Showing papers by "University of Kentucky published in 2021"

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.

Abstract: Background Sepsis poses a global threat to millions of lives. The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications. Methods We formed a panel of 60 experts from 22 countries and 11 members of the public. The panel prioritized questions that are relevant to the recognition and management of sepsis and septic shock in adults. New questions and sections were addressed, relative to the previous guidelines. These questions were grouped under 6 subgroups (screening and early treatment, infection, hemodynamics, ventilation, additional therapies, and long-term outcomes and goals of care). With input from the panel and methodologists, professional medical librarians performed the search strategy tailored to either specific questions or a group of relevant questions. A dedicated systematic review team performed screening and data abstraction when indicated. For each question, the methodologists, with input from panel members, summarized the evidence assessed and graded the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The panel generated recommendations using the evidence-to-decision framework. Recommendations were either strong or weak, or in the form of best practice statements. When evidence was insufficient to support a recommendation, the panel was surveyed to generate “in our practice” statements. Results The SSC panel issued 93 statements: 15 best practice statements, 15 strong recommendations, and 54 weak recommendations and no recommendation was provided for 9 questions. The recommendations address several important clinical areas related to screening tools, acute resuscitation strategies, management of fluids and vasoactive agents, antimicrobials and diagnostic tests and the use of additional therapies, ventilation management, goals of care, and post sepsis care. Conclusion The SSC panel issued evidence-based recommendations to help support key stakeholders caring for adults with sepsis or septic shock and their families.

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1 In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals) These rare variants provide insights into mutational processes and recent human evolutionary history The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 001% The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history

Reactive astrocyte nomenclature, definitions, and future directions

Abstract: Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021.

Abstract: Background Sepsis poses a global threat to millions of lives. The Surviving Sepsis Campaign (SSC) guidelines provide evidence-based recommendations on the recognition and management of sepsis and its complications. Methods We formed a panel of 60 experts from 22 countries and 11 members of the public. The panel prioritized questions that are relevant to the recognition and management of sepsis and septic shock in adults. New questions and sections were addressed, relative to the previous guidelines. These questions were grouped under 6 subgroups (screening and early treatment, infection, hemodynamics, ventilation, additional therapies, and long-term outcomes and goals of care). With input from the panel and methodologists, professional medical librarians performed the search strategy tailored to either specific questions or a group of relevant questions. A dedicated systematic review team performed screening and data abstraction when indicated. For each question, the methodologists, with input from panel members, summarized the evidence assessed and graded the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The panel generated recommendations using the evidence-to-decision framework. Recommendations were either strong or weak, or in the form of best practice statements. When evidence was insufficient to support a recommendation, the panel was surveyed to generate “in our practice” statements. Results The SSC panel issued 93 statements: 15 best practice statements, 15 strong recommendations, and 54 weak recommendations and no recommendation was provided for 9 questions. The recommendations address several important clinical areas related to screening tools, acute resuscitation strategies, management of fluids and vasoactive agents, antimicrobials and diagnostic tests and the use of additional therapies, ventilation management, goals of care, and post sepsis care. Conclusion The SSC panel issued evidence-based recommendations to help support key stakeholders caring for adults with sepsis or septic shock and their families.

Political Beliefs affect Compliance with Government Mandates

Abstract: We use the state-mandated stay-at-home orders during the coronavirus pandemic as a setting to study whether political beliefs inhibit compliance with government orders. Using geolocation data sourced from smartphones, we find residents in Republican counties are less likely to completely stay at home after a state order has been implemented relative to those in Democratic counties. Debit card transaction data shows that Democrats are more likely to switch to remote spending after state orders are implemented. Heterogeneity in factors such as Covid-19 risk exposure, geography, and county characteristics do not completely rule out our findings, suggesting political beliefs are an important determinant in the effectiveness of government mandates. Political alignment with officials giving orders may partially explain these partisan differences.

Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective: 2021 Update.

Abstract: A growing number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation also have atrial fibrillation. This poses challenges for their optimal antithrombotic management because patients with atrial fibrillation undergoing PCI require oral anticoagulation for the prevention of cardiac thromboembolism and dual antiplatelet therapy for the prevention of coronary thrombotic complications. The combination of oral anticoagulation and dual antiplatelet therapy substantially increases the risk of bleeding. Over the last decade, a series of North American Consensus Statements on the Management of Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention have been reported. Since the last update in 2018, several pivotal clinical trials in the field have been published. This document provides a focused updated of the 2018 recommendations. The group recommends that in patients with atrial fibrillation undergoing PCI, a non-vitamin K antagonist oral anticoagulant is the oral anticoagulation of choice. Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should be given to all patients during the peri-PCI period (during inpatient stay, until time of discharge, up to 1 week after PCI, at the discretion of the treating physician), after which the default strategy is to stop aspirin and continue treatment with a P2Y12 inhibitor, preferably clopidogrel, in combination with a non-vitamin K antagonist oral anticoagulant (ie, double therapy). In patients at increased thrombotic risk who have an acceptable risk of bleeding, it is reasonable to continue aspirin (ie, triple therapy) for up to 1 month. Double therapy should be given for 6 to 12 months with the actual duration depending on the ischemic and bleeding risk profile of the patient, after which patients should discontinue antiplatelet therapy and receive oral anticoagulation alone.

Less Sex, but More Sexual Diversity: Changes in Sexual Behavior during the COVID-19 Coronavirus Pandemic

Abstract: Recreational sex is a popular form of leisure that has been redefined by the COVID-19 (coronavirus) pandemic “Social distancing” rules have imposed limits on sex for leisure while also creating ne

Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease.

Abstract: Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

Modification of plant proteins for improved functionality: A review

Abstract: The market trend towards plant-based protein has seen a significant increase in the last decade. This trend has been projected to continue in the coming years because of the strong factors of sustainability and less environmental impact associated with the production of plant-based protein compared to animal, aside from other beneficial health claims and changes in consumers' dietary lifestyles. In order to meet market demand, there is a need to have plant-based protein ingredients that rival or have improved quality and functionality compared to the traditional animal protein ingredients they may replace. In this review article, we present a detailed and concise summary of the functionality challenges of some plant protein ingredients with associated physical, chemical, and biological processing techniques (traditional and emerging technologies) that have been attempted to enhance them. We cataloged the differences between several studies that seek to address the functionality challenges of selected plant-based protein ingredients without overtly commenting on a general technique that addresses the functionality of all plant-based protein ingredients. Additionally, we elucidated the chemistry behind some of these processing techniques and how they modify the protein structure for improved functionality. Although, many food industries are shifting away from chemical modification of proteins because of the demand for clean label product and the challenge of toxicity associated with scale-up of this technique, so physical and biological techniques are widely being adopted to produce a functional ingredient such as texturized vegetable proteins, hydrolyzed vegetable protein, clean label protein concentrates, de-flavored protein isolates, protein flour, and grits.

Metastable Dion-Jacobson 2D structure enables efficient and stable perovskite solar cells.

Abstract: The performance of three-dimensional (3D) organic-inorganic halide perovskite solar cells (PSCs) can be enhanced by surface treatment with 2D layered perovskites that have efficient charge transpor...

Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions.

Abstract: Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits. This bi-ancestral genome-wide association study of major depressive disorder (MDD) identified 178 risk variants. The results advance understanding of the biology of MDD and hint at new treatment possibilities.

Measurement of the anomalous precession frequency of the muon in the Fermilab Muon g-2 experiment

Abstract: The Muon g-2 Experiment at Fermi National Accelerator Laboratory (FNAL) has measured the muon anomalous precession frequency $\omega_a$ to an uncertainty of 434 parts per billion (ppb), statistical, and 56 ppb, systematic, with data collected in four storage ring configurations during its first physics run in 2018. When combined with a precision measurement of the magnetic field of the experiment's muon storage ring, the precession frequency measurement determines a muon magnetic anomaly of $a_{\mu}({\rm FNAL}) = 116\,592\,040(54) \times 10^{-11}$ (0.46 ppm). This article describes the multiple techniques employed in the reconstruction, analysis and fitting of the data to measure the precession frequency. It also presents the averaging of the results from the eleven separate determinations of \omega_a, and the systematic uncertainties on the result.

Genetic insights into biological mechanisms governing human ovarian ageing.

Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial

Abstract: Importance Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. Objective To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. Design, setting, and participants Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. Interventions Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. Main outcomes and measures The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. Results Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. Conclusions and relevance Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. Trial registration ClinicalTrials.gov Identifier: NCT03509350.

Trust in VANET: A Survey of Current Solutions and Future Research Opportunities

Abstract: Security and privacy will play a pivotal role in the commercialization of Vehicular Ad-hoc NETworks (VANETs). Traditionally, both cryptographic and non-cryptographic approaches have been used by researchers to address security and privacy issues and achieve secure Intelligent Transportation System (ITS) applications. However, some security goals such as trust and reputation, are still hard to achieve through conventional cryptographic approaches. Trust is the degree of certainty with which the received information is accepted and acted upon. Historically trust has been computed for both the content generator and the content itself with former known as entity trust and the latter known as data trust. Both entity and content trust are equally important to support trustworthy communication in VANET. We review, analyze, and compare some of the recently proposed trust establishment and management mechanisms (from 2014 to 2019) in vehicular networks. Furthermore, we also discuss the weaknesses and inadequacies of existing trust establishment and management approaches when deployed in a VANET environment. Finally, we discuss some future challenges that will need to be addressed for trustworthy communications in vehicular networks.

DNA Repair Pathways in Cancer Therapy and Resistance.

Abstract: DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer. As the primary anti-cancer therapies, ionizing radiation and chemotherapeutic agents induce cell death by directly or indirectly causing DNA damage, dysregulation of the DNA damage response may contribute to hypersensitivity or resistance of cancer cells to genotoxic agents and targeting DNA repair pathway can increase the tumor sensitivity to cancer therapies. Therefore, targeting DNA repair pathways may be a potential therapeutic approach for cancer treatment. A better understanding of the biology and the regulatory mechanisms of DNA repair pathways has the potential to facilitate the development of inhibitors of nuclear and mitochondria DNA repair pathways for enhancing anticancer effect of DNA damage-based therapy.

Phylogenomics Reveals Ancient Gene Tree Discordance in the Amphibian Tree of Life.

Abstract: Molecular phylogenies have yielded strong support for many parts of the amphibian Tree of Life, but poor support for the resolution of deeper nodes, including relationships among families and orders. To clarify these relationships, we provide a phylogenomic perspective on amphibian relationships by developing a taxon-specific Anchored Hybrid Enrichment protocol targeting hundreds of conserved exons which are effective across the class. After obtaining data from 220 loci for 286 species (representing 94% of the families and 44% of the genera), we estimate a phylogeny for extant amphibians and identify gene tree-species tree conflict across the deepest branches of the amphibian phylogeny. We perform locus-by-locus genealogical interrogation of alternative topological hypotheses for amphibian monophyly, focusing on interordinal relationships. We find that phylogenetic signal deep in the amphibian phylogeny varies greatly across loci in a manner that is consistent with incomplete lineage sorting in the ancestral lineage of extant amphibians. Our results overwhelmingly support amphibian monophyly and a sister relationship between frogs and salamanders, consistent with the Batrachia hypothesis. Species tree analyses converge on a small set of topological hypotheses for the relationships among extant amphibian families. These results clarify several contentious portions of the amphibian Tree of Life, which in conjunction with a set of vetted fossil calibrations, support a surprisingly younger timescale for crown and ordinal amphibian diversification than previously reported. More broadly, our study provides insight into the sources, magnitudes, and heterogeneity of support across loci in phylogenomic data sets.[AIC; Amphibia; Batrachia; Phylogeny; gene tree-species tree discordance; genomics; information theory.].

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis

Abstract: Importance Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals,ABCA7,TREM2, and an intergenic locus at 5q35 were previously implicated. Objective To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures Diagnosis of Alzheimer disease. Results A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking geneEDEM1(3p26;P = 8.9 × 10−7), near the immune response geneALCAM(3q13;P = 9.3 × 10−7), withinGPC6(13q31;P = 4.1 × 10−7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and withinVRK3(19q13.33;P = 3.5 × 10−7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus nearIGF1Rat 15q26 (P = 1.7 × 10−9) and 6 additional loci with suggestive significance (P ≤ 5 × 10−7) such asAPI5 at 11p12 (P = 8.8 × 10−8) andRBFOX1at 16p13 (P = 5.4 × 10−7) were identified. Gene expression data from brain tissue demonstrate association ofALCAM, ARAP1, GPC6, andRBFOX1with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, onlyAPOE,ABCA7,TREM2,BIN1,CD2AP,FERMT2, andWWOXwere implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

Nonmonotonic Energy Dependence of Net-Proton Number Fluctuations

Abstract: Nonmonotonic variation with collision energy (sqrt[s_{NN}]) of the moments of the net-baryon number distribution in heavy-ion collisions, related to the correlation length and the susceptibilities of the system, is suggested as a signature for the quantum chromodynamics critical point. We report the first evidence of a nonmonotonic variation in the kurtosis times variance of the net-proton number (proxy for net-baryon number) distribution as a function of sqrt[s_{NN}] with 3.1 σ significance for head-on (central) gold-on-gold (Au+Au) collisions measured solenoidal tracker at Relativistic Heavy Ion Collider. Data in noncentral Au+Au collisions and models of heavy-ion collisions without a critical point show a monotonic variation as a function of sqrt[s_{NN}].

Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program.

Abstract: We conducted genome-wide association analyses of over 250,000 participants of European (EUR) and African (AFR) ancestry from the Million Veteran Program using electronic health record-validated post-traumatic stress disorder (PTSD) diagnosis and quantitative symptom phenotypes. Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood–anxiety–neuroticism) factor. Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment. Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in individuals of European and African ancestry provide insights into its relationship with anxiety and depressive disorders and identify potential candidates for drug repositioning.

Industry 4.0 for sustainable manufacturing: Opportunities at the product, process, and system levels

Abstract: Limited resource availability and the negative environmental and societal impacts of traditional manufacturing have motivated the need for sustainable manufacturing. Product, process, and system integration, considering the interdependent sustainability impacts, is vital for sustainable manufacturing. Industry 4.0 and its constituent technologies offer significant potential to advance manufacturing competitiveness. Can the implementation of more sustainable manufacturing practices be facilitated or enhanced by using Industry 4.0 technologies? Current literature fall short in comprehensively addressing this question. Most treat either Industry 4.0 as a single technology, or sustainable manufacturing very broadly, without an in-depth consideration of the impacts on products, processes, and systems. To address this gap, this paper presents a comparative analysis examining individual Industry 4.0 technologies and their potential impact on sustainable manufacturing. A framework based on product, process, and systems sustainability metrics clusters is applied to examine these impacts. The findings reveal that literature is still limited in identifying opportunities for sustainability improvement at the different levels using Industry 4.0 technologies; the impact on many criteria related to product, process, or system level sustainability due to Industry 4.0 technologies have not yet been examined. The comparative analysis, and other literature, are used to provide further directions for future research and opportunities on leveraging Industry 4.0 technologies for more sustainable manufacturing. The implications for industry by way of offering a framework to identify potential solutions to enhance sustainable manufacturing performance using Industry 4.0 technologies are also discussed.