bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Gout with Brain Reserve and Vulnerability to Neurodegenerative Disease
Authors: Topiwala Anya , Mankia Kulveer , Bell Steven , Webb Alastair , Ebmeier Klaus P , Howard Isobel , Wang Chaoyue , Alfaro-Almagro Fidel , Miller Karla , Burgess Stephen , Smith Stephen , Nichols Thomas E 
Published: November 2022

AbstractObjectivTo assess the associations between gout, brain structure, and neurodegenerative disease incidence.MethodsUsing observational and Mendelian randomization analyses we investigated causal relationships between gout and brain health. Exposures included gout diagnosis (from self-report, linked health records and death records) and genetically proxied gout and serum urate. Outcomes were neuroimaging markers of brain structure and neurodegenerative disease incidence (ascertained through self-report, health records and death reports). Cox proportional hazards models were used to examine time to neurodegenerative disease diagnosis.Results11,735 UK Biobank participants (mean age 55.5±8.0 years and 50.5% female) had a diagnosis of gout (n=1165 in MRI subset). Dementia was ascertained in 3126 individuals over a mean follow-up time of 12.4±1.9 years. Gout patients had smaller global and regional brain volumes and higher brain iron markers. Genetic associations mirrored observational associations. Genetically proxied gout associated with lower global grey matter volume (beta= -0.05[-0.08 to -0.01]). Participants with gout had higher incidence of all-cause dementia (hazard ratio (HR)=1.60, 95% confidence interval (CI) [1.38-1.85]), Parkinson’s disease (HR=1.43[1.15 to 1.79]), and probable essential tremor (HR=6.75[5.69 to 8.00]). Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis (HR=7.40[4.95 to 11.07]).ConclusionsThese findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases.Key pointsWhat is already known on this topic?Studies of neurodegenerative disease risk in gout are contradictory.Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain.What this study adds?In this prospective cohort study gout was associated with smaller brain volumes and higher incidence of multiple neurodegenerative diseases.Mendelian randomization analyses suggested gout is causally related to brain structure.How might this study affect research, practice or policy?Our findings emphasise the importance for clinicians of assessing for motor and cognitive impairments amongst gout patients, particularly in early years after diagnosis.
Patterns of West Nile virus in the Northeastern United States using negative binomial and mechanistic trait-based models
Authors: Keyel Alexander C. 
Published: November 2022

AbstractWest Nile virus primarily infects birds and mosquitoes but has also caused over 2000 human deaths, and >50,000 reported human cases. Present-day West Nile virus risk was described for the Northeastern United States, using a negative binomial model. Changes in risk due to climate change were examined for the next decade using a temperature-trait model. West Nile virus risk was generally expected to increase over the next decade due to changes in temperature, but the changes in risk were generally small. Many, but not all, populous counties in the northeast are already near peak risk. Several years in a row of low case numbers is consistent with a negative binomial, and should not be interpreted as a change in disease dynamics. Public health budgets need to be prepared for the expected infrequent years with higher-than-average cases. Absence of reported cases from low-population counties is consistent with similar risk as nearby counties with cases.
Using species richness calculations to model the global profile of unsampled pathogenic variants: Examples fromBRCA1andBRCA2
Authors: Rao Nandana D. , Shirts Brian H. 
Published: November 2022

AbstractThere have been many surveys of genetic variation inBRCA1andBRCA2to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate “variant richness” and determine how many germline pathogenicBRCA1/2variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenicBRCA1/2variants and identified those expected to be most common. Data was obtained from a literature search including studies conducted globally that tested the entirety ofBRCA1/2for pathogenic variation. Across countries, 45% to 88% of variants were estimated to be missing, i.e., present in the population but not observed in study data. Estimated variant frequencies in each country showed a higher proportion of rare variants compared to recurrent variants. The median prevalence estimate ofBRCA1/2pathogenic variant carriers was 0.64%.BRCA1c.68_69del is likely the most recurrentBRCA1/2variant globally due to its estimated prevalence in India. Modeling variant richness using ecology methods may assist in evaluating clinical targeted assays by providing a picture of what is observed with estimates of what is still unknown.
Glucocorticoid-regulated bidirectional enhancer RNA transcription pinpoints functional genetic variants linked to asthma
Authors: Sasse Sarah K. , Dahlin Amber , Sanford Lynn , Gruca Margaret A. , Gupta Arnav , Gally Fabienne , Wu Ann Chen , Iribarren Carlos , Dowell Robin D. , Weiss Scott T. , Gerber Anthony N. 
Published: November 2022

AbstractGenome-wide association studies of asthma have not explained environmental risk or variable clinical efficacy of glucocorticoids. Bidirectional enhancer RNA (eRNA) transcription is a widespread response to environmental signals and glucocorticoids. Therefore, we investigated whether single nucleotide polymorphisms (SNPs) within dynamically regulated eRNA-transcribing regions contribute to genetic variation in asthma. Through applying multivariate regression modeling with permutation-based significance thresholding to a large clinical cohort, we identified novel associations between asthma and 35 SNPs located in eRNA-transcribing regions implicated in regulating diverse cellular processes relevant to asthma. Functional validation established thatrs258760(mean allele frequency = 0.34, asthma odds ratio = 0.95; P = 5.04E-03) eliminates an active aryl hydrocarbon receptor (AHR) response element linked to transcriptional regulation of the glucocorticoid receptor gene by AHR ligands commonly found in air pollution. Our findings establish eRNA signatures as a tool for discovery of functional genetic variants and define a novel link between air pollution, glucocorticoid signaling and asthma.
Altered Resting-State Functional Connectivity in the Anterior Versus Posterior Hippocampus in Post-traumatic Stress Disorder: The Central Role of the Anterior Hippocampus
Authors: Chaposhloo Mohammad , Nicholson Andrew A. , Becker Suzanna , McKinnon Margaret C. , Lanius Ruth , Shaw Saurabh Bhaskar ,   Alzheimer’s Disease Neuroimaging Initiative
Published: November 2022

AbstractBackgroundPost-traumatic stress disorder can be viewed as a memory disorder, with trauma-related flashbacks being a core symptom. Given the central role of the hippocampus in autobiographical memory, surprisingly, there is mixed evidence concerning altered hippocampal functional connectivity in PTSD. We shed light on this discrepancy by considering the distinct roles of the anterior versus posterior hippocampus and examine how this distinction may map onto whole-brain resting-state functional connectivity patterns among those with and without PTSD.MethodsWe first assessed whole-brain between-group differences in the functional connectivity profiles of the anterior and posterior hippocampus within a publicly available data set of resting-state fMRI data fromn=31 male Vietnam War veterans diagnosed with PTSD andn=29 age-matched combat-exposed male controls. Next, the connectivity patterns of each subject within the PTSD group were correlated with their PTSD symptom scores. Finally, the between-group differences in whole-brain functional connectivity profiles discovered for the anterior and posterior hippocampal seeds were used to prescribe post-hoc ROIs, which were then used to perform ROI-to-ROI functional connectivity and graph-theoretic analyses.ResultsThe PTSD group showed increased functional connectivity of the anterior hippocampus with affective brain regions (anterior/posterior insula, orbitofrontal cortex, temporal pole) and decreased functional connectivity of the anterior/posterior hippocampus with regions involved in processing bodily selfconsciousness (supramarginal gyrus). Notably, decreased anterior hippocampus connectivity with the posterior cingulate cortex /precuneus was associated with increased PTSD symptom severity. The left anterior hippocampus also emerged as a central locus of abnormal functional connectivity, with graph-theoretic measures suggestive of a more central hub-like role in those with PTSD compared to trauma-exposed controls.ConclusionsOur results highlight that the anterior hippocampus plays a critical role in the neurocircuitry underlying PTSD and underscore the importance of the differential roles of hippocampal sub-regions in serving as biomarkers of PTSD.
Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models
Authors: Pusch Fabian , Dorado García Heathcliff , Xu Robin , Gürgen Dennis , Bei Yi , Brueckner Lotte , Röefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Chamorro González Rocío , Eggert Angelika , Schulte Johannes H. , Hundsdörfer Patrick , Seifert Georg , Haase Kerstin , Schaefer Beat , Wachtel Marco , Kühl Anja A. , Ortiz Michael V. , Wengner Antje M. , Scheer Monika , Henssen Anton G. 
Published: November 2022

AbstractThe small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in >40 cell lines and >30 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailedin vitroandin vivomolecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib outperformed standard of care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical anti-tumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients.Statement of translational relevanceElimusertib is a small molecule inhibitor of ATR. ATR inhibitors have shown promising results as anticancer agents in adult cancers, but there is limited information on their effectiveness in pediatric solid tumors. Using a cohort of 32 patient-derived xenografts from pediatric solid tumors, we here evaluated the therapeutic potential of elimusertibin vivo. Elimusertib reduced tumor volume growth in all samples. Elimusertib had very limited toxicity and was potent even in tumors with preexisting chemoresistance. Our preclinical data indicates that elimusertib is a safe and potent therapeutic option for pediatric solid tumors. This data may serve as a rationale for the development of pediatric clinical trials for ATR inhibitors.
Genomic innovation and horizontal gene transfer shaped plant colonization and biomass degradation strategies of a globally prevalent fungal pathogen
Authors: Sahu Neha , Indic Boris , Wong-Bajracharya Johanna , Merényi Zsolt , Ke Huei-Mien , Ahrendt Steven , Monk Tori-Lee , Kocsubé Sándor , Drula Elodie , Lipzen Anna , Bálint Balázs , Henrissat Bernard , Andreopoulos Bill , Martin Francis M. , Harder Christoffer Bugge , Rigling Daniel , Ford Kathryn L. , Foster Gary D. , Pangilinan Jasmyn , Papanicolaou Alexie , Barry Kerrie , LaButti Kurt , Virágh Máté , Koriabine Maxim , Yan Mi , Riley Robert , Champramary Simang , Plett Krista L. , Grigoriev Igor V. , Tsai Isheng Jason , Slot Jason , Sipos György , Plett Jonathan , Nagy László G. 
Published: November 2022

AbstractMembers of the fungal genusArmillariaare necrotrophic pathogens with efficient plant biomass-degrading strategies. The genus includes some of the largest terrestrial organisms on Earth, spreading underground and causing tremendous losses in diverse ecosystems. Despite their global importance, the mechanism by whichArmillariaevolved pathogenicity in a clade of dominantly non-pathogenic wood-degraders (Agaricales) remains elusive. Here, using new genomic data, we show thatArmillariaspecies, in addition to widespread gene duplications andde novogene origins, appear to have at least 775 genes that were acquired via 101 horizontal gene transfer (HGT) events, primarily from Ascomycota. Functional and expression data suggest that HGT might have affected plant biomass-degrading and virulence abilities ofArmillaria, two pivotal traits in their lifestyle. We further assayed gene expression during root and cambium colonization, and report putative virulence factors, extensive regulation of horizontally acquired and wood-decay related genes as well as novel pathogenicity-induced small secreted proteins (PiSSPs). Two PiSSPs induced necrosis in live plants, suggesting they are potential virulence effectors conserved acrossArmillaria. Overall, this study details how evolution knitted together horizontally and vertically inherited genes in complex adaptive traits, such as plant biomass degradation and pathogenicity, paving the way for development of infection models for one of the most influential pathogens of temperate forest ecosystems.
An improved network alignment algorithm of dynamic protein interaction networks of floral development inArabidopsis
Authors: Ji Jiamin , Zheng Kailing , He Miao 
Published: November 2022

SummaryTo align the dynamic protein-protein interaction networks (DPINs) might help to better understand the molecular network genetic mechanisms of flower development inArabidopsis thaliana. In this paper, the microarray data of flower development inArabidopsiswere obtained from the gene expression omnibus (GEO) database. The active expressed genes at each time point were screened using σ method. The DPIN at each time point were reconstructed using search tool for the retrieval of interacting genes/proteins (STRING) and then visualized with Cytoscape, and enrichment analysis implemented using clusterProfiler package of the R language. We improved NetCoffee 2, a multi-time, multidimensional, and multi-level network alignment algorithm, NetCoffee 2+, was developed for floral development of A. thaliana. In this paper, a network alignment algorithm applied toA. thaliana, NetCoffee 2+, was developed, and the key proteins and protein complexes during floral development inA. thalianawere mined, with new potential ABCDE-like genes discovered.
ADrosophilaWolfram Syndrome 1 (WFS1) homologue synergises with the intracellular Ca2+release channel, IP3R to affect mitochondrial morphology and function
Authors: Kunnappallil Rose Sebastian , Hasan Gaiti 
Published: November 2022

AbstractWolfram syndrome (WFS) is an autosomal recessive neurodegenerative disorder, 90% of which is caused by loss of function of the endoplasmic reticular membrane protein Wolframin or WFS 1. Wolfram syndrome results in Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (DIDMOAD) in humans. In mammalian cells WFS1 interacts with the ER-localised intracellular Ca2+release channel, Inositol Trisphosphate Receptor 1 (IP3R1) required for IP3mediated Ca2+release from the endoplasmic reticulum.Here, we tested functional interactions between IP3R and WFS1 mutants in the context of organismal behaviour and neuronal mitochondrial morphology and physiology in a subset of central dopaminergic neurons ofDrosophila melanogaster. We show strong genetic interactions between trans-heterozygotes ofwfs1anditpr(IP3R) mutants by measuring flight deficits. Over-expression of wild-type cDNAs of either interacting partner,wfs1+oritpr+rescued the flight deficits. Cellular studies demonstrate changes in mitochondrial Ca2+entry accompanied by enlarged or swollen mitochondria and decreased mitochondrial content in genotypes that are flight defective. Inwfs1mutant as well aswfs1knockdown conditions a reduction in the number of dopaminergic neurons was observed.Thus, WFS1 interaction with the IP3R is required in flight regulating central dopaminergic neurons ofDrosophila, for optimal mitochondrial Ca2+entry and maintaining mitochondrial morphology. Our study demonstrates thatDrosophilacan be a good model system to understand the cellular and molecular basis of Wolfram syndrome, its impact on systemic physiology and suggests its use in testing putative pharmaceutical interventions.
Comparative pharmacology of direct oral anticoagulants and vitamin K antagonist
Authors: Kumar Arun HS 
Published: November 2022

AbstractBackgroundThe prevalence of thrombus and use of anticoagulants is routine in clinical cardiology practice. Vitamin K antagonists (VKA) and/or Direct oral anticoagulants (DOAC) are used for resolution of the thrombus. Despite similar anticoagulation efficacy, use of DOAC is preferred due to their superior safety margin and reduced risk of bleeding. Currently the following DOAC are available for the prevention of thrombosis, i.e., dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban. This study evaluates the comparative pharmacology of these DOAC and VKA to assess clinical preference.Materials and MethodsThe human specific targets of DOAC and VKA (Warfarin) were identified from the SwissTargetPrediction server and analysed for their affinity. The targets were subclassified into functional categories and the relative proportion of each of the functional categories among the total number of targets was estimated. A novel concentration affinity (CA) ratio system was developed for the drugs to assess their safety margin and compared.ResultsThe following targets were identified has high affinity targets of DOAC or VKA i.e., coagulation factor X, hERG, matriptase, multidrug and toxin extrusion protein 1, plasminogen, quinone reductase 1 & 2, serine protease hepsin, solute carrier family 22 member 2 and thrombin. Apixaban and rivaroxaban were observed to have superior anticoagulation pharmacology compared to the other DOAC or VKA. Edoxaban and betrixaban were observed to have affinity against hERG, which carries the risk of prolonging QT interval and triggering ventricular tachyarrhythmia.ConclusionThis study shows the comparative pharmacology of DOAC and VKA and suggests preferential use of apixaban or rivaroxaban due to their superior pharmacodynamic effects and wider safety margin.
Contribution of host species and pathogen clade to snake fungal disease hotspots in Europe
Authors: Blanvillain Gaëlle , Lorch Jeffrey M. , Joudrier Nicolas , Bury Stanislaw , Cuenot Thibault , Franzen Michael , Martínez-Freiría Fernando , Guiller Gaëtan , Halpern Bálint , Kolanek Aleksandra , Kurek Katarzyna , Lourdais Olivier , Michon Alix , Musilová Radka , Schweiger Silke , Szulc Barbara , Ursenbacher Sylvain , Zinenko Oleksandr , Hoyt Joseph R. 
Published: November 2022

Abstract1. Infectious diseases are influenced by interactions between host and pathogen, and are rarely homogenous across the landscape. Areas with elevated pathogen prevalence maintain a high force of infection, can facilitate pathogen spread to new regions, and may indicate areas with impacts on host populations. However, isolating the ecological processes that result in increases in infection prevalence and intensity remains a challenge.2. Here we elucidate the contribution of pathogen clade and host species in disease hotspots ofOphidiomyces ophidiicola,the pathogen that causes snake fungal disease, in 21 species of snakes infected with multiple pathogen strains across 10 countries in Europe.3. We found isolated areas of disease hotspots in a landscape where infections were otherwise low.O. ophidiicolaclade had important effects on transmission, and areas with multiple pathogen clades had higher host infection prevalence. Snake species identity further influenced infection, with most positive detections coming from theNatrixgenus. Most species present in the community only experienced increased levels of infection when multiple strains were present. However, one species,N. tessellata, appeared highly susceptible, having increased infection prevalence regardless of pathogen strain, indicating that this species may be important in pathogen maintenance.4. Our results suggest that both host and pathogen identity are essential components contributing to increased pathogen prevalence. More broadly, our findings indicate that coevolutionary relationships between hosts and pathogens may be key mechanisms explaining variation in landscape patterns of disease.
The usage of transcriptomics datasets as sources of Real-World Data for clinical trialling
Authors: Matos-Filipe Pedro , García-Illarramendi Juan Manuel , Jorba Guillem , Oliva Baldo , Farrés Judith , Mas José Manuel 
Published: November 2022

AbstractBackgroundRandomised Clinical Trials (RCT) reflect results within their specific controlled settings, necessitating further studies to understand outcomes across all possible scenarios. The usage of Real-World Data (RWD) has been recently considered to be a viable alternative to overcome these issues and complement clinical conclusions. Molecular profiles of patients captured by high-throughput measures reflect their medical conditions. When this information is linked to clinical and demographical information, nuances in transcriptomics data can uncover subtle variations in disease pathways among distinct patient groups. This work focuses on the construction of a patient repository database with molecular and clinical information resulting from the integration of publicly available transcriptomics datasets.ResultsPatient data were integrated into the patient repository by using a novel post-processing technique allowing for the usage of samples originating from different/multiple Gene Expression Omnibus (GEO) datasets. Our post-processing technique, which we have named MicroArray Cross-plAtfoRm pOst-prOcessiNg (MACAROON), aims to standardise and integrate transcriptomics data (considering batch effects and possible processing-originated artefacts). This process was able to better reproduce the down streaming biological conclusions in a 45% improvement compared to other methods available. Furthermore, RWD was mined from GEO samples’ metadata and a clinical and demographical characterisation of the database was obtained. RWD mining was done through a manually curated synonym dictionary allowing for the correct assignment (95.33% median accuracy; 80.14% average) of medical conditions.ConclusionsOur strategy produced a repository, which includes molecular, clinical and demographical RWD by integrating multiple public datasets. The exploration of these data facilitates the discovery of clinical outcomes and molecular pathways specific to predetermined patient populations.