors: Khalepai Miriam S. , Sturgeon Shannon , Done Andrea , Yates Tyler , Wardle Mark , Zapata Isain , Carter Susan 
Published: February 2023

ABSTRACTIntroductionThe utilization of high fidelity simulations across medical school campuses has grown in recent years as simulation is a useful tool in allowing students to practice real life scenarios in a safe space, as well as providing exposure to rarer cases in medicine. This study evaluated second and third-year medical students’ recognition and management of a postpartum hemorrhage (PPH) due to a retained placenta in SimMom®. The objective was to describe the methods and procedures used in PPH simulation to educate these students across two geographically separated medical school campuses. It became apparent that there is a need to standardize medical simulation to maintain the quality of medical education.MethodsA case-scenario simulation with retained tissue had a run-time of 10 minutes. Times were marked when students identified the retained placental tissue was the cause of hemorrhage and when students extracted the fragment. A debrief with faculty followed the scenario regarding performance and education about the “4 T’s”of post-partum hemorrhage differential diagnosis (Tone, Trauma, Tissue, Thrombin), and the students’ feelings towards the simulation were evaluated with a post simulation survey.ResultsDespite efforts to maintain consistent simulations between the two campuses, there was a significant difference of timing between the two campuses to successful completion of the simulation, as well as in the number of students that did not successfully complete the goals of the simulation. However, the post-simulation survey did show that students on both campuses found value in participating in the simulation.DiscussionThe performance across the two campuses was statistically different, which illustrates a need to standardize simulation education experiences across medical school campuses. However, this protocol was an effective way to educate students and allow students to have hands-on experience in diagnosing and treating a rare but deadly complication of childbirth. This initial study may facilitate expansion on this particular, topic, as well as suggest more simulation education delivery within the medical school curriculum.
Selective pressure by rifampicin modulates mutation rates and evolutionary trajectories of mycobacterial genomes
Authors: Cebrián-Sastre E. , Chiner-Oms A. , Torres-Pérez R. , Comas I. , Oliveros J.C. , Blázquez J. , Castañeda-García A. 
Published: February 2023

AbstractResistance to the frontline antibiotic rifampicin constitutes a challenge to the treatment and control of tuberculosis. Here, we analyzed the mutational landscape ofMycobacterium smegmatisduring long-term evolution with increasing concentrations of rifampicin, using a mutation accumulation assay combined with whole genome sequencing. Antibiotic treatment enhanced the acquisition of mutations, doubling the genome-wide mutation rate of the wild type cells. While antibiotic exposure led to extinction of almost all wild type lines, the hypermutable phenotype of the ΔnucSstrain (noncanonical mismatch repair deficient) provided an efficient response to the antibiotic, leading to high rates of survival. This adaptative advantage resulted in the emergence of higher levels of rifampicin resistance, an accelerated acquisition of drug resistance mutations inrpoB(β RNA polymerase) and a wider diversity of evolutionary pathways that led to drug resistance. Lastly, this approach revealed a subset of adaptive genes under positive selection with rifampicin that were able to drive novel rifampicin resistance mechanisms.
Genetic profiling ofPlasmodium ovale wallikerirelapses with microsatellite markers and whole-genome sequencing
Authors: Joste Valentin , Colard-Itté Emma , Guillochon Émilie , Ariey Frédéric , Coppée Romain , Clain Jérôme , Houzé Sandrine 
Published: February 2023

AbstractLikePlasmodium vivax, bothPlasmodium ovale curtisiandPlasmodium ovale wallikerihave the ability to cause relapse in humans, defined as recurring asexual parasitaemia originating from liver dormant forms subsequent to a primary infection. Here, we investigated relapse patterns inP. ovale wallikeriinfections from a cohort of travelers who were exposed to the parasite in Sub-Saharan Africa and then experienced relapses after their return to France. Using a novel set of eight highly polymorphic microsatellite markers, we genotyped 15P. ovale wallikerirelapses. For most relapses, the paired primary and relapse infections were highly genetically related (with 12 being homologous), an observation that was confirmed by whole-genome sequencing for the four relapses we further studied. This is, to our knowledge, the first genetic evidence of relapses inP. ovalespp.
Multi-input drug-controlled switches of mammalian gene expression based on engineered nuclear hormone receptors
Authors: Kretschmer Simon , Perry Nicholas , Zhang Yang , Kortemme Tanja 
Published: February 2023

AbstractProtein-based switches that respond to different inputs to regulate cellular outputs, such as gene expression, are central to synthetic biology. For increased controllability, multi-input switches that integrate several cooperating and competing signals for the regulation of a shared output are of particular interest. The nuclear hormone receptor (NHR) superfamily offers promising starting points for engineering multi-input-controlled responses to clinically approved drugs. Starting from the VgEcR/RXR pair, we demonstrate that novel (multi-)drug regulation can be achieved by exchange of the ecdysone receptor (EcR) ligand binding domain (LBD) for other human NHR-derived LBDs. For responses activated to saturation by an agonist for the first LBD, we show that outputs can be boosted by an agonist targeting the second LBD. In combination with an antagonist, output levels are tunable by up to three simultaneously present small-molecule drugs. Such high-level control validates NHRs as a versatile, engineerable platform for programming multi-drug-controlled responses.
Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses
Authors: Zvornicanin Sarah N. , Shaqra Ala M. , Huang Qiu Yu J. , Ornelas Elizabeth , Moghe Mallika , Knapp Mark , Moquin Stephanie , Dovala Dustin , Schiffer Celia A. , Yilmaz Nese Kurt 
Published: February 2023

AbstractWith the spread of SARS-CoV-2 throughout the globe to cause the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from beluga whale. Comparison with the apo structure of SW1 Mpro, which we also present here, enabled identifying structural arrangements upon inhibitor binding at the active site. The binding modes and interactions of two covalent inhibitors, PF-00835231 (lufotrelvir) bound to HKU15 and GC376 bound to SW1 Mpro, reveal features that may be leveraged to target diverse coronaviruses and toward structure-based design of pan-CoV inhibitors.
Revisiting “Cool Japan” in country-of-origin research: a commentary and future research directions
Authors: Miyamoto Junji , Shimizu Akira , Hayashi Junya , Cheah Isaac 
Published: February 2023

PurposeThis commentary and conceptual paper is aimed at investigating marketing perceptions of the country-of-origin (COO) perspectives, and emphasis is placed on the “Cool Japan” concept.Design/methodology/approachA review of research on COO and the concept of “Cool Japan” was conducted, including commentary of previous relevant theoretical frameworks.FindingsThe evidence has shown that the brand images of various COOs is dependent on their cultural exports. In the case of Japan, the “Cool Japan” initiative, which initiated the creation and dissemination of Japanese cultural contents such as anime, games and art, has led to tremendous and sustainable economic growth in Japan till date.Research limitations/implicationsAs previous studies on COO are wide-ranging, they are not exhaustively presented in this paper. However, the importance of considering not only animosity, which has traditionally been taken into account, but also the coolness aspect is suggested.Practical implicationsThis paper shows that “coolness” is an important concept when nations or regions consider their branding strategies and an integrated approach is needed.Originality/valueThis paper extends previous COO research and adds coolness to the traditional animosity. It also considers these in comparison across countries and goes as far as the need to propose a new scale. Conceptual findings from this paper would therefore provide future directions for advancing COO research Cool Japan.