bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer whole genome comparison of primary and metastatic solid tumors
Authors: Martínez-Jiménez Francisco , Movasati Ali , Brunner Sascha , Nguyen Luan , Priestley Peter , Cuppen Edwin , Van Hoeck Arne 
Published: April 2023

AbstractMetastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis of 7,152 whole-genome-sequenced tumors. In general, our analysis shows that metastatic tumors have a low intra-tumor heterogeneity, high genomic instability and increased frequency of structural variants with comparatively a modest increase in the number of small genetic variants. However, these differences are cancer type specific and are heavily impacted by the exposure to cancer therapies. Five cancer types, namely breast, prostate, thyroid, kidney clear carcinoma and pancreatic neuroendocrine, are a clear exception to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. These changes were supported by increased genomic instability and involved substantial differences in tumor mutation burden, clock-based molecular signatures and the landscape of driver alterations as well as a pervasive increase in structural variant burden. The majority of cancer types had either moderate genomic differences (e.g., cervical and colorectal cancers) or highly consistent genomic portraits (e.g., ovarian cancer and skin melanoma) when comparing early- and late-stage disease. Exposure to treatment further scars the tumor genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcases the potential of whole-genome analysis to understand tumor evolution and provides a valuable resource to further investigate the biological basis of cancer and resistance to cancer therapies.
The Pandemic Response Commons
Authors: Trunnell Matthew , Frankenberger Casey , Hota Bala , Hughes Troy , Martinov Plamen , Ravichandran Urmila , Shah Nirav S. , Grossman Robert L. ,   The Pandemic Response Commons Consortium
Published: April 2023

AbstractObjectiveA data commons is a software platform for managing, curating, analyzing, and sharing data with a community. The Pandemic Response Commons is a data commons designed to provide a data platform for researchers studying an epidemic or pandemic.MethodsThe pandemic response commons was developed using the open source Gen3 data platform and is based upon consortium, data, and platform agreements developed by the not-for-profit Open Commons Consortium. A formal consortium of Chicagoland area organizations was formed to develop and operate the pandemic response commons.ResultsWe developed a general pandemic response commons and an instance of it for the Chicagoland region called the Chicagoland COVID-19 Commons. A Gen3 data platform was set up and operated with policies, procedures and controls based upon NIST SP 800-53. A consensus data model for the commons was developed, and a variety of datasets were curated, harmonized and ingested, including statistical summary data about COVID cases, patient level clinical data, and SARS-CoV-2 viral variant data.Discussion and conclusionGiven the various legal and data agreements required to operate a data commons, a pandemic response commons is designed to be in place and operating at a low level prior to the occurrence of an epidemic, with the activities increasing as required during an epidemic. A regional instance of a Pandemic Response Commons is designed to be part of a broader data ecosystem or data mesh consisting of multiple regional commons supporting pandemic response through sharing of regional data.
Multi-omics analysis reveals a crucial role for Retinoic Acid in promoting epigenetic and transcriptional competence of anin vitromodel of human Pharyngeal Endoderm
Authors: Cipriano Andrea , Colantoni Alessio , Gomes Danielle , Moqri Mahdi , Parker Alexander , Caldwell Matthew , Briganti Francesca , Fiorentino Jonathan , Roncarolo Maria Grazia , Baldini Antonio , Weinacht Katja G , Tartaglia Gian Gaetano , Sebastiano Vittorio 
Published: April 2023

ABSTRACTIn vitrodifferentiation of human Pluripotent Stem Cells (hPSCs) into different cell types has enabled the study of developmental processes that are impossible to dissectin vivo. This innovation has allowed for the derivation of therapeutically relevant cell types that can be used for downstream applications and studies. The Pharyngeal Endoderm (PE) is considered an extremely relevant developmental tissue since it acts as a precursor to a plethora of organ systems such as Esophagus, Parathyroids, Thyroids, Lung, and Thymus. While several studies have highlighted the importance of these cells, anin vitroplatform to generate human PE cells is still missing. Here we fill this knowledge gap, by providing a novelin vitroprotocol for the derivation ofbona fidePE cells from hPSCs. We demonstrated that our PE cells robustly express Pharyngeal Endoderm markers, they are transcriptionally similar to PE cells isolated fromin vivomouse development and represent a transcriptionally homogeneous population. Importantly, we elucidated the contribution of Retinoic Acid in promoting a transcriptional and epigenetic rewiring of PE cells. In addition, we defined the epigenetic landscape of PE cells by combining ATAC-Seq and ChIP-Seq of histone modifications. The integration of these data led to the identification of new putative regulatory regions and to the generation of a gene regulatory network orchestrating the development of PE cells. By combining hPSCs differentiation with computational genomics, our work reveals the epigenetic dynamics that occur during human PE differentiation, providing a solid resource and foundation for research focused on the development of PE derivatives and modeling of their developmental defects in genetic syndromes.
Structural Thalamocortical Network Atrophy in Sporadic Behavioural Variant Frontotemporal Dementia
Authors: Jakabek David , Power Brian D. , Spotorno Nicola , Macfarlane Matthew D. , Walterfang Mark , Velakoulis Dennis , Nilsson Christer , Waldö Maria Landqvist , Lätt Jimmy , Nilsson Markus , van Westen Danielle , Lindberg Olof , Looi Jeffrey C. L. , Santillo Alexander F. 
Published: April 2023

AbstractUsing multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD). Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity. The main features predicting bvFTD group membership were bilateral anterior-dorsal thalamic atrophy, increase in mean diffusivity of thalamic projections, and frontotemporal cortical thinning. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes. Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.
Predicting climate-driven distribution shifts inHyalomma marginatum(Ixodidae)
Authors: Hekimoglu Olcay , Elverici Can , Kuyucu Arda Cem 
Published: April 2023

AbstractHyalomma marginatumis an important tick species which is the main vector of Crimean-Congo haemorrhagic fever (CCHF) and spotted fever. The species is predominantly distributed in parts of Southern Europe, North Africa and West Asia. However, due to ongoing climate change and increasing reports ofH. marginatumin central and northern Europe, the expansion of this range poses a potential future risk. In this study, we employed an Ecological Niche Modelling (ENM) approach to model the current and future climatic suitability ofH. marginatum. Using high resolution climatic variables from the Chelsa dataset and an updated list of locations forH. marginatum, we constructed 2 models under current environmental conditions using MaxEnt: a more specific model for only current conditions, and a more general model for both current conditions and future projections under the ssp370 and ssp585 scenarios. Our models show that the climatically suitable region forH. marginatummatches the current distributional area in the Mediterranean basin and West Asia. When applied to future projections, our models suggest a considerable expansion ofH. marginatum’s range in the north in Europe as a result of rising temperatures. However, they also predict a decline in central Anatolia, potentially due to the exacerbation of drought conditions in that region.SubjectsEcology, Entomology, Epidemiology, Infectious Diseases, Climate Change Biology
Progranulin maintains blood pressure and vascular tone dependent on EphrinA2 and Sortilin1 receptors and eNOS activation
Authors: Bruder-Nascimento Ariane , Awata Wanessa M.C. , Alves Juliano V. , Singh Shubhnita , Costa Rafael M. , Bruder-Nascimento Thiago 
Published: April 2023

AbstractBackgroundThe mechanisms determining vascular tone are still not completely understood, even though it is a significant factor in blood pressure management. Many circulating proteins have a significant impact on controlling vascular tone. Progranulin (PGRN) displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether PGRN sustains the vascular tone that helps regulate blood pressure.MethodsWe used male and female C57BL6/J wild type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) to understand the impact of PGRN on vascular contractility and blood pressure.ResultsWe found that male and female PGRN-/- mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which are restored by supplementing the mice with recombinant PGRN (rPGRN). Inex vivoexperiments, rPGRN attenuated the vascular contractility to noradrenaline in male and female PGRN+/+ arteries, which was blunted by blocking EphrinA2 or Sortlin1. To understand the mechanisms whereby PGRN evokes anti-contractile effects, we inhibited endothelial factors. L-NAME [nitric oxide (NO) synthase (NOS) inhibitor] prevented the PGRN effects, whereas indomethacin (cyclooxygenases inhibitor) only affected the contractility in arteries incubated with vehicle, indicating the PGRN increases nitric oxide and decreases contractile prostanoids. Finally, rPGRN induced endothelial NOS (eNOS) phosphorylation and NO production in isolated mesenteric endothelial cells.ConclusionCirculating PGRN regulates vascular tone and blood pressure via EphrinA2 and Sortlin1 receptors and eNOS activation. Collectively, our data suggest that deficiency in PGRN is a cardiovascular risk factor and that PGRN might be a new therapeutic avenue to treat high blood pressure.Clinical PerspectiveWhat is new?PGRN displays vascular anti-contractile effects dependent on EphrinA2 and Sortilin1 receptors and nitric oxide formation in male and femaleDeficiency in PGRN triggers high blood pressure and induces vascular dysfunction characterized by hypercontractility to noradrenalinePGRN supplementation restores blood pressure and vascular dysfunction in PGRN-deficient miceWhat are the clinical implications?PGRN deficiency is associated with neurodegenerative diseases including neuronal ceroid lipofuscinosis and frontotemporal dementia (FTD). Our study reveals that a lack of PGRN might be associated with vascular dysfunction and high blood pressureSupplementation with PGRN might be a potential therapeutic route to treat high blood pressure and diseases associated with vascular dysfunctionReduction in PGRN might be a target to screen for higher cardiovascular risk
The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors
Authors: Hardy Rachel E. , Chung Injae , Yu Yizhou , Loh Samantha H.Y. , Morone Nobuhiro , Soleilhavoup Clement , Travaglio Marco , Serreli Riccardo , Panman Lia , Cain Kelvin , Hirst Judy , Martins Luis M. , MacFarlane Marion , Pryde Kenneth R 
Published: April 2023

SummaryAntipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent ‘third’-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ∼5-15% of patients. However, it is not fully understand how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adultDrosophila melanogasterconsistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.
Improved inference of population histories by integrating genomic and epigenomic data
Authors: Sellinger Thibaut , Johannes Frank , Tellier Aurélien 
Published: April 2023

AbstractWith the availability of high quality full genome polymorphism (SNPs) data, it becomes feasible to study the past demographic and selective history of populations in exquisite detail. However, such inferences still suffer from a lack of statistical resolution for recent, e.g. bottlenecks, events, and/or for populations with small nucleotide diversity. Additional heritable (epi)genetic markers, such as indels, transposable elements, microsatellites or cytosine methylation, may provide further, yet untapped, information on the recent past population history. We extend the Sequential Markovian Coalescent (SMC) framework to jointly use SNPs and other hyper-mutable markers. We are able to 1) improve the accuracy of demographic inference in recent times, 2) uncover past demographic events hidden to SNP-based inference methods, and 3) infer the hyper-mutable marker mutation rates under a finite site model. As a proof of principle, we focus on demographic inference inA. thalianausing DNA methylation diversity data from 10 European natural accessions. We demonstrate that segregating Single Methylated Polymorphisms (SMPs) satisfy the modelling assumptions of the SMC framework, while Differentially Methylated Regions (DMRs) are not suitable as their length exceeds that of the genomic distance between two recombination events. Combining SNPs and SMPs while accounting for site-and region-level epimutation processes, we provide new estimates of the glacial age bottleneck and post glacial population expansion of the EuropeanA. thalianapopulation. Our SMC framework readily accounts for a wide range of heritable genomic markers, thus paving the way for next generation inference of evolutionary history by combining information from several genetic and epigenetic markers.
Bidirectional transcription at thePPP2R2Bgene locus in spinocerebellar ataxia type 12
Authors: Zhou Chengqian , Liu Hans B. , Bakhsh Fatemeh J. , Wu Bin , Ying Mingyao , Margolis Russell L. , Li Pan P. 
Published: April 2023

AbstractOBJECTIVESpinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by expansion of a CAG repeat in thePPP2R2B gene. Here we tested the hypothesis that thePPP2R2B antisense(PPP2R2B-AS1) transcript containing a CUG repeat is expressed and contributes to SCA12 pathogenesis.METHODSExpression ofPPP2R2B-AS1transcript was detected in SCA12 human induced pluripotent stem cells (iPSCs), iPSC-derived NGN2 neurons, and SCA12 knock-in mouse brains using strand-specific RT-PCR (SS-RT-PCR). The tendency of expandedPPP2R2B-AS1(expPPP2R2B-AS1) RNA to form foci, a marker of toxic processes involving mutant RNAs, was examined in SCA12 cell models by fluorescencein situhybridization. The toxic effect ofexpPPP2R2B-AS1transcripts on SK-N-MC neuroblastoma cells was evaluated by caspase 3/7 activity. Western blot was used to examine the expression of repeat associated non-ATG-initiated (RAN) translation ofexpPPP2R2B-AS1transcript in SK-N-MC cells.RESULTSThe repeat region inPPP2R2Bgene locus is bidirectionally transcribed in SCA12 iPSCs, iPSC-derived NGN2 neurons, and SCA12 mouse brains. TransfectedexpPPP2R2B-AS1transcripts are toxic to SK-N-MC cells, and the toxicity may be mediated, at least in part, by the RNA secondary structure. TheexpPPP2R2B-AS1transcripts form CUG RNA foci in SK-N-MC cells.expPPP2R2B-AS1transcript is translated in the Alanine ORF via repeat-associated non-ATG (RAN) translation, which is diminished by single nucleotide interruptions within the CUG repeat, and MBNL1 overexpression.INTERPRETATIONThese findings suggest thatPPP2R2B-AS1contributes to SCA12 pathogenesis, and may therefore provide a novel therapeutic target for the disease.
Bridging the gap from knowledge to action: Implementation of the data to policy (D2P) training program at sub-national levels in Zambia
Authors: Banda Kutha , Zimba Rabson , Chilengi-Sakala Sandra , Shakwelele Hilda , Akinola Olatubosun Akinnola 
Published: April 2023

AbstractKnowledge translation is the synthesis, exchange, and application of knowledge by relevant stakeholders to accelerate the benefits of global and local innovation in strengthening health systems. In Zambia, research evidence is recognized as a critical element for the development of sound policies. This requires deliberate efforts towards generating, harvesting, and utilizing evidence from research and program data to inform decision-making. In response, the National Health Research Authority with support from the Clinton Health Access Initiative adapted a data to policy curriculum for use at sub-national levels and conducted training for 17 healthcare workers. The objectives of the training were to build the capacity of healthcare workers in analyzing research and other data to inform policy and programming as well as to develop six policy briefs for presentation to policymakers.The curriculum combines epidemiology with economic analysis and modeling to develop informative policy briefs. Sixteen modules were covered and delivered during periodic interactive workshops led by facilitators and mentorship was done in-between sessions. This was done within 6 months from February to August 2022. To assess the participants understanding, Kirkpatrick learning evaluation model was adapted upto level 3; we utilized a pre and posttest method of assessment.At pre-test, about 71% of the participants scored below 50 percent, while at posttest, all the participants scored above 50%. Six policy briefs were successfully developed covering Sexual Reproductive Maternal Newborn Child Adolescent Health and Nutrition topics. Implementation of this program provided a lot of learnings for programs aimed at improving uptake of evidence into action. One of the key learnings was that conducting economic evaluations and mathematical modelling of proposed policy interventions was critical in informing the decision-makers of the cost and benefits of the interventions. Policy options proposed in the policy brief were largely accepted by key stakeholders and proposed for piloting.
Enhancing Infectious Intestinal Disease diagnosis through metagenomic and metatranscriptomic sequencing of over 1000 human diarrhoeal samples
Authors: Cunningham-Oakes Edward , Perez-Sepulveda Blanca M. , Li Yan , Hinton Jay C. D. , Nelson Charlotte A. , McIntyre K. Marie , Wardeh Maya , Haldenby Sam , Gregory Richard , Iturriza-Gómara Miren , Hertz-Fowler Christiane , O’Brien Sarah J. , Cunliffe Nigel A. , Darby Alistair C. 
Published: April 2023

AbstractFundamental issues in the traditional surveillance of diarrhoeal disease need to be addressed. The limitations of traditional microbiological diagnostic methods often mean that the cause of diarrhoea remains unknown, especially for novel or difficult-to-isolate pathogens. Sequencing samples directly, without isolating pathogens, would address this issue. However, we must ensure that sequencing also captures pathogens that are detectable using current diagnostic methods.We show that metagenomic and metatranscriptomic approaches can effectively detect nine gastrointestinal pathogens in the UK. Metatranscriptomics shows increased sensitivity of detection for pathogens likeCampylobacter,Clostridioides difficile,CryptosporidiumandGiardia, while metagenomics is more effective for detecting pathogens such asAdenovirus, pathogenicEscherichia coli,Salmonella,Shigella, andYersinia enterocolitica. Certain pathogens were detected by both metagenomic and metatranscriptomic sequencing. Metatranscriptomics gave near-complete genome coverage for Human mastadenovirus F and detectedCryptosporidiumvia capture ofCryptosporidium parvumvirus (CSpV1). A comprehensive transcriptomic profile ofSalmonellaEnteritidis was recovered from the stool of a patient with a laboratory-confirmedSalmonellainfection.This study highlights the power of direct sequencing of human samples to augment GI pathogen surveillance and clinical diagnostics. Metatranscriptomics was best for capturing a wide breadth of pathogens and was more sensitive for this purpose. We propose that metatranscriptomics should be considered for future surveillance of gastrointestinal pathogens. This study has generated a rich data resource of paired metagenomic and metatranscriptomic datasets, direct from over 1000 patient stool samples. We have made these data publicly available to promote the improved understanding of pathogens associated with infectious intestinal diseases.