bluuebunny/crossref_metadata_2025_split huggingface dataset:
An EBV-associated atypical B cell signature in clinically isolated syndrome is implicated in progression of multiple sclerosis
Authors: SoRelle Elliott D. , Haukenfrers Ellora , Jain Vaibhav , Abramson Karen , Hocke Emily , Cooney Laura A. , Harris Kristina M. , Zamvil Scott S. , Gregory Simon G. , Luftig Micah A. 
Published: March 2023

ABSTRACTExpansion and pathogenicity of CD19+/CD20+/CD11c+/T-bet+atypical B cells (ABCs) are hallmarks of numerous autoimmune disorders and chronic infections. In many such cases Epstein-Barr virus (EBV) is another associated or etiologic factor, though EBV involvement in these diseases remains poorly understood. Notably, the expansion of pro-inflammatory ABCs and a putative causal role for EBV have been identified independently in multiple sclerosis (MS). A common precipitating event in MS onset is Clinically Isolated Syndrome (CIS), a neuroinflammatory demyelinating condition of which 60-80% of cases progress to relapsing-remitting MS (RRMS). Here we report single-cell gene and surface protein expression (scRNA/CITE-seq) in peripheral B cells collected longitudinally from patients with CIS during the Immune Tolerance Network STAyCIS Trial. We focus on the transcriptomic signatures of ABCs from this cohort, publicly available scRNA-seq datasets from six other autoimmune and chronic infectious diseases, andin vitroEBV infection. Conservation of an expanded ABC expression profile across diseases establishes ABC dysregulation as a feature of CIS. Critically, we also observed transcriptomic features that distinguished CIS andde novoEBV-infected ABCs from those found in healthy controls and other disease contexts. Outcome stratification of CIS samples revealed a rare yet distinctive pro-inflammatory ABC subset that was significantly underrepresented in long-term non-progressor (LTNP) versus cases with RRMS activity (∼5-fold difference). Collectively, this study provides evidence for altered ABC regulation – possibly arising from niche-specific responses to EBV infection – preceding MS onset.SUMMARYSingle-cell transcriptomics establishes an EBV-associated signature in T-bet+atypical B cells in CIS and a pro-inflammatory phenotype underrepresented in patients with no disease progression.
Mechanistic modeling of social conditions into disease predictions for public health intervention-analyses: application to HIV
Authors: Gopalappa Chaitra , Khoshegbhal Amir 
Published: March 2023

AbstractBackgroundAs social and economic conditions are key determinants of HIV, the ‘National HIV/AIDS Strategy (NHAS)’, in addition to care and treatment metrics, aims to address mental health, unemployment, food insecurity, and housing instability, as a strategic plan for the Ending the HIV Epidemic initiative. Mechanistic models of HIV play a key role in identifying cost-effective intervention strategies, however, social conditions are typically not part of the modeling framework. HIV projections are typically simulated by modeling care and sexual behaviors, and transmissions as functions of those behaviors.MethodsWe developed a methodological framework, using Markov random field model to estimate joint probability distributions between social conditions and behaviors, to incorporate in a mechanistic model to simulate behaviors as functions of social conditions and HIV transmissions as a function of behaviors. As demonstration, we conducted two numerical applications in a national-level agent-based network model, Progression and Transmission of HIV (PATH 4.0). The first modeled care behavior (using viral suppression as proxy) as a function of depression, neighborhood, housing, poverty, education, insurance, and employment status. The second modeled sexual behaviors (number of partners and condom-use) as functions of employment, housing, poverty, and education status, using exchange sex as a mediator. Both simulated HIV transmissions and disease progression as functions of behaviors. We conducted what-if intervention analyses to estimate the impact of an ideal 100% efficacious intervention strategy.ResultsIf we intervene on HIV infected persons with the social needs modeled here, such that their care behavior increases to become equal to that among persons who do not have those social needs, the overall viral suppression in persons with diagnosed HIV infection increases from 65.5% to 80% (79% to 83%), resulting in a 10-year cumulative national incidence reduction of 29% (20% to 41%). If we address the social needs modeled here among persons who exchange sex, such that their sexual behavior becomes equal to that among those who do not exchange sex, we can expect a 10-year cumulative national incidence reduction of 6% (2.5% to 14%).ConclusionsWe developed a methodological framework for modeling social conditions into intervention decision-analytic models, using the limited data to present two demonstrative applications. Routinely monitoring quantitative data on associations between social conditions and HIV risk behaviors, and efficacy of structural interventions can help develop a comprehensive mechanistic model to identify cost-effective intervention combinations and inform public health strategic plans.
Phenome-wide association study to explore the long-term symptoms after infection with novel coronavirus in the UK Biobank
Authors: Zhang Kai , Liu Xiaowen , Fu Ping , Zhao Yingqi , Yu Qingqing , Liu Shuling , Xue Fuzhong 
Published: March 2023

AbstractBackgroundObservational research studies have shown that even after the acute phase, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect patients, and increase the risk of cardiovascular, mental, metabolic, and other disorders. However, the spectrum of diseases for individuals with a genetic predisposition to COVID-19 remains unclear.MethodsWe leveraged individual-level data from UK Biobank to implement a phenome-wide association study to explore the relationships between COVID-19 and 1061 diseases. Then, the inverse-variance weighted (IVW) method was adopted with summary-level data from global consortiums as sensitivity analyses combined with other MR methods with different model assumptions to identify robust associations.FindingsThe PheWAS found severe respiratory, hospitalized, and susceptibility COVID-19 had detrimental effects on 36, 37, and 51 kinds of diseases, separately. The IVW test found severe respiratory COVID-19 had detrimental effects on breast cancer [OR 95% CI: 1.065 (1.000-1.133)], pan-cancer [OR 95% CI: 1.002 (1.000-1.004)], and Alzheimer’s disease [OR 95% CI: 1.042 (1.005-1.081)], etc. Hospitalized COVID-19 had detrimental effects on ischemic stroke (IS) [OR 95%CI: 1.049 (1.001-1.100)], breast cancer [OR 95%CI: 1.139 (1.011-1.283)], and pan-cancer [OR 95%CI: 1.003 (1.000-1.006)], etc. Susceptibility COVID-19 had detrimental effects on deep vein thrombosis (DVT) of lower extremities [OR 95%CI: 2.392 (1.167-4.902)], venous thromboembolism [OR 95%CI: 1.962 (1.115-3.453)], pulmonary heart disease/diseases of pulmonary circulation [OR 95%CI: 1.767 (1.142-2.733)], IS (large artery atherosclerosis) [OR 95%CI: 1.405 (1.025-1.927)], myocardial infarction [OR 95%CI: 1.235 (1.012-1.509)], heart failure [OR 95%CI: 1.140 (1.009-1.287)], etc.InterpretationThis study describes the extensive link between genetically determined COVID-19 and a broad range of diseases, especially those of the circulatory system, neuropsychiatric system, neoplasms, immune system, and digestive systems. Early detection and management of post-COVID-19 conditions could be tremendously beneficial to public health.FundingThis work was supported by the National Natural Science Foundation of China (81773547 and 82173625) and the National Key Research and Development Program (2020YFC2003500).
Animal-vectored nutrient flows across resource gradients influence the nature of local and meta-ecosystem functioning
Authors: Rizzuto Matteo , Leroux Shawn J. , Schmitz Oswald J. , Wal Eric Vander , Wiersma Yolanda F. , Heckford Travis R. 
Published: March 2023

AbstractOrganisms moving across landscapes connect ecosystems in space and time, mediating nutrient, energy, and biomass exchanges. Meta-ecosystem ecology offers a framework to study how these flows affect ecosystem functions in space and time. However, meta-ecosystem models often represent consumer movement as diffusion along gradients of resources. Crucially, this assumes that consumer movement connects the same trophic compartments among patches of the same ecosystem. Yet, empirical evidence shows that organisms move across different ecosystems and connect diverse trophic compartments in diffusive and non-diffusive ways. Here, we derive a two-patch meta-ecosystem model that accounts for both types of organismal movement, and we investigate their influences on local and meta-ecosystem functions. We integrate two novel approaches in this classic meta-ecosystem model: a dispersers’ pool to capture the fraction of moving organisms and time scales separation to partition local and regional dynamics. We show that non-diffusive consumer movement increases landscape heterogeneity while diffusive consumer movement enhances source-sink dynamics. Local ecosystem differences driven by consumer movement type are less prevalent at meta-ecosystem extents. Thus, movement type is essential for predicting local ecosystem dynamics. Our results support recent calls to explicitly consider the role of consumers in shaping and maintaining ecosystem functions in space and time.
Polygenic regression uncovers trait-relevant cellular contexts through pathway activation transformation of single-cell RNA sequencing data
Authors: Ma Yunlong , Deng Chunyu , Zhou Yijun , Zhang Yaru , Qiu Fei , Jiang Dingping , Zheng Gongwei , Li Jingjing , Shuai Jianwei , Zhang Yan , Yang Jian , Su Jianzhong 
Published: March 2023

SummaryAdvances in single-cell RNA sequencing (scRNA-seq) techniques have accelerated functional interpretation of disease-associated variants discovered from genome-wide association studies (GWASs). However, identification of trait-relevant cell populations is often impeded by inherent technical noise and high sparsity in scRNA-seq data. Here, we developed scPagwas, a computational approach that uncovers trait-relevant cellular context by integrating pathway activation transformation of scRNA-seq data and GWAS summary statistics. scPagwas effectively prioritizes trait-relevant genes, which facilitates identification of trait-relevant cell types/populations with high accuracy in extensive simulated and real datasets. Cellular-level association results identified a novel subpopulation of naïve CD8+ T cells related to COVID-19 severity, and oligodendrocyte progenitor cell and microglia subsets with critical pathways by which genetic variants influence Alzheimer’s disease. Overall, our approach provides new insights for the discovery of trait-relevant cell types and improves the mechanistic understanding of disease variants from a pathway perspective.
Multi-omic dissection of ancestral heat stress memory responses inBrachypodium distachyon
Authors: Xinghai Zheng , Tan Qiao Wen , Lim Peng Ken , Mutwil Marek 
Published: March 2023

AbstractStressful environmental conditions, including heat stress (HS), are a major limiting factor in crop yield. Understanding the molecular mechanisms of plant stress memory and resilience is important for engineering more resistant plants and improving crop yield. To study how the different gene regulatory layers change upon repeated HS and how these layers are interconnected, we performed a dense temporal atlas of gene expression, alternative splicing, small and long noncoding RNAs, and DNA methylation inBrachypodium distachyon. Results show that a second HS induces changes in coding and noncoding RNA expression and alternative splicing and that DNA demethylation is responsible for mediating differential gene expression. We identified a long noncoding RNA regulatory network and provided evidence that lncRNAs positively regulate gene expression, while miRNAs are implicated in alternative splicing events. We reconstructed the ancestral heat memory network of flowering plants by comparing the dynamic responses ofArabidopsis thalianaandBrachypodium distachyon. These findings enhance our understanding of the complex inter-layer cross-talk governing HS resilience and memory and identify novel genes essential for these processes.
COVID-19 vaccination coverage and linkages with public willingness to receive vaccination prior to vaccine roll-out: Evidence from Rwanda
Authors: Ndishimye Pacifique , Martinez Gustavo S. , Hewins Benjamin , Ostadgavahi Ali Toloue , Kumar Anuj , Sharma Mansi , Karuhije Janvier , Nkeshimana Menelas , Nsanzimana Sabin , Kelvin David 
Published: March 2023

AbstractThe rapid development of multiple SARS-CoV-2 vaccines within one year of the virus’s emergence is unprecedented and redefines the timeline for vaccine approval and rollout. Consequently, over 13 billion COVID-19 vaccine doses have been administered worldwide, accounting for ∼70% of the global population. Despite this steadfast scientific achievement, many inequalities exist in vaccine distribution and procurement, particularly in low- and middle-income countries such as those in Africa. This stems from the cost of COVID-19 vaccines, storage and cold-chain challenges, distribution to remote areas, proper personnel training, and so on. In addition to logistical challenges, many developed nations rapidly procured available vaccines, administering second and third doses and leaving many developing nations without the first dose. In this paper, we explore the level of reception to COVID-19 vaccines prior to their availability in Rwanda using a survey-based approach. While several countries reported spikes in vaccine hesitancy generally coinciding with new information, new policies, or newly reported vaccine risks, Rwanda functions as an exemplar for controlling disease burden and educating locals regarding the benefits of vaccination. We show that, even before COVID-19 vaccines were available, many Rwandans (97%) recognized the importance of COVID-19 vaccination and (93%) were willing to receive a COVID-19 vaccine following vaccine availability. Our results underscore the level of preparedness in Rwanda, which rivals and outcompetes many developed nations in terms of vaccination rate (nearing 80% in Rwanda), vaccine acceptance, and local knowledge relating to vaccination. Furthermore, in addition to the whole-of-government coordination as well as tailored delivery approach, previously developed practices relating to vaccination and communication surrounding the Ebola Virus Disease may have compounded the COVID-19 vaccine program in Rwanda, prior to its implementation.
Divergent functional connectivity changes associated with white matter hyperintensities
Authors: Santillo Alexander F. , Strandberg Tor O. , Reislev Nina H. , Nilsson Markus , Stomrud Erik , Spotorno Nicola , van Westen Danielle , Hansson Oskar 
Published: March 2023

AbstractAge-related white matter hyperintensities are a common feature and known to negatively impact structural integrity, functional connectivity and cognitive performance. However, this has yet to be fully understood mechanistically. We analysed multiple MRI modalities acquired in 465 non-demented individuals from the Swedish BioFINDER study including 334 cognitively normal and 131 participants with mild cognitive impairment. White matter hyperintensities were automatically quantified using fluid-attenuated inversion recovery MRI and parameters from diffusion tensor imaging were estimated in major white matter fibre tracts. We calculated fMRI resting state-derived functional connectivity within and between predefined cortical regions structurally linked by the white matter tracts and evaluated how change in functional connectivity is affected by white matter lesions and related to cognition, in the form of executive function and processing speed. We examined the functional changes using a measure of sample entropy. As expected hyperintensities were associated with disrupted structural white matter integrity and were linked to reduced functionalinterregionallobar connectivity, which related to decreased processing speed and executive function. Simultaneously, hyperintensities were also associated with increasedintraregionalfunctional connectivity, but only within the frontal lobe. This phenomenon was also associated with reduced cognitive performance. The increased connectivity was linked to increased entropy (reduced predictability and increased complexity) of the involved voxels’ blood oxygenation level dependent signal. Our findings expand our previous understanding of the impact of white matter hyperintensities on cognition by describing novel mechanisms that may be important beyond this particular type of brain lesions.
Mechanism of GTPase activation of a prokaryotic small Ras-like GTPase MglA by an asymmetrically interacting MglB dimer
Authors: Chakraborty Sukanya , Kanade Manil , Gayathri Pananghat 
Published: March 2023

AbstractCell polarity oscillations inMyxococcus xanthusmotility are driven by a prokaryotic small Ras-like GTPase, MglA, which switches from one cell pole to the other in response to extracellular signals. MglA dynamics is regulated by MglB, which functions both as a GAP (GTPase activating protein) and a GEF (guanine nucleotide exchange factor) for MglA. With an aim to dissect the role of asymmetry in the dual GAP and GEF activities of MglB, we generated a functional MglAB complex by co-expressing MglB with a linked construct of MglA and MglB. This strategy enabled us to generate mutations of individual MglB protomers (MglB1linked to MglA or MglB2) and delineate their role in GEF and GAP activities. We establish that the C-terminal helix of MglB1, but not MglB2, stimulates nucleotide exchange through a site away from the nucleotide-binding pocket, confirming an allosteric mechanism. Interaction between the N-terminal β-strand of MglB1and β0of MglA is essential for the GEF activity of MglB. Specific residues of MglB2which interact with Switch-I of MglA partially contribute to its GAP activity. Thus, the role of the MglB2protomer in the GAP activity of MglB is limited to restricting the conformation of MglA active site loops by steric hindrance. The direct demonstration of the allosteric mechanism of GEF action provides us new insights into the regulation of small Ras-like GTPases, a feature potentially present in many uncharacterized GEFs.
Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells
Authors: Gu Li , Zhu Yahui , Lee Maiya , Nguyen Albert , Ryujin Nicolas T , Huang Jian , Chamseddine Shadi , Xiao Lianchun , Mohamed Yehia I. , Kaseb Ahmed O. , Karin Michael , Shalapour Shabnam 
Published: March 2023

AbstractAlthough viral hepatocellular carcinoma (HCC) is declining, non-viral HCC, which often is the end-stage of non-alcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICI) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a small portion of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell mediated tumor regression and postulated that anti-fibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1 induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8+T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with inhibition of TGF-β receptor signaling, collagen deposition and depletion of immunosuppressive fibroblasts.SignificanceImmune checkpoint inhibitors are used in HCC treatment but overall response rates for single agent PD-1/PD-L1 blockers have remained stubbornly low. Using a mouse model of NASH-driven HCC, we show that co-treatment with the safe and inexpensive angiotensin II receptor inhibitor losartan substantially enhanced anti-PD-1 triggered HCC regression. Although losartan did not influence the reinvigoration of exhausted CD8+T cells it considerably enhanced their intratumoral invasion, which we postulated to be compromised by peritumoral fibrosis. Indeed, the beneficial effect of losartan correlated with inhibition of TGF-β signaling and collagen deposition, and depletion of immunosuppressive fibroblasts. Losartan should be evaluated for its adjuvant activity in HCC patients undergoing PD-1/PD-L1 blocking therapy.
The significant yet short-term influence of research covidization on journal citation metrics
Authors: Zheng Xiang , Ni Chaoqun 
Published: March 2023

AbstractCOVID-19 has emerged as a major research hotspot in recent years, leading to increased publications and citations of related papers. While concerns exist about the potential citation boost in journals publishing these papers, the specifics are not fully understood. This study uses a generalized difference-in-differences approach to examine the impact of publishing COVID-19 papers on journal citation metrics in the Health Sciences fields. Findings indicate that journals publishing COVID-19 papers in 2020 received significantly higher citation premiums due to COVID-19 in 2020 and continued to benefit from the premium in 2021 in certain fields. In contrast, journals that began publishing COVID-19 papers in 2021 experienced weaker citation premiums. Although the publication volume of non-COVID-19 papers also surged, these papers experienced insignificant or negative citation gains, even when published in the same journals as COVID-19 papers. COVID-19 papers published in high-impact journals brought more significant citation premiums to journals in most fields. These citation premiums can affect various citation-based journal metrics, such as our simulated impact factor, to different degrees. The results highlight a “gold rush” pattern in which early entrants establish their citation advantage in research hotspots and caution against using citation-based metrics for research assessment.