bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decomposition of phenotypic heterogeneity in autism reveals distinct and coherent genetic programs
Authors: Litman Aviya , Sauerwald Natalie , Snyder LeeAnne Green , Foss-Feig Jennifer , Park Christopher Y. , Hao Yun , Dinstein Ilan , Theesfeld Chandra L. , Troyanskaya Olga G. 
Published: August 2024

AbstractUnraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory, and clinical manifestations of the many forms of the condition. Here, we leveraged broad phenotypic data from a large cohort with matched genetics to characterize classes of autism and their patterns of core, associated, and co-occurring traits, ultimately demonstrating that phenotypic patterns are associated with distinct genetic and molecular programs. We used a generative mixture modeling approach to identify robust, clinically-relevant classes of autism which we validate and replicate in a large independent cohort. We link the phenotypic findings to distinct patterns ofde novoand inherited variation which emerge from the deconvolution of these genetic signals, and demonstrate that class-specific common variant scores strongly align with clinical outcomes. We further provide insights into the distinct biological pathways and processes disrupted by the sets of mutations in each class. Remarkably, we discover class-specific differences in the developmental timing of genes that are dysregulated, and these temporal patterns correspond to clinical milestone and outcome differences between the classes. These analyses embrace the phenotypic complexity of children with autism, unraveling genetic and molecular programs underlying their heterogeneity and suggesting specific biological dysregulation patterns and mechanistic hypotheses.
A Modeling Analysis on Eliminating Racial/Ethnic Disparities in HIV Incidence in the United States
Authors: Jacobson Evin Uzun , Viguerie Alex , Bates Laurel , Hicks Katherine , Honeycutt Amanda A. , Carrico Justin , Lyles Cynthia , Farnham Paul G. 
Published: August 2024

AbstractBackgroundDespite progress in HIV prevention and treatment, resulting in overall incidence reductions in the United States, large racial/ethnic (r/e) disparities in HIV incidence remain due to stigma, discrimination, racism, poverty, and other social and structural factors.SettingWe used the HIV Optimization and Prevention Economics (HOPE) model to analyze which intervention strategies provide the most effective path towards eliminating r/e disparities in HIV incidence.MethodsWe considered four intervention scenarios for 2023-2035, which focused on eliminating r/e disparities by 2027 in the HIV care continuum only, HIV prevention services only, both continuum and prevention services, and a final scenario where prevention and care levels for Black and Hispanic/Latino were set to maximum feasible levels. The primary outcome is the incidence-rate-ratio (IRR) for Black and Hispanic/Latino populations compared to Other populations (of whom 89% are White) with the goal of IRRs ≤ 1 by 2035.ResultsAll scenarios reduced IRRs but onlyMaximum Feasibleeliminated HIV incidence disparities by 2035, with respective IRRs of 0.9 and 1.1 among the Black and Hispanic/Latino populations, compared to 6.5 and 4.1 in the baseline scenario.Continuum-onlywas more effective at reducing disparities (2035 IRRs of 4.7 for Black and 3.1 for Hispanic/Latino populations) thanPrevention-only(6.1 and 3.7 respectively).ConclusionsWith no prioritized changes, our simulation showed that r/e disparities in HIV incidence persist through 2035. Elimination of r/e incidence disparities by 2035 is only possible if maximum HIV prevention and care levels for Black and Hispanic/Latino populations can be realized by 2027.
The diagnostic value of plasma phosphorylated tau 181 in Alzheimer’s disease within the Chinese population: A systematic review and meta-analysis
Authors: Yan Keqiang , He Shuxin , Jia Xiaodong , Li Haiyan , Liu Dequan , Chen Jianchun 
Published: August 2024

AbstractAmong all related biomarkers, plasma phosphorylated tau (p-tau181) has demonstrated strong diagnostic performance in the very early stages of Alzheimer’s disease (AD), showing significant differences between AD patients and healthy controls. The aim of our present systematic review and meta-analysis was to roundly evaluate the clinical diagnostic value of plasma p-tau181 based on the Simoa platform in Chinese populations. We systematically searched five databases (Embase, PubMed, Cochrane Library, MEDLINE, and Web of Science) from inception to May 11th, 2024, as well as the references of retrieved relevant articles. We included prospective cohort studies and retrospective case-control studies in our analysis. Out of 1165 identified articles, 10 met the inclusion criteria for meta-analysis. Our quantitative analysis showed that plasma p-tau181 levels were significantly increased in patients with AD and mild cognitive impairment (MCI) compared to healthy controls (standard mean difference [SMD]: 1.45 [1.25 – 1.65], p<0.00001; SMD: 0.55 [0.31 – 0.78], p<0.00001) and were lower in MCI patients compared to AD patients (SMD: -0.88 [-0.93 – -0.82], p<0.00001). The reference values for plasma p-tau181 were 4.48 [95% confidence interval (CI): 4.01 – 5.00] for AD patients, 2.86 [95% CI: 2.45 – 3.34] for MCI patients, and 2.09 [95% CI: 1.90 – 2.30] for healthy controls. The meta-analysis confirmed that plasma p-tau181 significantly increases from healthy controls to mild cognitive impairment (MCI) and then to AD in the Chinese population. We also provide reliable reference values for plasma p-tau181, which contribute to the early diagnosis of AD in Chinese clinical settings.
Reimagining Cryptogenic Stroke Care: Collaborative Care and Inpatient Insertable Cardiac Monitors for Detection of Atrial Fibrillation
Authors: Herial Nabeel A. , Frisch Daniel R. , Miller Elan , Patel Priyadarshee , Munoz Alfredo , Warren Melissa , Khalife Jane , Majmundar Shyam , Farkas Nathan , Alam Shaista , Dharia Robin , Tzeng Diana , Pavri Behzad B. , Ho Reginald T. , Greenspon Arnold , Bell Rodney , Jabbour Pascal , Rosenwasser Robert 
Published: August 2024

AbstractBackgroundAtrial fibrillation (AF) is a known risk factor of ischemic stroke and AF-related stroke is twice more likely to be fatal. Long-term cardiac rhythm monitoring using insertable cardiac monitors (ICMs) has greater diagnostic yield compared to conventional monitoring in detecting AF, and clinical utility of ICMs is established in cryptogenic stroke, strokes due to large artery atherosclerosis and small vessel disease. A registry-based study was conducted to evaluate inpatient implantation of ICMs and feasibility of vascular and interventional neurologists as implanters using novel collaborative clinical care pathway for cryptogenic stroke.MethodsMultiyear data from a hospital-based registry at a comprehensive stroke center was reviewed to evaluate inpatient ICM implantation and test feasibility of vascular and interventional neurologists/VIN as implanters of ICMs together with cardiology using a novel collaborative care pathway. Reviewed data included number of ICMs, implantation trend, inpatient vs. outpatient setting, time to ICM implantation, inpatient workflow including defined roles of team members, and AF detection rate.ResultsTotal of 290 ICMs for cryptogenic stroke were implanted when patients where in the hospital and 78 as outpatient after discharge during the study period of 3 years. The majority of inpatient ICM implants were performed by VIN (n=181) and ICM use for cryptogenic stroke increased by 130%. Average time to inpatient ICM implant was 4.1 days with 77% in 5 and 95.5% within 10 days post-stroke. Average time to out-patient ICM placement was 57 days. AF detection rate of 36.5% was noted at 24 months with a collaborative care pathway.DiscussionInpatient implantation of ICMs is feasible and was performed safely and efficiently by VIN together with cardiology using a collaborative care pathway. Increase in utilization of ICMs and higher AF detection rates were noted. Findings support innovative efforts to improve access and close the gaps in delivery of cryptogenic stroke care to ultimately reduce the secondary stroke burden.Clinical PerspectiveDirect inpatient implantation of ICMs in cryptogenic stroke allows increased rates of early long-term cardiac rhythm monitoring and detection of AF.Collaborative clinical practice with inpatient ICM implantation by vascular and interventional neurologists is feasible and safe. This novel approach could potentially increase access to cardiac rhythm monitoring and exemplify patient-centered care.
Comparison of the results of in-person and mobile phone surveys for a health facility assessment in Tajikistan: a validation study protocol
Authors: Fernandez Pablo Amor , Neill Rachel , Bhatia Ruchika , Sharma Jigyasa , Andrews Kathryn , Neelsen Sven , Pinder Etoile , Abdullaev Marifat , Safarova Firuza , Latypova Mutriba , Sjoblom Mirja Channa , Ahmed Tashrik , Peters Michael A. , Sheffel Ashley , Hashemi Tawab , Hansen Peter Meredith , Muhsinzoda Gafur , Shapira Gil 
Published: August 2024

ABSTRACTHealth facility assessments provide important data to measure the quality of health services delivered to populations. These assessments are comprehensive, resource intensive, and periodic to inform medium-to-longer-term policies. However, in absence of other reliable data sources, country decision makers often rely on outdated data to address service delivery challenges that change more frequently. High-frequency phone surveys are a potential option to improve the efficiency and timeliness of collecting time-sensitive service delivery indicators in-between comprehensive in-person assessments. The objectives of this study are to assess the reliability, concurrent criterion validity, and non-response rates in a rapid phone-based health facility assessment developed by the Global Financing Facility’s FASTR initiative compared to a comprehensive in-person health facility assessment developed by the World Bank’s Service Delivery Indicators Health Program. The in-person survey and corresponding in-person item verification will serve as the gold standard. Both surveys will be administered to an identical sample of 500 health facilities in Tajikistan using the same data collection entity. To assess reliability, percent agreement, Cohens Kappa, and prevalence and bias adjusted Kappa will be calculated. To assess concurrent criterion validity, sensitivity and specificity will be calculated, with a cut-off of .7 used for adequate validity. The study will further compare response rates and dropout rates of both surveys using simple t-tests and balance tests to identify if the characteristics of the phone-based and in-person survey samples are similar after accounting for any differences in survey response rates. The results of this study will provide important insights into the reliability and validity of phone-based data collection approaches for health facility assessments. This is critical as Ministries of Health seek to establish and sustain more continuous data collection, analysis, and use of health facility-level data to complement periodic in-person assessments to improve the quality of services provided to their populations.
Predicting the global economic costs of biological invasions by tetrapods
Authors: Bodey Thomas W , Cuthbert Ross N. , Diagne Christophe , Marino Clara , Turbelin Anna , Angulo Elena , Fantle-Lepczyk Jean , Pincheira-Donoso Daniel , Courchamp Franck , Hudgins Emma J 
Published: August 2024

AbstractGlobalisation has steadily accelerated rates of biological invasions worldwide, leading to widespread environmental perturbations that often translate into rapidly expanding socioeconomic costs. Although such monetary costs can be estimated based on the observed effects of invasions, the pathways that lead invasive species to become economically impactful remain poorly understood. Here, we implement the first global-scale test of the hypothesis that adaptive traits that influence demographic resilience predict economic costs, using invasive terrestrial vertebrates as models given their rising impacts and well-catalogued characteristics. Our results reveal that total global costs of invasive tetrapods are conservatively in the tens of billions of dollars, with the vast majority due to damage costs from invasive mammals. These monetary impacts are predicted by longevity, female maturation age, diet and invasional pathway traits, although the directionality of predicted economic impacts also varied by trait across classes. Alarmingly, costs remain unknown for >90% of recorded established alien tetrapods worldwide, and across the majority of invaded countries. These huge socio-economic costs demonstrate the necessity of mitigating tetrapod invasions and filling knowledge gaps. Effective identification of traits predictive of costs among and within these groups can facilitate the prioritisation of resources to efficiently target the most damaging existing and emerging invasive tetrapod species.
Differences in isotopic compositions of individual grains and aggregated seed samples affect interpretation of ancient plant cultivation practices
Authors: James Nathaniel F. , Winter-Schuh Christine , Kenoyer J. Mark , Guedes Jade D’Alpoim , Makarewicz Cheryl A. 
Published: August 2024

AbstractThe stable carbon (δ13C) and nitrogen (δ15N) isotope analysis of charred archaeological grains provides a remarkably precise scale of information: the growing conditions under which a plant was cultivated in a single field and season. Here we investigate how the measurement of single individual grains or aggregate ‘bulk’ samples for carbon and nitrogen isotopes impacts how we characterize variation and, consequently, our interpretations of ancient cultivation practices. Using experimentally grown barley (Hordeum vulgarevar.nudum), this work investigates δ13C and δ15N intra-panicle variation between both uncharred and charred individual grains from four plants. We found limited intra- and inter-panicle isotopic variation in single grain isotope values, ca. 0.5‰ in δ13C and ca. 1‰ in δ15N, reemphasizing the degree to which grains are representative of their local growing conditions. To explore the interpretive impact of aggregate versus single-grain isotopic sampling, we measured charred barley recovered from a single storage context excavated from Trench 42 (ca. 1900 BCE) at Harappa. Aggregate samples of a random selection of Trench 42 barley demonstrated remarkable inter-sample homogeneity, with a less than 0.5‰ difference in δ13C and δ15N values, reinforcing the ability of aggregate samples to capture a representative isotopic average of a single depositional context. However, the measurement of single-grains revealed moderate 2–3‰ variation in δ13C, and an outstandingly wide isotopic variation of ca. 8‰ in δ15N values, indicating the degree to which cultivation practices varied beyond what the bulk samples indicated. These results highlight how decisions in the selection and measurement of archaeological grains for isotopic analysis impact data resolution, with profound consequences for understanding past agricultural diversity.
Investigation of cell mechanics and migration on DDR2-expressing neuroblastoma cell line
Authors: Vessella Theadora , Rozen Esteban , Shohet Jason , Wen Qi , Zhou Hong Susan 
Published: August 2024

AbstractNeuroblastoma is a devastating disease accounting for ~15% of all childhood cancer deaths. Collagen content and fiber association within the tumor stroma influence tumor progression and metastasis. High expression levels of collagen receptor kinase, Discoidin domain receptor II (DDR2), are associated with poor survival of neuroblastoma patients. Additionally, cancer cells generate and sustain mechanical forces within their enviroment as a part of their normal physiology. Despite this, whether collagen activated DDR2 signaling dysregulate these migration forces is still elusive. To address these questions, a shRNA DDR2 knockdown neuroblastoma cell line (SH-SY5Y) was engineered to evaluate the consequence of DDR2 on cellular mechanics. Atomic force microscopy and traction force microscopy were utlizing to unveil the biophysical altercations. DDR2 down-regulation was found to significantly reduce proliferation, cell stiffness, and cellular elongation. Aditionally, DDR2 down-regulated cells had decreased traction forces when plated on collagen coated elastic substrates. Together, these results highlight the important role that DDR2 has in reducing migration mechanics in neuroblastoma and might be a promising target for future therapies.
Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models
Authors: Chin Marcus Y. , Joy David A. , Samaddar Madhuja , Rana Anil , Chow Johann , Miyamoto Takashi , Calvert Meredith 
Published: August 2024

AbstractMitochondria undergo dynamic morphological changes depending on cellular cues, stress, genetic factors, or disease. The structural complexity and disease-relevance of mitochondria have stimulated efforts to generate image analysis tools for describing mitochondrial morphology for therapeutic development. Using high-content analysis, we measured multiple morphological parameters and employed unbiased feature clustering to identify the most robust pair of texture metrics that described mitochondrial state. Here, we introduce a novel image analysis pipeline to enable rapid and accurate profiling of mitochondrial morphology in various cell types and pharmacological perturbations. We applied a high-content adapted implementation of our tool, MitoProfilerHC, to quantify mitochondrial morphology changes in i) a mammalian cell dose response study and ii) compartment-specific drug effects in primary neurons. Next, we expanded the usability of our pipeline by using napari, a Python-powered image analysis tool, to build an open-source version of MitoProfiler and validated its performance and applicability. In conclusion, we introduce MitoProfiler as both a high-content-based and an open-source method to accurately quantify mitochondrial morphology in cells, which we anticipate to greatly facilitate mechanistic discoveries in mitochondrial biology and disease.
Allosteric Regulation of Pyruvate Kinase Enables Efficient and Robust Gluconeogenesis by Preventing Metabolic Conflicts and Carbon Overflow
Authors: She Fukang , Anderson Brent W. , Khana Daven B. , Zhang Shenwei , Steinchen Wieland , Fung Danny K. , Lucas Lauren N. , Lesser Nathalie G. , Stevenson David M. , Astmann Theresa J. , Bange Gert , van Pijkeren Jan-Peter , Amador-Noguez Daniel , Wang Jue D. 
Published: August 2024

AbstractGlycolysis and gluconeogenesis are reciprocal metabolic pathways that utilize different carbon sources. Pyruvate kinase catalyzes the irreversible final step of glycolysis, yet the physiological function of its regulation is poorly understood. Through metabolomics and enzyme kinetics studies, we discovered that pyruvate kinase activity is inhibited during gluconeogenesis in the soil bacteriumBacillus subtilis. This regulation involves an extra C-terminal domain (ECTD) of pyruvate kinase, which is essential for autoinhibition and regulation by metabolic effectors. Introducing a pyruvate kinase mutant lacking the ECTD intoB. subtilisresulted in defects specifically under gluconeogenic conditions, including inefficient carbon utilization, slower growth, and decreased resistance to the herbicide glyphosate. These defects are not caused by the phosphoenolpyruvate-pyruvate-oxaloacetate futile cycle. Instead, we identified two significant metabolic consequences of pyruvate kinase dysregulation during gluconeogenesis: increased carbon overflow into the medium and failure to expand glycolytic intermediates such as phosphoenolpyruvate (PEP). In silico analysis revealed that in wild-type cells, an expanded PEP pool enabled by pyruvate kinase regulation is critical for the thermodynamic feasibility of gluconeogenesis. Our findings underscore the importance of allosteric regulation during gluconeogenesis in coordinating metabolic flux, efficient energy utilization, and antimicrobial resistance.
RAF inhibitors activate the integrated stress response by direct activation of GCN2
Authors: Gilley Rebecca , Kidger Andrew M. , Neill Graham , Severson Paul , Byrne Dominic P. , Kenneth Niall S. , Bollag Gideon , Zhang Chao , de Oliveira Taiana Maia , Eyers Patrick A. , Bayliss Richard , Masson Glenn R. , Cook Simon J. 
Published: August 2024

AbstractParadoxical RAF activation by chemical RAF inhibitors (RAFi) is a well-understood ‘on-target’ biological and clinical response. In this study, we show that a range of RAFi drive ERK1/2-independent activation of the Unfolded Protein Response (UPR), including expression of ATF4 and CHOP, that required the translation initiation factor eIF2α. RAFi-induced ATF4 and CHOP expression was not reversed by inhibition of PERK, a known upstream activator of the eIF2α-dependent Integrated Stress Response (ISR). Rather, we found that RAFi exposure activated GCN2, an alternate eIF2α kinase, leading to eIF2α-dependent (and ERK1/2-independent) ATF4 and CHOP expression. The GCN2 kinase inhibitor A-92, GCN2 RNAi, GCN2 knock-out or ISRIB (an eIF2α antagonist) all reversed RAFi-induced expression of ATF4 and CHOP indicating that RAFi require GCN2 to activate the ISR. RAFi also activated full-length recombinant GCN2in vitroand in cells, generating a characteristic ‘bell-shaped’ concentration-response curve, reminiscent of RAFi-driven paradoxical activation of WT RAF dimers. Activation of the ISR by RAFi was abolished by GCN2 kinase dead mutations and M802A or M802G gatekeeper mutations, suggesting that RAFi bind directly to the GCN2 kinase domain; this was supported by mechanistic structural models of RAFi interaction with GCN2. Since the ISR is a critical pathway for determining cell survival or death, our observations may be relevant to the clinical use of RAFi, where paradoxical GCN2 activation may be a previously unappreciated off-target effect that may modulate tumour cell responses.
Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne Muscular Dystrophy
Authors: Novak James S. , Lischin Amy , Uapinyoying Prech , Hindupur Ravi , Moon Young Jae , Bhattacharya Surajit , Tiufekchiev Sarah , Barone Victoria , Mázala Davi A. G. , Gamu Iteoluwakishi H. , Walters Gabriela , Jaiswal Jyoti K. 
Published: August 2024

AbstractAbsence of dystrophin protein causes cardiac dysfunction in patients with Duchenne muscular dystrophy (DMD). Unlike boys with DMD, the common mouse model of DMD (B10-mdx) does not manifest cardiac deficits until late adulthood. This has limited our understanding of the mechanism and therapeutic approaches to target the pediatric onset of cardiac pathology in DMD. Here we show that themdxmouse model on the DBA/2J genetic background (D2-mdx) displays juvenile-onset cardiac degeneration. Molecular and histological analysis revealed that cardiac damage in this model is linked to increased leukocyte chemotactic signaling and an inability to resolve inflammation. These deficiencies result in chronic inflammation and fibrotic conversion of the extracellular matrix (ECM) in the juvenile D2-mdx heart. To address these pathologies, we tested the utility of pro-resolution therapy to clear chronic cardiac inflammation. Use of an N-formyl peptide receptor (FPR) agonist helped physiologically resolve inflammation and mitigate the downstream events that lead to fibrotic degeneration of cardiomyocytes, preventing juvenile onset cardiac muscle loss. These results establish the utility of D2-mdxmodel to study events associated with pediatric-onset cardiac damage and demonstrates pro-resolution therapy as an alternate to anti-inflammatory therapy for treating cardiac degenerative pathology responsible for cardiomyopathy in DMD patients.