bluuebunny/crossref_metadata_2025_split huggingface dataset:
The complete cell atlas of an aging multicellular organism
Authors: Roux Antoine E. , Yuan Han , Podshivalova Katie , Hendrickson David , Kerr Rex , Kenyon Cynthia , Kelley David R. 
Published: June 2022

AbstractHere we describe a single-cell atlas of aging for the nematode Caenorhabditis elegans. This unique resource describes the expression across adulthood of over 20,000 genes among 211 groups of cells that correspond to virtually every cell type in this organism. Our findings suggest that C. elegans aging is not random and stochastic in nature, but rather characterized by coordinated changes in functionally related metabolic and stress-response genes in a highly cell-type specific fashion. Aging signatures of different cell types are largely different from one another, downregulation of energy metabolism being the only nearly universal change. Some biological pathways, such as genes associated with translation, DNA repair and the ER unfolded protein response, exhibited strong (in some cases opposite) changes in subsets of cell types, but many more were limited to a single cell type. Similarly, the rates at which cells aged, measured as genome-wide expression changes, differed between cell types; some of these differences were tested and validated in vivo by measuring age-dependent changes in mitochondrial morphology. In some, but not all, cell types, aging was characterized by an increase in cell-to-cell variance. Finally, we identified a set of transcription factors whose activities changed coordinately across many cell types with age. This set was strongly enriched for stress-resistance TFs known to influence the rate of aging. We tested other members of this set, and discovered that some, such as GEI-3, likely also regulate the rate of aging. Our dataset can be accessed and queried at c.elegans.aging.atlas.research.calicolabs.com/.
UK Biobank release and systematic evaluation of optimised polygenic risk scores for 53 diseases and quantitative traits
Authors: Thompson Deborah J. , Wells Daniel , Selzam Saskia , Peneva Iliana , Moore Rachel , Sharp Kevin , Tarran William A. , Beard Edward J. , Riveros-Mckay Fernando , Giner-Delgado Carla , Palmer Duncan , Seth Priyanka , Harrison James , Futema Marta ,   Genomics England Research Consortium, McVean Gil , Plagnol Vincent , Donnelly Peter , Weale Michael E. 
Published: June 2022

AbstractWe present and assess the UK Biobank (UKB) Polygenic Risk Score (PRS) Release, a set of PRSs for 28 diseases and 25 quantitative traits being made available on the individuals in UKB. We also release a benchmarking software tool to enable like-for-like performance evaluation for different PRSs for the same disease or trait. Extensive benchmarking shows the PRSs in the UKB Release to outperform a broad set of 81 published PRSs. For many of the diseases and traits we also validate the PRS algorithms in other cohorts. The availability of PRSs for 53 traits on the same set of individuals also allows a systematic assessment of their properties, and the increased power of these PRSs increases the evidence for their potential clinical benefit.
Dysfunctional cortical gradient topography in treatment resistant major depression
Authors: Pasquini Lorenzo , Fryer Susanna L. , Eisendrath Stuart J. , Segal Zindel V. , Lee Alex J. , Brown Jesse A. , Saggar Manish , Mathalon Daniel H. 
Published: June 2022

AbstractBackgroundTreatment-Resistant Depression (TRD) refers to patients with major depressive disorder who do not remit after two or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts this hierarchical cortical organization.MethodsWe analyzed resting-state fMRI data from a mindfulness-based intervention study in 56 TRD patients and 28 healthy controls. Using novel gradient extraction tools, measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. Within TRD, baseline cortical gradient dispersion measures were correlated with baseline clinical measures (anxiety, depression, mindfulness), as well as with changes in these measures following treatment with either mindfulness-based therapy or a health enhancement program.ResultsCortical gradient dispersion was reduced within major intrinsic brain networks in TRD. Reduced cortical gradient dispersion correlated with increased network modularity assessed through graph theory-based measures of network topology. Lower dispersion among Default Mode Network regions, a transmodal system linked to depression symptomatology, related to current levels of trait anxiety, depression, and mindfulness, but not to changes in these domains following treatment.ConclusionsOur findings reveal widespread alterations in cortical gradient architecture in TRD, implicating a significant role for the Default Mode Network in mediating depression, anxiety, and lower mindfulness in patients.
Rapid detection of myeloid neoplasm fusions using Single Molecule Long-Read Sequencing
Authors: Sala-Torra Olga , Reddy Shishir , Hung Ling-Hong , Beppu Lan , Wu David , Radich Jerald , Yeung Ka Yee , Yeung Cecilia CS 
Published: June 2022

AbstractRecurrent gene fusions are common drivers of disease pathophysiology in leukemias. Identification of these structural variants helps stratify disease by risk and assists with therapy choice. Current fusion detection methods require long turnaround time (7-10 days) or advance knowledge of the genes involved in the fusions. To address the need for rapid identification of clinically actionable fusion genes in heme malignancies without a-priori knowledge of the genes, we describe a long-read sequencing DNA assay designed with CRISPR guides to select and enrich for recurrent leukemia fusion genes. By applying rapid sequencing technology based on nanopores, we sequenced long pieces of genomic DNA and successfully detected fusion genes in cell lines and primary specimens (e.g., BCR-ABL1, PML-RARA, CBFB-MYH11, KMT2A-AF4) using cloud-based bioinformatics workflows with novel custom fusion finder software. We detected fusion genes in 100% of cell lines with the expected breakpoints and confirmed the presence or absence of a recurrent fusion gene in 12 of 14 patient cases. With our optimized assay and cloud-based bioinformatics workflow, these assays and analyses could be performed in under 8 hours.Key pointsWe describe a CRISPR-Cas9 enrichment Nanopore sequencing assay with streamlined bioinformatics that outperforms other fusion detectors.We successfully detected both fusion genes and specific breakpoints in CML, APL, and AML in under 8 hours in 80% of patients.Visual Abstract (Figure 1)We successfully detected fusion genes in hematological malignancies with a fast and efficient long-read sequencing workflow in under 8 hours. The method makes the genomic characterization of BCR-ABL1 DNA breakpoint in patients quick and simple, which potentiates design of patient specific primers for personalized monitoring MRD assays.Our assay is based on a CRISPR-Cas9 non-amplification enrichment library preparation strategy and uses Nanopore sequencing single stranded genomic DNA coupled with streamlined bioinformatic workflow containing a novel fusion detector software which outperforms current fusion detection software.
Immunogenicity following two doses of BBIBP-CorV vaccine and a third booster dose with viral vector and Mrna COVID-19 vaccines against delta and omicron variants in prime immunized adults with two doses of BBIBP-CorV vaccine
Authors: Chansaenroj Jira , Suntronwong Nungruthai , Kanokudom Sitthichai , Assawakosri Suvichada , Yorsaeng Ritthideach , Vichaiwattana Preeyaporn , Klinfueng Sirapa , Wongsrisang Lakana , Srimuan Donchida , Thatsanatorn Thaksaporn , Thongmee Thanunrat , Auphimai Chompoonut , Nilyanimit Pornjarim , Wanlapakorn Nasamon , Sudhinaraset Natthinee , Poovorawan Yong 
Published: June 2022

AbstractCoronavirus disease 2019 (COVID-19) booster vaccination is being comprehensively evaluated globally due to waning immunity and the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Therefore, this study aimed to evaluate antibody responses in individuals vaccinated with two doses of BBIBP-CorV vaccine and to explore the boosting effect of the different vaccine platforms in BBIBP-CorV-primed healthy adults, including viral vector vaccine (AZD122) and mRNA vaccines (BNT162b2 and mRNA-1273). The results showed that, in the BBIBP-CorV prime group, the total receptor-binding domain (RBD) immuno-globulin (Ig) and anti-RBD IgG levels waned significantly at 3 months after receiving the second dose. However, after the booster, RBD-specific binding antibody levels increased. Neutralizing antibody measured by a surrogate neutralization test showed of inhibition over 90% against the SARS-CoV-2 delta variant but less than 70% against omicron variant after the third dose on day 28. All booster vaccines could induce the total IFN-□ T-cell response. The reactogenicity was acceptable and well tolerated without serious adverse events. This study supported administration of the third dose with either viral vector or mRNA vaccine for the BBIBP-CorV-primed individuals to stimulate antibody and T cell responses.
Home-use Photobiomodulation Device Treatment Outcomes for COVID-19
Authors: Lim Lew , Hosseinkhah Nazanin , Buskirk Mark V. , Berk Andrea , Loheswaran Genane , Abbaspour Zara , Karimpoor Mahta , Smith Alison , Au Yoke N. , Ho Kai F , Pushparaj Abhiram , Zahavi Michael , White Alexander , Rubine Jonathan , Zidel Brian , Henderson Christopher , Clayton Russell G. , Tingley David R. , Miller David J. , Karimpoor Mahroo , Hamblin Michael R. 
Published: June 2022

ABSTRACTBACKGROUNDThere is need for non-pharmaceutical treatments for COVID-19. A home-use photobiomodulation (PBM) device was tested as Treatment in a randomized clinical trial.METHODS294 patients were randomized with equal allocation to Treatment or Standard of Care (Control). 199 qualified for efficacy analyses. The Treatment group self-treated for 20 minutes twice daily, for the first 5 days, and subsequently once daily for 30 days. A validated respiratory questionnaire was used, and patients were monitored remotely. The primary endpoint was the time-to-recovery (3 consecutive days of no sickness) for general sickness. The Kaplan-Meier method and the Cox Proportional Hazards model were primary methods of analyses.RESULTSTreatment patients with collective 0-12 days of symptoms, at moderate-to-severe level on Day 1 of Treatment, did not recover significantly faster than Control. However, for patients with 0-7 days of symptoms there was a significant mean difference of 3 days: Treatment, 18 days (95% CI, 13-20) vs. Control, 21 days (95% CI, 15-28), P=0.050. The Treatment:Control hazard ratio at 1.495 (95% CI, 0.996-2.243), P=0.054 exceeded the pre-trial target of 1.44. Treated patients exceeding 7 days symptoms duration were more tired and had lower energy. None of the patients in the Treatment group suffered death or hospitalization while the Control group had 1 death and 3 severe adverse events requiring hospitalization.CONCLUSIONSPatients with up to 7 days of symptoms at moderate-to-severe levels on first day of Treatment can expect faster recovery for general sickness and several respiratory symptoms. (Funded by Vielight Inc.;ClinicalTrials.govnumber,NCT04418505.)
More than Mycobacterium tuberculosis: specific site-of-disease microbial communities, functional capacities, and their distinct clinical profiles in tuberculous lymphadenitis
Authors: Nyawo Georgina , Naidoo Charissa , Wu Benjamin , Sulaiman Imran , Clemente Jose , Li Yonghua , Minnies Stephanie , Reeve Byron , Moodley Suventha , Rautenbach Cornelia , Wright Colleen , Singh Shivani , Whitelaw Andrew , Schubert Pawel , Warren Robin , Segal Leopoldo , Theron Grant 
Published: June 2022

ABSTRACTBackgroundLymphadenitis is the most common extrapulmonary tuberculosis (EPTB) manifestation and a major cause of death. The microbiome is important to human health but uninvestigated in EPTB. We profiled the site-of-disease lymph node microbiome in tuberculosis lymphadenitis (TBL).MethodsFine needle aspiration biopsies (FNABs) were collected from 159 pre-treatment presumptive TBL patients in Cape Town, South Africa. 16S Illumina MiSeq rRNA gene sequencing was done.ResultsWe analysed 89 definite TBLs (dTBLs) and 61 non-TBLs (nTBLs), which had similar α-but different β-diversities (p=0.001). Clustering identified five lymphotypes prior to TB status stratification: Mycobacterium-, Prevotella- and Streptococcus-dominant lymphotypes were more frequent in dTBLs whereas a Corynebacterium-dominantlymphotype and a fifth lymphotype (no dominant taxon) were more frequent in nTBLs. When restricted to dTBLs, clustering identified a Mycobacterium-dominant lymphotype with low α-diversity and other non-Mycobacterium-dominated lymphotypes (termed Prevotella-Corynebacterium and Prevotella-Streptococcus). The Mycobacterium dTBL lymphotype was associated with HIV-positivity and clinical features characteristic of severe lymphadenitis (e.g., node size). dTBL microbial communities were enriched with potentially proinflammatory microbial short chain fatty acid metabolic pathways (propanoate, butanoate) vs. those in nTBLs. 11% (7/61) of nTBLs had Mycobacterium reads.ConclusionsTBL at the site-of-disease is not microbially homogenous and distinct microbial community clusters exist that are associated with different immunomodulatory potentials and clinical characteristics. Non-Mycobacterium-dominated dTBL lymphotypes, which contain taxa potentially targeted by TB treatment, represent less severe potentially earlier stage disease. These investigations lay foundations for studying the microbiome’s role in lymphatic TB and the long-term clinical significance of lymphotypes requires prospective evaluation.
Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic
Authors: Lizcano-Perret Belén , Lardinois Cécile , Wavreil Fanny , Hauchamps Philippe , Herinckx Gaëtan , Sorgeloos Frédéric , Vertommen Didier , Gatto Laurent , Michiels Thomas 
Published: June 2022

AbstractProteins from some unrelated pathogens, including viruses and bacteria can recruit and activate cellular p90-ribosomal protein S6 kinases (RSKs) through a common linear motif. Our data suggested that such pathogens’ proteins might act as adapters to dock the kinase toward specific substrates. We explored this hypothesis using the Cardiovirus leader protein (L) as a paradigm. L is known to trigger phenylalanine-glycine nucleoporins (FG-NUPs) hyperphosphorylation and nucleocytoplasmic trafficking perturbation. Using a biotin ligase fused to either RSK or to L, we identified FG-NUPs as primary partners of the L-RSK complex in infected cells. Mutant analysis shows that L uses distinct motifs to recruit RSK and to dock the L-RSK complex toward the FG-NUPs. Using an analog-sensitive RSK2 mutant kinase, we show that, in infected cells, L can trigger RSK to use NUP98 and NUP214 as direct substrates. Our data illustrate a novel virulence mechanism where pathogens’ proteins retarget cellular protein kinases toward specific substrates.
Transposable element-mediated rearrangements are prevalent in human genomes
Authors: Balachandran Parithi , Walawalkar Isha A. , Flores Jacob I. , Dayton Jacob N. , Audano Peter A. , Beck Christine R. 
Published: June 2022

ABSTRACTTransposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and appreciated. Structural variants mediated by transposons, which we call transposable element-mediated rearrangements (TEMRs), are less well studied, and the mechanisms leading to their formation as well as their broader impact on human diversity are poorly understood. Here, we identify 493 unique TEMRs across the genomes of three individuals. While homology directed repair is the dominant driver of TEMRs, our sequence-resolved TEMR resource allows us to identify complex inversion breakpoints, triplications or other high copy number polymorphisms, and additional complexities. TEMRs are enriched in genic loci and can create potentially important risk alleles such as a deletion in TRIM65, a known cancer biomarker and therapeutic target. These findings expand our understanding of this important class of structural variation, the mechanisms responsible for their formation, and establish them as an important driver of human diversity.
Modelling Vaccination Strategies for the Control of Marburg Virus Disease Outbreaks
Authors: Qian George Y , Edmunds W John , Bausch Daniel G , Jombart Thibaut 
Published: June 2022

AbstractMarburg virus disease is an acute haemorrhagic fever caused by Marburg virus. Marburg virus is zoonotic, maintained in nature in Egyptian fruit bats, with occasional spillover infections into humans and nonhuman primates. Although rare, sporadic cases and outbreaks occur in Africa, usually associated with exposure to bats in mines or caves, and sometimes with secondary human-to-human transmission. Outbreaks outside of Africa have also occurred due to importation of infected monkeys. Although all previous Marburg virus disease outbreaks have been brought under control without vaccination, there is nevertheless the potential for large outbreaks when implementation of public health measures is not possible or breaks down. Vaccines could thus be an important additional tool and development of several candidate vaccines is under way. We developed a branching process model of Marburg virus transmission and investigated the potential effects of several prophylactic and reactive vaccination strategies in settings driven primarily by multiple spillover events as well as human-to-human transmission. Our results show a low basic reproduction number which varied across outbreaks, from 0.5 [95% CI: 0.05 – 1.8] to 1.2 [95% CI: 1.0 – 1.9] but a high case fatality ratio. Of six vaccination strategies explored, a combination of ring and targeted vaccination of high-risk groups was generally most effective, with a probability of controlling potential outbreaks of 0.88 (95% CI: 0.85 - 0.91) compared with 0.65 (0.60 - 0.69) for no vaccination, especially if the outbreak is driven by zoonotic spillovers and the vaccination campaign initiated as soon as possible after onset of the first case.Author SummaryMarburg virus disease is a rare but acute haemorrhagic fever caused by Marburg virus. We developed a branching process model of Marburg virus transmission and used this model to investigate potential prophylactic and reactive vaccination strategies in settings driven primarily by multiple spillover events as well as human-to-human transmission. We calculate a low basic reproduction number which varied across outbreaks, from 0.5 [95% CI: 0.05 – 1.8] to 1.2 [95% CI: 1.0 – 1.9].Of the six vaccination strategies explored, a combination of ring and targeted vaccination of high-risk groups was generally most effective, with a probability of controlling potential outbreaks of 0.88 (95% CI: 0.85 - 0.91) compared with 0.65 (0.60 - 0.69) for no vaccination, especially if the outbreak is driven by zoonotic spillovers and the vaccination campaign initiated as soon as possible after onset of the first case.
A Model for Understanding the Causes and Consequences of Walking Impairments
Authors: Schwartz Michael H. , Steele Katherine M. , Ries Andrew J. , Georgiadis Andrew G. , MacWilliams Bruce A. 
Published: June 2022

AbstractWalking is an important skill with positive impacts on health, function, and well-being. Many disorders impair walking and its positive impacts through a variety of complex and interrelated mechanisms. Any attempt to understand walking impairments, or the effects of interventions intended to treat these impairments, must respect this complexity. Therefore, our main objectives in conducting this study were to (1) propose a comprehensive model for quantifying the causes and consequences of walking impairments and (2) demonstrate the potential utility of the model for supporting clinical care and addressing basic scientific questions related to walking.To achieve these goals, we introduced a model, described by a directed acyclic graph, consisting of 10 nodes and 23 primary causal paths. We gave detailed descriptions of each node and path based on domain knowledge. We then demonstrated the model’s utility using a large sample of gait data (N = 9504) acquired as part of routine care at a regional referral center. We analyzed five relevant examples that involved many of the model’s nodes and paths. We computed causal effect magnitudes as Shapley values and displayed the overall importance of variables (mean absolute Shapley value), the variation of Shapley values with respect to underlying variables, and Shapley values for individual observations (case studies).We showed that the model was plausible, captured some well-known cause-effect relationships, provided new insights into others, and generated novel hypotheses requiring further testing through simulation or experiment. To aid in transparency, reproducibility, and future enhancements we have included an extensively commented Rmarkdown file and a deidentified data set.
Quantitative Assessment of Aortic Hemodynamics for Varying Left Ventricular Assist Device Outflow Graft Angles and Flow Pulsation
Authors: Sahni Akshita , McIntyre Erin E. , Pal Jay D. , Mukherjee Debanjan 
Published: June 2022

AbstractLeft ventricular assist devices (LVADs) comprise a primary treatment choice for advanced heart failure patients. Treatment with LVAD is commonly associated with complications like stroke and gastrointestinal (GI) bleeding, which adversely impacts treatment outcomes, and causes fatalities. The etiology and mechanisms of these complications can be linked to the fact that LVAD outflow jet leads to an altered state of hemodynamics in the aorta as compared to baseline flow driven by aortic jet during ventricular systole. Here, we present a framework for quantitative assessment of aortic hemodynamics in LVAD flows realistic human vasculature, with a focus on quantifying the differences between flow driven by LVAD jet and the physiological aortic jet when no LVAD is present. We model hemodynamics in the aortic arch proximal to the LVAD outflow graft, as well as in the abdominal aorta away from the LVAD region. We characterize hemodynamics using quantitative descriptors of flow velocity, stasis, helicity, vorticity and mixing, and wall shear stress. These are used on a set of 27 LVAD scenarios obtained by parametrically varying LVAD outflow graft anastomosis angles, and LVAD flow pulse modulation. Computed descriptors for each of these scenarios are compared against the baseline flow, and a detailed quantitative characterization of the altered state of hemodynamics due to LVAD operation (when compared to baseline aortic flow) is compiled. These are interpreted using a conceptual model for LVAD flow that distinguishes between flow originating from the LVAD outflow jet (and its impingement on the aorta wall), and flow originating from aortic jet during aortic valve opening in normal physiological state.