bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain hubs defined in the group do not overlap with regions of high inter-individual variability
Authors: Smith D.M. , Kraus B. T. , Dworetsky A. , Gordon E. M. , Gratton C. 
Published: October 2021

AbstractConnector ‘hubs’ are brain regions with links to multiple networks. These regions are hypothesized to play a critical role in brain function. While hubs are often identified based on group-average functional magnetic resonance imaging (fMRI) data, there is considerable inter-subject variation in the functional connectivity profiles of the brain, especially in association regions where hubs tend to be located. Here we investigated how group hubs are related to locations of inter-individual variability, to better understand if hubs are (a) relatively conserved across people, (b) locations with malleable connectivity, leading individuals to show variable hub profiles, or (c) artifacts arising from cross-person variation. To answer this question, we compared the locations of hubs and regions of strong idiosyncratic functional connectivity (“variants”) in both the Midnight Scan Club and Human Connectome Project datasets. Group hubs defined based on the participation coefficient did not overlap strongly with variants. These hubs have relatively strong similarity across participants and consistent cross-network profiles. Consistency across participants was further improved when participation coefficient hubs were allowed to shift slightly in local position. Thus, our results demonstrate that group hubs defined with the participation coefficient are generally consistent across people, suggesting they may represent conserved cross-network bridges. More caution is warranted with alternative hub measures, such as community density, which are based on spatial proximity and show higher correspondence to locations of individual variability.
Physarum polycephalum: Establishing an Assay for Testing Decision-making Under Shifting Somatic Boundaries
Authors: Levin Samuel P. , Levin Michael 
Published: October 2021

AbstractPrior studies of decision-making generally assume a fixed agent which maximizes utility among its various options. Physarum polycephalum is a popular model for basal cognition that can be cut into pieces that may or may not re-join. We exploited this capacity to develop a novel assay in which radical changes to the agent itself are among the options of the decision-making process. Specifically, we transected a Physarum culture in the presence of a food reward that was located closer to the new smaller piece. In this scenario, the newly created branch must choose between exploiting the reward itself, or first re-connecting with the original mass (and sharing the nutrient reward across a large body). We report a pilot study establishing a protocol in which the number of agents is part of the decision-making process. We observed that despite the presence of food, new branches strongly prefer to merge back to the syncytium before exploiting the reward. Many improvements to the protocol are possible, to extend this effort to understand the interplay between behavioral options and the structure and boundary of the individual making choices in its environment.
Nuclear PHGDH promotes neutrophil recruitment to drive liver cancer progression
Authors: Zhu Hongwen , Yu Hua , Zhou Hu , Zhu Wencheng , Wang Xiongjun 
Published: October 2021

AbstractMetabolic dysregulation and the communications between cancer and immune cells are emerging as two essential features of malignant tumors. In this study, we observed that nuclear localization of phosphoglycerate dehydrogenase (PHGDH) associates with poor prognosis of liver cancer patients, and Phgdh is required for liver cancer progression in a mouse model. Unexpectedly, the impairment of Phgdh enzyme activity exerts a slight effect on liver cancer model, indicating PHGDH contributes to liver cancer progression mainly depending on its non-metabolic roles with nuclear location. PHGDH uses its ACT domain to bind cMyc in nuclear and forms a transactivation axis “PHGDH/p300/cMyc/AF9” which drives CXCL1/8 gene expression. Chemokines CXCL1/8 promotes neutrophils recruitment and then supports tumor associated macrophages (TAMs) filtration in liver, thereby urging liver cancer into advanced stages. Forced cytosolic location of PHGDH or destruction of the PHGDH/cMyc interaction abolishes the oncogenic function of nuclear PHGDH. Collectively, this study reveals a non-metabolic role of PHGDH with altered cellular location in liver cancer, and suggests a promising drug target for liver cancer therapy by targeting the interaction between PHGDH and “undruggable” cMyc.
RTX-KG2: a system for building a semantically standardized knowledge graph for translational biomedicine
Authors: Wood E. C. , Glen Amy K. , Kvarfordt Lindsey G. , Womack Finn , Acevedo Liliana , Yoon Timothy S. , Ma Chunyu , Flores Veronica , Sinha Meghamala , Chodpathumwan Yodsawalai , Termehchy Arash , Roach Jared C. , Mendoza Luis , Hoffman Andrew S. , Deutsch Eric W. , Koslicki David , Ramsey Stephen A. 
Published: October 2021

AbstractBackgroundBiomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API).ResultsTo create aknowledge providersystem within the Translator project, we have developed RTX-KG2, an open-source software system for building—and hosting a web API for querying—a biomedical knowledge graph that uses an Extract-Transform-Load (ETL) approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink.ConclusionRTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API atarax.rtx.ai/api/rtxkg2/v1.2/openapi.json. The code to build RTX-KG2 is publicly available atgithub:RTXteam/RTX-KG2.
Adaptation of peristaltic pumps for laminar flow experiments
Authors: Abello Javier , Yien Yvette Y. , Stratman Amber N. 
Published: October 2021

AbstractEndothelial cells (ECs) are the primary cellular constituent of blood vessels that are in direct contact with hemodynamic forces over the course of a lifetime. Throughout the body, vessels experience different types of blood flow patterns and rates that alter vascular architecture and cellular behavior. Because of the complexities of studying blood flow in an intact organism, particularly during development, modeling of blood flow in vitro has become a powerful technique for studying hemodynamic dependent signaling mechanisms in ECs. While commercial flow systems that recirculate fluids exist, many commercially available pumps are peristaltic and best model pulsatile flow conditions. However, there are many important in vivo situations in which ECs experience laminar flow conditions, such as along long, straight stretches of the vasculature. To understand EC function under these situations, it is important to be able to consistently model laminar flow conditions in vitro. Here, we outline a method to reliably adapt commercially available peristaltic pumps to reproducibly study laminar flow conditions. Our proof of concept study focuses on 2-dimensional (2D) models but could be further adapted to 3-dimensional (3D) environments to better model in vivo scenarios such as organ development. Our studies make significant inroads into solving technical challenges associated with flow modeling, and allow us to conduct functional studies towards understanding the mechanistic role of flow forces on vascular architecture, cellular behavior, and remodeling during a variety of physiological contexts.
Comparative assessment of methods for short-term forecasts of COVID-19 hospital admissions in England at the local level
Authors: Meakin Sophie , Abbott Sam , Bosse Nikos , Munday James , Gruson Hugo , Hellewell Joel , Sherratt Katherine ,   CMMID COVID-19 Working Group, Funk Sebastian 
Published: October 2021

AbstractBackgroundForecasting healthcare demand is essential in epidemic settings, both to inform situational awareness and facilitate resource planning. Ideally, forecasts should be robust across time and locations. During the COVID-19 pandemic in England, it is an ongoing concern that demand for hospital care for COVID-19 patients in England will exceed available resources.MethodsWe made weekly forecasts of daily COVID-19 hospital admissions for National Health Service (NHS) Trusts in England between August 2020 and April 2021 using three disease-agnostic forecasting models: a mean ensemble of autoregressive time series models, a linear regression model with 7-day-lagged local cases as a predictor, and a scaled convolution of local cases and a delay distribution. We compared their point and probabilistic accuracy to a mean-ensemble of them all, and to a simple baseline model of no change from the last day of admissions. We measured predictive performance using the Weighted Interval Score (WIS) and considered how this changed in different scenarios (the length of the predictive horizon, the date on which the forecast was made, and by location), as well as how much admissions forecasts improved when future cases were known.ResultsAll models outperformed the baseline in the majority of scenarios. Forecasting accuracy varied by forecast date and location, depending on the trajectory of the outbreak, and all individual models had instances where they were the top- or bottom-ranked model. Forecasts produced by the mean-ensemble were both the most accurate and most consistently accurate forecasts amongst all the models considered. Forecasting accuracy was improved when using future observed, rather than forecast, cases, especially at longer forecast horizons.ConclusionsAssuming no change in current admissions is rarely better than including at least a trend. Using confirmed COVID-19 cases as a predictor can improve admissions forecasts in some scenarios, but this is variable and depends on the ability to make consistently good case forecasts. However, ensemble forecasts can make forecasts that make consistently more accurate forecasts across time and locations. Given minimal requirements on data and computation, our admissions forecasting ensemble could be used to anticipate healthcare needs in future epidemic or pandemic settings.
Diagnostic Value of Genetic Mutation Analysis and Mutation Profiling of cfDNA in Intraocular Fluid for Vitreoretinal Lymphoma
Authors: Chen Xiaoqing , Hu Yunwei , Su Wenru , Yang Shizhao , Wang Xiaoxiao , Zhang Ping , Hong Xiaoyu , Liang Chuqiao , Qian Zhuyun , Li Ziqiang , Tao Yong , Huang Huiqiang , Liang Dan 
Published: October 2021

AbstractObjectiveVitreoretinal lymphoma (VRL) is a rare but aggressive masquerade syndrome, with challenging diagnosis. Since the tumor-related genetic mutation analysis based on cell-free DNA (cfDNA) are underutilized in ocular oncology, we aimed to test the VRL diagnostic value of cfDNA genetic mutation analysis using intraocular fluid (IOF) samples and to identify its mutation profile.SubjectsSeventeen VRL and 6 uveitis patients from Zhongshan Ophthalmic Centre were selected as training group, and 5 VRL and 5 uveitis patients from Beijing Chaoyang Hospital were selected as validation group.MethodsThe medical records and genetic mutation analysis using a panel containing 446 tumor-related genes of included patients were retrospectively reviewed. We analyzed the mutation profile, and identified the molecular subtypes and subdivisions of B-cell differentiation pathways of our VRL patients.Main outcomesThe cfDNA genetic mutations detected in IOF.ResultsThe VRL patients from the training group exhibited abundant cfDNA mutations in IOF (sensitivity 100%), while only 2 out of 6 uveitis patients were positive (specificity 67%). However, the number of cfDNA mutations observed in VRL patients was higher than that of uveitis patients. The mutation-positive patients from the validation group were diagnosed with VRL while the mutation-negative patients were diagnosed with uveitis (sensitivity and specificity 100%). VRL patients were characterized by the high mutation frequencies of PIM1, MYD88, CD79B, ETV6, and IRF4.ConclusionsThe genetic mutation analysis of IOF samples represents a feasible diagnosis method for VRL with 100% sensitivity; it could track genetic profiles; thus, revealing genetic heterogeneity of VRL.Statement of translational relevanceThe anterior chamber paracentesis and diagnostic vitrectomy have been widely used in ophthalmic clinics, as they are less invasive sampling techniques for liquid biopsies. Genetic mutation analysis of cell-free DNA (cfDNA) of intraocular fluid using a panel containing 446 targeted genes represents a feasible method with 100% sensitivity for vitreoretinal lymphoma (VRL) diagnosis. Furthermore, it can address cytological diagnostic issues including limited cellular yield, cell lysis associated with the fragile nature of lymphoma cells, and high risks associated with retinal tissue biopsies. Furthermore, it allows for genetic profile tracking, having the potential to reveal genetic heterogeneity and molecular characteristics of VRL in the future
Circulatory neutrophils exhibit enhanced neutrophil extracellular trap formation in early puerperium: NETs at the nexus of thrombosis and immunity?
Authors: Giaglis Stavros , Chowdhury Chanchal Sur , van Breda Shane Vontelin , Stoikou Maria , Schaefer Guenther , Buser Andreas , Walker Ulrich A. , Lapaire Olav , Hoesli Irene , Hasler Paul , Hahn Sinuhe 
Published: October 2021

AbstractPregnancy is associated with elevated maternal levels of cell-free DNA of neutrophil extracellular trap (NET) origin, as circulatory neutrophils exhibit increased spontaneous NET formation, mainly driven by G-CSF and finely modulated by sex hormones. The postpartum period, on the other hand, involves physiological alterations consistent with the need for protection against infections and fatal haemorrhage. Our findings indicate that all relevant serum markers of neutrophil degranulation and NET release are substantially augmented postpartum. Neutrophil pro-NETotic activity in vitro is also upregulated particularly in post-delivery neutrophils. Moreover, maternal puerperal neutrophils exhibit a strong pro-NETotic phenotype, associated with increased levels of all key players in the generation of NETs – citH3, MPO, NE and ROS, compared to non-pregnant and pregnant controls. Intriguingly, post-delivery NET formation is independent of G-CSF in contrast to late gestation and complemented by the presence of TF on the NETs, alterations in the platelet activity status, and activation of the coagulation cascade, triggered by circulating microparticles. Taken together, our results reveal the highly pro-NETotic and potentially procoagulant nature of postpartum neutrophils, bridging an overt immune activation with possible harmful thrombotic incidence.
The intestinal circadian clock drives microbial rhythmicity to maintain gastrointestinal homeostasis
Authors: Heddes Marjolein , Altaha Baraa , Niu Yunhui , Reitmeier Sandra , Kleigrewe Karin , Haller Dirk , Kiessling Silke 
Published: October 2021

SummaryDiurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the host’s circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for circadian microbiota composition and function, which is required to balance the host’s gastrointestinal homeostasis.
Conserved chromatin and repetitive patterns reveal slow genome evolution in frogs
Authors: Bredeson Jessen V. , Mudd Austin B. , Medina-Ruiz Sofia , Mitros Therese , Smith Owen K. , Miller Kelly E. , Lyons Jessica B. , Batra Sanjit S. , Park Joseph , Berkoff Kodiak C. , Plott Christopher , Grimwood Jane , Schmutz Jeremy , Aguirre-Figueroa Guadalupe , Khokha Mustafa K. , Lane Maura , Philipp Isabelle , Laslo Mara , Hanken James , Kerdivel Gwenneg , Buisine Nicolas , Sachs Laurent M. , Buchholz Daniel R. , Kwon Taejoon , Smith-Parker Heidi , Gridi-Papp Marcos , Ryan Michael J. , Denton Robert D. , Malone John H. , Wallingford John B. , Straight Aaron F. , Heald Rebecca , Hockemeyer Dirk , Harland Richard M. , Rokhsar Daniel S. 
Published: October 2021

AbstractFrogs are an ecologically diverse and phylogenetically ancient group of living amphibians that include important vertebrate cell and developmental model systems, notably the genusXenopus. Here we report a high-quality reference genome sequence for the western clawed frog,Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species,Eleutherodactylus coqui,Engystomops pustulosusandHymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., centric) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding, surrounded by pericentromeric LINE/L1 elements. We explored chromosome structure across frogs, using a dense meiotic linkage map forX. tropicalisand chromatin conformation capture (HiC) data for all species. Abundant satellite repeats occupy the unusually long (∼20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible association of centromeric chromatin, and of telomeres, reflecting a Rabl configuration similar to the “bouquet” structure of meiotic cells. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.
The pathobiology ofMycobacterium abscessusrevealed through phenogenomic analysis
Authors: Boeck Lucas , Burbaud Sophie , Skwark Marcin , Pearson Will H. , Sangen Jasper , Weimann Aaron , Everall Isobel , Bryant Josephine M , Malhotra Sony , Bannerman Bridget P. , Kierdorf Katrin , Blundell Tom L. , Dionne Marc S. , Parkhill Julian , Floto R. Andres 
Published: October 2021

ABSTRACTThe medical and scientific response to emerging pathogens is often severely hampered by ignorance of the genetic determinants of virulence, drug resistance, and clinical outcomes that could be used to identify therapeutic drug targets and forecast patient trajectories1–5. Taking the newly emergent multidrug-resistant bacteriaMycobacterium abscessusas an example6, we show that combining high dimensional phenotyping with whole genome sequencing in a phenogenomic analysis can rapidly reveal actionable systems-level insights into bacterial pathobiology. Usingin vitroandin vivophenotyping, we discovered three distinct clusters of isolates, each associated with a different clinical outcome. We combined genome-wide association studies (GWAS) with proteome-wide computational structural modelling7to define likely causal variants, and employed direct coupling analysis (DCA)8to identify co-evolving, and therefore potentially epistatic, gene networks. We then usedin vivoCRISPR-based silencing to validate our findings, defining a novel secretion system controlling virulence inM. abscessus, and illustrating how phenogenomics can reveal critical pathways within emerging pathogenic bacteria.
Transfer of Knowledge from Model Organisms to Evolutionarily Distant Non-Model Organisms: The CoralPocillopora damicornisMembrane Signaling Receptome
Authors: Kumar Lokender , Brenner Nathanael , Sledzieski Sam , Olaosebikan Monsurat , Lynn-Goin Matthew , Putnam Hollie , Yang JK , Lewinski Nastassja , Singh Rohit , Daniels Noah M. , Cowen Lenore , Klein-Seetharaman Judith 
Published: October 2021

AbstractWith the ease of gene sequencing and the technology available to study and manipulate non-model organisms, the need to translate our understanding of model organisms to non-model organisms has become an urgent problem. For example, mining of large coral and their symbiont sequence data is a challenge, but also provides an opportunity for understanding functionality and evolution of these and other non-model organisms. Much more information than for any other eukaryotic species is available for humans, especially related to signal transduction and diseases. However, the coral cnidarian host and human have diverged over 700 million years ago and homologies between proteins are therefore often in the gray zone or undetectable with traditional BLAST searches. We introduce a two-stage approach to identifying putative coral homologues of human proteins. First, through remote homology detection using Hidden Markov Models, we identify candidate human homologues in the cnidarian genome. However, for many proteins, the human genome alone contains multiple family members with similar or even more divergence in sequence. In the second stage, therefore, we filter the remote homology results based on the functional and structural plausibility of each coral candidate, shortlisting the coral proteins likely to be true human homologues. We demonstrate our approach with a pipeline for mapping membrane receptors in humans to membrane receptors in corals, with specific focus on the stony coral,P. damicornis. More than 1000 human membrane receptors mapped to 335 coral receptors, including 151 G protein coupled receptors (GPCRs). To validate specific sub-families, we chose opsin proteins, representative GPCRs that confer light sensitivity, and Toll-like receptors, representative non-GPCRs, which function in the immune response, and their ability to communicate with microorganisms. Through detailed structure-function analysis of their ligand-binding pockets and downstream signaling cascades, we selected those candidate remote homologues likely to carry out related functions in the corals. This pipeline may prove generally useful for other non-model organisms, such as to support the growing field of synthetic biology.