bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromosome 9p21.3 Coordinates Cell Intrinsic and Extrinsic Tumor Suppression
Authors: Barriga Francisco M. , Tsanov Kaloyan M. , Ho Yu-Jui , Sohail Noor , Zhang Amy , Baslan Timour , Wuest Alexandra N. , Priore Isabella Del , Meškauskaitė Brigita , Livshits Geulah , Alonso-Curbelo Direna , Simon Janelle , Chaves-Perez Almudena , Bar-Sagi Dafna , Iacobuzio-Donahue Christine A. , Notta Faiyaz , Chaligne Ronan , Sharma Roshan , Pe’er Dana , Lowe Scott W. 
Published: August 2022

SUMMARYSomatic chromosomal deletions are prevalent in cancer, yet their functional contributions remain ill-defined. Among the most prominent of these events are deletions of chromosome 9p21.3, which disable a cell intrinsic barrier to tumorigenesis by eliminating the CDKN2A/B tumor suppressor genes. However, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletions have not been functionally characterized. To dissect how 9p21.3 and other genomic deletions impact cancer, we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy that enables flexible modeling of megabase-sized deletions. Generation of 9p21.3-syntenic deletions in a mouse model of pancreatic cancer revealed that concomitant loss of Cdkn2a/b and the IFN cluster led to immune evasion and metastasis compared to Cdkn2a/b-only deletions. Mechanistically, IFN co-deletion disrupted type I IFN signaling, altered antigen-presenting cells, and facilitated escape from CD8+ T cell surveillance in a cell extrinsic manner requiring loss of interferon epsilon (Ifne). Our results establish co-deletions of the IFN cluster as a pervasive route to tumor immune evasion and metastasis, revealing how deletions can disable physically linked cell intrinsic and extrinsic tumor suppression. Our study establishes a framework to dissect the functions of genomic deletions in cancer and beyond.
Phylogeography and transmission ofM. tuberculosisspanning prisons and surrounding communities in Paraguay
Authors: Sanabria Gladys Estigarribia , Sequera Guillermo , Aguirre Sarita , Méndez Julieta , dos Santos Paulo César Pereira , Gustafson Natalie Weiler , Ortiz Analía , Cespedes Cynthia , Martínez Gloria , García-Basteiro Alberto L. , Andrews Jason R. , Croda Julio , Walter Katharine S. 
Published: August 2022

AbstractRecent rises in incident tuberculosis (TB) cases in Paraguay and the increasing concentration of TB within prisons highlight the urgency of targeting strategies to interrupt transmission and prevent new infections. However, whether specific cities or carceral institutions play a disproportionate role in transmission remains unknown. We conducted prospective genomic surveillance, sequencing 471M. tuberculosisgenomes, from inside and outside prisons in Paraguay’s two largest urban areas, Asunción and Ciudad del Este, from 2016 to 2021. We found genomic evidence of frequent recent transmission within prisons and transmission linkages spanning prisons and surrounding populations. We identified a signal of frequentM. tuberculosisspread between urban areas and marked recent population size expansion of the three largest genomic transmission clusters. Together, our findings highlight the urgency of strengthening TB control programs to reduce transmission risk within prisons, where, in Paraguay, incidence was 70 times that outside prisons in 2021.Financing agenciesNational Institutes of Health grants R01 AI130058 (JRA) and R01 AI149620 (JRA and JC). Paraguay National Commission of Science and Technology grant CONACYT PIN 15-705 (GES and GS).
Air filtration mitigates aerosol levels both during and after OGD procedures
Authors: Phillips Frank , Crowley Jane , Warburton Samantha , Parra-Blanco Adolfo , Gordon George S.D. 
Published: August 2022

AbstractObjectivesUpper GI endoscopies are aerosol generating procedures (AGPs), increasing risk of spreading airborne pathogens. We aim to quantify mitigation of airborne particles via improved ventilation, specifically laminar flow theatres and portable HEPA filters, during and after upper GI endoscopies.MethodsThis observational study included patients undergoing routine oral gastroscopy in a standard endoscopy room with 15-17 air changes per hour, a standard endoscopy room with portable HEPA filtration unit, and a laminar flow theatre with 300 air changes per hour. A particle counter (diameter range 0.3µm-25µm) took measurements 10cm from the mouth. Three analyses were performed: whole procedure particle counts, event-based counts and air clearance estimation using post-procedure counts.ResultsCompared to a standard endoscopy room, for whole procedures we observe a 28.5x reduction in particle counts in laminar flow (p<0.001) but no significant effect of HEPA filtration (p=0.50). For event analysis we observe for lateral flow theatres reduction in particles >5µm for oral extubation (12.2x, p<0.01), reduction in particles <5µm for coughing/gagging (6.9x, p<0.05) and reduction for all sizes in anaesthetic throat spray (8.4x, p<0.01) but no significant effect of HEPA filtration. However, we find that in the fallow period between procedures HEPA filtration reduces particle clearance times by 40%.ConclusionsLaminar flow theatres are highly effective at dispersing aerosols immediately after production and should be considered for high-risk cases where patients are actively infectious or supply of PPE is limited. Portable HEPA filers can safely reduce fallow time between procedures by 40%.
Self-Management of Diabetic Patients from the Urban Areas in Bangladesh
Authors: Hossain Md. Jubayer , Towhid Syeda Tasneem , Akter Sumona , Shahjahan Muhibullah , Roy Tilottoma , Akter Bithi , Nodee Tanjum Ahmed 
Published: August 2022

AbstractBackgroundThis study aimed to determine the knowledge about self-management and the effects of diabetes on the daily activities among adult patients with Type 1 and Type 2 diabetes in Bangladesh.MethodologyA cross-sectional study was conducted from April to August 2021 on diabetic patients from Dhaka and the Rangpur district in Bangladesh. A structured questionnaire was used to collect data from study participants. This study’s researchers collected data via phone interview. The collected data was analyzed using Python (Version 3.8), Pandas, and ResearchPy (A Python package for research data analysis).ResultsOut of the 303 participants, all are middle-class service holders with an urban sedentary lifestyle. 69.64% and 30.3% are male and female, respectively, with 66% having post-secondary education and 35% having smoking habits. Most (68.32%) had onset of diabetic symptoms between 36-50 years, 23.43% with Type I and 41.9% with Type II diabetes. However, 34.65% of participants couldn’t answer about their ailment definitively. 22.44% of participants were on regular insulin shots within 3 months of the first diagnosis, and 90% were satisfied with managing diabetes. However, 54.46% admitted to adopting an altered lifestyle after becoming diabetic. Males and females with both types of diabetes showed significantly different comorbidities in a paired 2-tailed t-test (0.012 and 0.02 for Type I and Type II, respectively). The male participants showed higher incidences of cardiac issues, while females showed a higher propensity to hypertension. 85% of participants were confident about their medication, course of management, prognosis, diet, and lifestyle for controlling diabetes.ConclusionsThe disparity in the number of male and female participants and the high percentage of participants with no factual information about their prognosis need to be targeted for further study, and a patient-friendly engagement/ information dissemination action plan should be helpful.
Use of human albumin solution in a secondary hospital: an observational, retrospective, cross-sectional study
Authors: Rodriguez Mauriz Rosa , Monzó Patricia , Rudi Sola Nuria , Villagrasa Ares , Borràs Trias Laura 
Published: August 2022

ABSTRACTHuman albumin solution (HAS) is a plasma-derived product used for a wide variety of clinical indications, although only some of these are supported by solid scientific evidence.ObjectivesThe primary aim of this study was to analyze the level of evidence supporting the clinical indications for which HAS is used at a secondary care hospital. Secondary objectives were to evaluate dosing appropriateness and perform a subanalysis of the internal medicine department.MethodsRetrospective, observational, multidisciplinary study of adults who received at least one dose of HAS during 2019. We analyzed sociodemographic, clinical, laboratory, and pharmacotherapy variables. The indications for which HAS was used were classified into the four evidence-based categories established by the American Society for Apheresis: high priority (category I), reasonable evidence (II), weak evidence (III), and treatment not recommended (IV). Clinical guideline recommendations were used to evaluate dosing appropriateness.ResultsThe study population comprised 142 patients (41% women), mean (SD) age of 66 (14) years. The main admission diagnoses were decompensated cirrhosis (32%) and septic shock (31%). In total, 223 courses of HAS were prescribed. The main indications were treatment of anasarca and hypoalbuminemia (32%), prevention of paracentesis-induced circulatory dysfunction after large-volume paracentesis (17%), resuscitation in septic shock (13%), and treatment of protein malnutrition (9%). Just 26% of hospital-wide indications were supported by strong evidence (category I); 13% category II, 8% category III, and 53% category IV. In the internal medicine department, 36% of indications were in category I, 16% in category III, 48% in category IV. An appropriate dosing regimen was used in just four category I indications.ConclusionsA large proportion of HAS indications at our hospital are supported by weak evidence. Training to promote the rational use of HAS is needed. Protocols and local clinical guidelines could help standardize and optimize its use.
Isoform-level transcriptome-wide association uncovers extensive novel genetic risk mechanisms for neuropsychiatric disorders in the human brain
Authors: Bhattacharya Arjun , Vo Daniel D. , Jops Connor , Kim Minsoo , Wen Cindy , Hervoso Jonatan L. , Pasaniuc Bogdan , Gandal Michael J. 
Published: August 2022

ABSTRACTIntegrative methods, like colocalization and transcriptome-wide association studies (TWAS), identify transcriptomic mechanisms at only a fraction of trait-associated genetic loci from genome-wide association studies (GWAS). Here, we show that a reliance on reference functional genomics panels of only total gene expression greatly contributes to this reduced discovery. This is particularly relevant for neuropsychiatric traits, as the brain expresses extensive, complex, and unique alternative splicing patterns giving rise to multiple genetically-regulated transcript-isoforms per gene. Integrating highly correlated transcript-isoform expression with GWAS requires methodological innovations.We introduce isoTWAS, a multivariate framework to integrate genetics, isoform-level expression, and phenotypic associations in a step-wise testing framework, and evaluate it using data from the Genotype-Tissue Expression (GTEx) Project, PsychENCODE Consortium, and other sources. isoTWAS shows three main advantages. First, joint, multivariate modeling of isoform expression fromcis-window SNPs improves prediction by ∼1.8-2.4 fold, compared to univariate modeling. Second, compared to gene-level TWAS, these improvements in prediction lead to ∼1.9-2.5-fold increase in the number of testable genes and a median of 25-70% increase in cross-validated prediction of total gene expression, with the added ability to jointly capture expression and splicing mechanisms. In external validation, isoform-centric models predicted gene expression at percent variance explained >1% for 50% more genes than gene-centric models. Third, across 15 neuropsychiatric traits, isoTWAS increased discovery of trait associations within GWAS loci over TWAS, capturing ∼60% more unique loci and 95% of loci detected by TWAS. Results from extensive simulations showed no increase in false discovery rate and reinforce isoTWAS’s advantages in prediction and trait mapping power over TWAS, especially when genetic effects on expression vary across isoforms of the same gene. We illustrate multiple biologically-relevant isoTWAS-identified trait associations undetectable by gene-level methods, including isoforms ofAKT3,CUL3, andHSPD1with schizophrenia risk, andPCLOwith multiple disorders.The isoTWAS framework addresses an unmet need to consider the transcriptome on the transcript-isoform level to increase discovery of trait associations, especially for brain-relevant traits.
A Census of Clinical Trials Conducted Under the US Exception from Informed Consent Rule
Authors: Snyder Krista L. , Merz Jon F. 
Published: August 2022

AbstractBackgroundThe US Food and Drug Administration and National Institutes of Health adopted the Exception from Informed Consent (EFIC) rule in 1996, permitting waiver of informed consent for certain emergency research, including trials funded by the federal government. The rule requires that prospective consent be sought when practicable from patients or their Legally Authorized Representative(s) (LAR), and for those enrolled without consent, the patient or their LAR must be given information and an opportunity to opt-out from continued participation at the earliest opportunity. We sought to census the trials conducted under the EFIC rule to facilitate research to better understand how the rule is being used.MethodsWe conducted a multi-pronged search to try and identify all trials conducted under the EFIC rule, drawing on numerous reviews, Medline and Google searches (including of theclinicaltrials.govregistry), examination of the FDA’s docket, posting an inquiry on the IRB Forum, and email requests to lead authors of all published EFIC trials and related review articles. We describe the trials, when they were started and completed, and whether they were terminated early.ResultsWe identified a total of 105 trials as of April 1, 2022: 77 complete, 10 recruiting, 10 registered onclinicaltrials.govbut not yet recruiting, 5 trials that were abandoned before enrolling any subjects, and 3 trials in early planning. Nine of the 77 completed trials were pilot or feasibility trials. Of 68 completed full trials, 30 (44.1%) were terminated early. The most common reason for early termination was futility or safety (17 trials, 25.0%) followed by poor recruitment (9 trials, 13.2%). The rate of conduct of trials has been remarkably constant since 2001, with roughly 18 trials started in each 5-year period.ConclusionsThe rate of early termination of EFIC trials for futility or safety appears higher than for other kinds of clinical research. We provide the list of trials in a Supplement for further in-depth data collection and analysis of this set of trials.
Correlated variation between the splanchnocranium and basicranium in the Toy rabbit
Authors: Parés-Casanova Pere M. 
Published: August 2022

AbstractThe aim of this study was to explore and compare patterns of morphological covariation, including symmetrical deviations, between splanchnocranium and the basicranium in Toy rabbit, a type of paedomorphic rabbit. A sample of 32 skulls of adult Toy rabbits was studied on digital pictures on ventral aspects by means of geometric morphometric methods. A set of 7 landmarks were located on the horizontal plane of the splanchnocranial ventral bones (palatine process of the maxillary bone [processus palatinus maxillae] + palatine bone [lamina horizontalis ossis palatini]), and a set of 8 landmarks were on the basicranium (sphenoid [os sphenoidale] + basilar part of the occipital bone [pars basilaris] + bulla tympanica). Both fluctuating and directional asymmetries were detected on both blocks, being the asymmetry more important among splanchnocranial bones. It appeared also a significant relationship (allometry) between size and shape, especially in the basicranium, as well a significant relationship between the two blocks. From results we deduce that, although normally cranial base usually reaches adult size before the face, in paedomorphic animals the face stops its growth earlier than basicranium, resulting in their proportionally reduced splanchnocranium, the typical brachyfacial morphology for paedomorphy. In other words, our results support the hypothesis of an early stop of facial pattern development in neoteny -the retention of juvenile characteristics into adulthood-, which can affect vital structures. So, further research should expand on clinical data of paedomorphic animals in order to advance in the understanding of pathological results of this growth anomaly.
Development of an adenosquamous carcinoma histopathology-selective lung cancer graft model
Authors: Lähdeniemi I.A.K. , Devlin J.R. , Nagaraj A.S. , Talwelkar S.S. , Bao J. , Linnavirta N. , Şeref Vujaklija C. , Kiss E.A. , Hemmes A. , Verschuren E.W. 
Published: August 2022

AbstractPreclinical tumor models with native tissue microenvironments provide essential tools to understand how heterogeneous tumor phenotypes relate to drug response. Here, we present syngeneic graft models of aggressive, metastasis-prone histopathology-specific NSCLC tumor types driven by KRAS mutation and loss of LKB1 (KL): adenosquamous carcinoma (ASC) and adenocarcinoma (AC). We show that subcutaneous injection of primary KL-ASC cells results in squamous cell carcinoma (SCC) tumors with high levels of stromal infiltrates, lacking the source heterogeneous histotype. Despite forming subcutaneous tumors, intravenously injected KL-AC cells were unable to form lung tumors. In contrast, intravenous injection of KL-ASC cells leads to their lung re-colonization and lesions recapitulating the mixed AC and SCC histopathology, tumor immune suppressive microenvironment and oncogenic signaling profile of source tumors, demonstrating histopathology-selective phenotypic dominance over genetic drivers. Pan-ERBB inhibition increased survival, while selective ERBB1/EGFR inhibition did not, suggesting a role of ERBB network crosstalk in resistance to ERBB1/EGFR. This immunocompetent NSCLC lung colonization model hence phenocopies key properties of the metastasis-prone ASC histopathology, and serves as a preclinical model to dissect therapy responses and metastasis-associated processes.
A cosmic view of ‘tundra gardens’: satellite imagery provides a landscape-scale perspective of Arctic fox ecosystem engineering
Authors: Johnson-Bice Sean M. , Roth James D. , Markham John H. 
Published: August 2022

AbstractAnimal ecology has benefitted greatly from advancements in remote sensing technology and data availability in recent decades. Most animal ecology studies using remote sensing data have focused on assessing how environmental characteristics shape animal abundance, distribution, or behavior. But the growing availability of high-resolution remote sensing data offers new opportunities to study how animals, in turn, shape ecosystems. We use high-spatiotemporal resolution Sentinel-2 satellite imagery to evaluate the effects of Arctic fox (Vulpes lagopus) denning activity on vegetation. Arctic fox dens are characterized with unique vegetation relative to the surrounding area, presumably due to decades of nutrient accumulation and bioturbation. We use an imagery-derived metric (NDVI) to compare maximum plant productivity and plant phenology patterns on Arctic fox dens vs. reference sites, i.e., points generated within areas of preferred denning habitat as predicted from a habitat selection analysis. We show that high-resolution satellite imagery can be used effectively to quantify the effects of Arctic fox denning activity on vegetation. Plant productivity and the rate of green up were both greater on fox dens compared to reference sites. Productivity on these preferred-habitat (reference) sites was lower than average productivity on the tundra (i.e., random sites), indicating that foxes primarily establish dens in low-productivity areas. Our findings support previous studies that proposed Arctic foxes function as ecosystem engineers in low Arctic ecosystems by converting sites of low productivity into sites of high productivity through their denning activity. Plant productivity was unrelated to recent den occupancy patterns, indicating fox denning activity has long-term legacy effects on plants that last well beyond the lifetime of foxes. We add to the growing body of literature that recognizes predators can be drivers of landscape heterogeneity and influence ecosystem dynamics through patch-scale pathways, such as by concentrating nutrients into localized areas. Our study demonstrates the efficacy of using remote sensing technologies to advance our understanding of the functional roles that predators specifically, and animals generally, occupy in ecosystems.
Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan
Authors: Grzegorzewski Jan , Brandhorst Janosch , König Matthias 
Published: August 2022

ABSTRACTThe cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of DXM and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as described by the AS system, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping using the urinary cumulative metabolic ratio (UCMR), DXM/(DXO+DXO-Glu). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.