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Amber L Beitelshees,1,* Deepak Voora,2,* Joshua P Lewis,1,* 1Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA; 2Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke School of Medicine, Durham, NC, USA*All authors contributed equally to this work Abstract: In recent years, substantial effort has been made to better understand the influence of genetic factors on the efficacy and safety of numerous medications. These investigations suggest that the use of pharmacogenetic data to inform physician decision-making has great potential to enhance patient care by reducing on-treatment clinical events, adverse drug reactions, and health care-related costs. In fact, integration of such information into the clinical setting may be particularly applicable for antiplatelet and anticoagulation therapeutics, given the increasing body of evidence implicating genetic variation in variable drug response. In this review, we summarize currently available pharmacogenetic information for the most commonly used antiplatelet (ie, clopidogrel and aspirin) and anticoagulation (ie, warfarin) medications. Furthermore, we highlight the currently known role of genetic variability in response to next-generation antiplatelet (prasugrel and ticagrelor) and anticoagulant (dabigatran) agents. While compelling evidence suggests that genetic variants are important determinants of antiplatelet and anticoagulation therapy response, significant barriers to clinical implementation of pharmacogenetic testing exist and are described herein. In addition, we briefly discuss development of new diagnostic targets and therapeutic strategies as well as implications for enhanced patient care. In conclusion, pharmacogenetic testing can provide important information to assist clinicians with prescribing the most personalized and effective antiplatelet and anticoagulation therapy. However, several factors may limit its usefulness and should be considered. Keywords: pharmacogenetics, clopidogrel, warfarin, anticoagulant, aspirin, precision medicine

Although aspirin is a well-established antiplatelet agent, the mechanisms of aspirin resistance remain poorly understood. Metabolomics allows for measurement of hundreds of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. We defined the metabolic signature of aspirin exposure in subjects from the Heredity and Phenotype Intervention Heart Study. Many metabolites, including known aspirin catabolites, changed on exposure to aspirin, and pathway enrichment analysis identified purine metabolism as significantly affected by drug exposure. Furthermore, purines were associated with aspirin response, and poor responders had higher postaspirin adenosine and inosine levels than did good responders (n = 76; both P < 4 × 10(-3)). Using our established "pharmacometabolomics-informed pharmacogenomics" approach, we identified genetic variants in adenosine kinase associated with aspirin response. Combining metabolomics and genomics allowed for more comprehensive interrogation of mechanisms of variation in aspirin response--an important step toward personalized treatment approaches for cardiovascular disease.

The DEIMOS spectrograph is a multi-object spectrograph being built for Keck II. DEIMOS was delivered in February 2002, became operational in May, and is now about three-quarters of the way through its commissioning period. This paper describes the major problems encountered in completing the spectrograph, with particular emphasis on optical quality and image motion. The strategies developed to deal with these problems are described. Overall, commissioning is going well, and it appears that DEIMOS will meet all of its major performance goals.

Genetic variation in the platelet endothelial aggregation receptor 1 ( PEAR1) gene, most notably rs12041331, is implicated in altered on-aspirin platelet aggregation and increased cardiovascular event risk. We prospectively tested the effects of aspirin administration at commonly prescribed doses (81, 162, and 324 mg/day) on agonist-induced platelet aggregation by rs12041331 genotype in 67 healthy individuals. Prior to aspirin administration, rs12041331 minor allele carriers had significantly reduced adenosine diphosphate (ADP)-induced platelet aggregation compared with noncarriers ( P = 0.03) but was not associated with other platelet pathways. In contrast, rs12041331 was significantly associated with on-aspirin platelet aggregation when collagen and epinephrine were used to stimulate platelet aggregation ( P < 0.05 for all associations), but not ADP. The influence of PEAR1 rs12041331 on platelet aggregation is pathway-specific and is altered by aspirin at therapeutic doses, but not in a dose-dependent manner. Additional studies are needed to determine the impact of PEAR1 on cardiovascular events in aspirin-treated patients. [ABSTRACT FROM AUTHOR]

While many unconventional treatments are benign or helpful, potentially dangerous quackeries are still being peddled. Can you winnow the wheat from the chaff? [ABSTRACT FROM AUTHOR]

Understanding the ecological interactions that underlie marine ecosystem functioning requires sufficient data describing habitat use by mobile species. Hawksbill turtles Eretmochelys imbricata are considered a key species in coral reef-associated communities, owing to their specific foraging preferences, yet new information is still revealing details of the spatial and temporal aspects of habitat use. We used passive acoustic telemetry to monitor the movements of 18 juvenile hawksbills (minimum curved carapace length: 32.0-59.7 cm, mean ± SD = 43.9 ± 6.7 cm) at a developmental foraging site in a Mesoamerican barrier reef, Lighthouse Reef Atoll in Belize (tracking duration 10-1414 d, mean ± SD = 570 ± 484 d). Although specific home ranges were difficult to quantify, several turtles showed high site fidelity over timescales of months to years, with occasional wide-ranging use of the atoll. Diel variation in the number of detections received strongly suggest nocturnal resting. Long-term tracking data reveal 3 degrees of site fidelity across the atoll, based on the number of detection days near individual stations: high residency (n = 4 turtles), sequential residency (n = 5), and transient behavior (n = 4). These variations in movement raise questions about the differentiation of foraging habitats and degree of individual specialization within this population, as well as the influences of microhabitats and human disturbance.

Abstract: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

Antiplatelet therapy with a P2Y 12 receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss-of-function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on-clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by CES1 G143E genotype (N = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate-stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E-allele carriers vs. non-carriers, respectively, p = 3.8 × 10 -5 ). Similar significant effects on platelet aggregation were also noted between 143E-allele carriers versus non-carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, p = 0.04), epinephrine (44.4 vs. 18.8%, p = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, p = 3.7 × 10 -3 ). In contrast, no relationship between CES1 G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on-clopidogrel platelet aggregation is substantially modified by CES1 G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response-modifying alleles in CES1., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Geographical remoteness, limited resources, and socioeconomic disparities contribute to the migration of rural Alaska Native Elders to urban areas to access medical services and resources, improve economic situations, or reunite with family. We compared the discourse of 12 Elders in Anchorage who previously lived in four remote traditional villages in the Norton Sound region (ages 60-84) and 13 Elders in those villages (ages 48-80). Using Gee's discourse analysis framework, two patterns emerged detailing cultural effects on identity and Eldership, illuminating differences in the self-evaluation of successful aging based on cultural influences and the role of contextual factors.

HcpR is a CRP-family transcriptional regulator found in many Gram-negative anaerobic bacteria. In the perio-pathogen Porphyromonas gingivalis, HcpR is crucial for the response to reactive nitrogen species such as nitric oxide (NO). Binding of NO to the heme group of HcpR leads to transcription of the redox enzyme Hcp. However, the molecular mechanisms of heme binding to HcpR remain unknown. In this study we present the 2.3 Å structure of the P. gingivalis HcpR. Interdomain interactions present in the structure help to form a hydrophobic pocket in the N-terminal sensing domain. A comparison analysis with other CRP-family members reveals that the molecular mechanisms of HcpR-mediated regulation may be distinct from other family members. Using docking studies, we identify a putative heme binding site in the sensing domain. In vitro complementation and mutagenesis studies verify Met68 as an important residue in activation of HcpR. Finally, heme binding studies with purified forms of recombinant HcpR support Met68 and His149 residues as important for proper heme coordination in HcpR.

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS., Competing Interests: Additional Declarations: There is NO Competing Interest. DECLARATION OF INTERESTS A.C.F. is a consultant and equity holder in Treeline Biosciences and has previously served as a scientific advisor for AbbVie and has received research funding from IDP Pharma. K.V. receives support from AstraZeneca. R.L. is an inventor of a provisional patent on targeted killing of EBV-positive cancer cells by CRISPR/dCas9-mediated EBV reactivation. S.B. is Consultant for Caris Lifescience and has received honoraria from SpringWorks for an educational lecture. K.V. receives support from AstraZeneca with no relationship to the present study. The authors declare that these listed activities have no relationship to the present study.

Predominantly Western-based biomedical models of successful aging have been used to research, understand, and explain successful aging among diverse populations. With an increasingly heterogeneous older adult population nationwide, scholars have been exploring Indigenous understandings of successful aging. To add to the accumulation of knowledge of diverse Alaska Native populations, this study involved semi-structured qualitative interviews with 20 Unangan Elders from the Aleutian and Pribilof Islands. This community-based participatory research study explores the aging experiences and conceptualization of successful aging of these Elders from this remote and culturally distinct region of Alaska. Thematic analysis was employed to identify themes related to successful aging within this specific region, which supported our previous four themes, or characteristics, of Alaska Native successful aging: physical health, social support and emotional well-being, generativity as a traditional way of life, and community engagement and Inidgenous cultural generativity. Each of these themes or characteristics of Eldership is intertwined and together support successful aging within two remote communities in the Bering Sea. The findings of this study illuminate how Alaska Native Elders can live in geographically diverse regions of the State, yet the values and teachings they possess on successful aging possess the same cultural values and teachings. This study highlighted two new emerging constructs that influence Alaska Native Elders' successful aging based on geographical location. Findings contribute to the thematic saturation of the four main successful aging domains while outlining the importance of future research to conduct deeper investigations into the role of environment and history on Elders' perceptions and understanding of aging., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R 2  = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT., (© 2024. The Author(s).)

Abstract: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Rational design of catalysts relies on a deep understanding of the active centers. The structure and activity distribution of active centers on a surface are two of the central issues in catalysis and important targets of theoretical and experimental investigations. Herein, we report a machine learning-driven adequate sampling (MLAS) framework for obtaining a statistical understanding of the chemical environment near catalyst sites. Combined strategies were implemented to achieve highly efficient sampling, including the decomposition of degrees of freedom, stratified sampling, Gaussian process regression, and well-designed constraint optimization. The MLAS framework was applied to the rate-determining step in NH 3 synthesis, namely the N 2 activation process. We calculated the produced population function, P A , which provides a comprehensive and intuitive understanding of active centers. The MLAS framework can be broadly applied to other more complicated catalyst materials and reaction networks.

Although there is renewed optimism in biomarker research in schizophrenia, there is also need for greater inclusion of historically underrepresented groups in the research. In the present study, we surveyed 599 African American, 352 American Indian/Alaska Native, and 725 NonHispanic White participants about their attitudes toward research, knowledge and attitudes about schizophrenia, and willingness to engage in biomarker testing. Attitudes toward research were examined using the standardized 7-item Research Attitudes Questionnaire (RAQ) measure. Using structural equation modeling (SEM), we tested our predictive model of the likelihood of willingness to engage in biomarker testing for schizophrenia risk. Members of historically underrepresented groups were less willing to engage in biomarker testing. Overall, attitudes toward research, particularly trust, influenced biomarker testing willingness. These findings suggest that factors influencing willingness to engage in schizophrenia biomarker testing may be modifiable by outreach engagement and education., Competing Interests: Declaration of competing interest Dr. DC Gooding, the primary author, is a Deputy Editor for Psychiatry Research and was not involved in the editorial review or the decision to publish this article. The other authors (DAM, EU, CAVH, JPL, FPC, CEG) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Successful aging in rural Alaska communities has been established as a characteristic best described by reaching "Eldership," conveying reverence and respect from the community and implying leadership responsibilities. Most Alaska Native (AN) Elders believe that aging successfully or aging well happens within their home communities. However, limited rural resources lead Elders to relocate to urban settings. While protective factors supporting aging well in rural communities have been established, little is known about which factors support aging well after relocation to an urban setting. This exploratory, qualitative, community-based participatory research study explored AN Elder's (ages 48-84) experiences comparing successful aging within four rural Alaska communities and of Elders who relocated from a rural to an urban community. Thirteen rural-based Elders and 12 urban-based Elders semi-structured interviews were compared to explore how successful aging was experienced similarly and differently in rural and urban settings. To age well in urban Alaska, access to health care services, family, and community engagement were essential. The main challenges for urban Elders involved establishing a sense of community, intergenerational involvement, and the ability to continue traditional ways of living. This research identified challenges, similarities, and differences in aging well in an urban community. The findings of this study inform practices, services, and policies to improve existing urban services and initiate needed urban services to foster successful aging after relocation from remote rural areas into urban communities in Alaska., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: This paper outlines the unique culturally driven cyclical migration of Alaska Native (AN) Elders, distinct from previously described migration patterns in that Elders spend extended time in more than one community. We describe this Indigenous cyclical migration of AN Elders and its influence on their identity and later life health and well-being., Methods: Interviews with 124 AN Elders were conducted across 5 regions of Alaska: Bristol Bay, Interior, Norton Sound, Aleutian Pribilof Islands, and Southcentral. Within this sample, 87 participants engaged in cyclical migration. Thematic analysis was employed to identify themes related to Elders' cyclical migration between rural and urban communities and the impact on their identity and later life health and well-being., Results: We identified 2 distinct patterns of Indigenous cyclical migration-Elders living primarily in rural communities migrating to urban communities and Elders living primarily in urban communities migrating to rural communities. Elders engaged in these 2 patterns of cyclical migration to maintain cultural practices, access social, and health care services to maintain their physical health and well-being, and continue their community roles contributing to their AN Elder identity., Discussion: This study builds upon existing migration theories by introducing a cyclical pattern uniquely driven by AN identity, culture, and traditional practices. Findings illustrate how AN communities can support Elders who experience cyclical migration patterns to ensure they age successfully in both locations. Future research should explore cyclical migration patterns among other Indigenous populations with migration histories., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Most research on pharmaceutical presence in the environment to date has focused on smaller scale assessments of freshwater and riverine systems, relying mainly on assays of water samples, while studies in marine ecosystems and of exposed biota are sparse. This study investigated the pharmaceutical burden in bonefish (Albula vulpes), an important recreational and artisanal fishery, to quantify pharmaceutical exposure throughout the Caribbean Basin. We sampled 74 bonefish from five regions, and analyzed them for 102 pharmaceuticals. We assessed the influence of sampling region on the number of pharmaceuticals, pharmaceutical assemblage, and risk of pharmacological effects. To evaluate the risk of pharmacological effects at the scale of the individual, we proposed a metric based on the human therapeutic plasma concentration (H T PC), comparing measured concentrations to a threshold of 1/3 the H T PC for each pharmaceutical. Every bonefish had at least one pharmaceutical, with an average of 4.9 and a maximum of 16 pharmaceuticals in one individual. At least one pharmaceutical was detected in exceedance of the 1/3 H T PC threshold in 39% of bonefish, with an average of 0.6 and a maximum of 11 pharmaceuticals exceeding in a Key West individual. The number of pharmaceuticals (49 detected in total) differed across regions, but the risk of pharmacological effects did not (23 pharmaceuticals exceeded the 1/3 H T PC threshold). The most common pharmaceuticals were venlafaxine (43 bonefish), atenolol (36), naloxone (27), codeine (27), and trimethoprim (24). Findings suggest that pharmaceutical detections and concentration may be independent, emphasizing the need to monitor risk to biota regardless of exposure diversity, and to focus on risk quantified at the individual level. This study supports the widespread presence of pharmaceuticals in marine systems and shows the utility of applying the H T PC to assess the potential for pharmacological effects, and thus quantify impact of exposure at large spatial scales., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennifer S. Rehage reports financial support and equipment, drugs, or supplies were provided by Bonefish & Tarpon Trust. Jennifer S. Rehage reports financial support was provided by United States Environmental Protection Agency., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis., (© 2023. The Author(s).)

Introduction: Individuals living in rural communities are at heightened risk for Alzheimer's disease and related dementias (ADRD), which parallels other persistent place-based health disparities. Identifying multiple potentially modifiable risk factors specific to rural areas that contribute to ADRD is an essential first step in understanding the complex interplay between various barriers and facilitators., Methods: An interdisciplinary, international group of ADRD researchers convened to address the overarching question of: "What can be done to begin minimizing the rural health disparities that contribute uniquely to ADRD?" In this state of the science appraisal, we explore what is known about the biological, behavioral, sociocultural, and environmental influences on ADRD disparities in rural settings., Results: A range of individual, interpersonal, and community factors were identified, including strengths of rural residents in facilitating healthy aging lifestyle interventions., Discussion: A location dynamics model and ADRD-focused future directions are offered for guiding rural practitioners, researchers, and policymakers in mitigating rural disparities., Highlights: Rural residents face heightened Alzheimer's disease and related dementia (ADRD) risks and burdens due to health disparities. Defining the unique rural barriers and facilitators to cognitive health yields insight. The strengths and resilience of rural residents can mitigate ADRD-related challenges. A novel "location dynamics" model guides assessment of rural-specific ADRD issues., (© 2023 the Alzheimer's Association.)

Bacteria have to persist under low iron conditions in order to adapt to the nutritional immunity of a host. Since the knowledge of iron stimulon of Bacteroidetes is sparse, we examined oral (Porphyromonas gingivalis and Prevotella intermedia) and gut (Bacteroides thataiotaomicron) representatives for their ability to adapt to iron deplete and iron replete conditions. Our transcriptomics and comparative genomics analysis show that many iron-regulated mechanisms are conserved within the phylum. They include genes upregulated in low iron, as follows: fldA (flavodoxin), hmu (hemin uptake operon), and loci encoding ABC transporters. Downregulated genes were frd (ferredoxin), rbr (rubrerythrin), sdh (succinate dehydrogenase/fumarate reductase), vor (oxoglutarate oxidoreductase/dehydrogenase), and pfor (pyruvate:ferredoxin/flavodoxin oxidoreductase). Some genus-specific mechanisms, such as the sus of B. thetaiotaomicron coding for carbohydrate metabolism and the xusABC coding for xenosiderophore utilization were also identified. While all bacteria tested in our study had the nrfAH operon coding for nitrite reduction and were able to reduce nitrite levels present in culture media, the expression of the operon was iron dependent only in B. thetaiotaomicron. It is noteworthy that we identified a significant overlap between regulated genes found in our study and the B. thetaiotaomicron colitis study (W. Zhu, M. G. Winter, L. Spiga, E. R. Hughes et al., Cell Host Microbe 27:376-388, 2020, http://dx.doi.org/10.1016/j.chom.2020.01.010). Many of those commonly regulated genes were also iron regulated in the oral bacterial genera. Overall, this work points to iron being the master regulator enabling bacterial persistence in the host and paves the way for a more generalized investigation of the molecular mechanisms of iron homeostasis in Bacteroidetes . IMPORTANCE Bacteroidetes are an important group of anaerobic bacteria abundant both in the oral and gut microbiomes. Although iron is a required nutrient for most living organisms, the molecular mechanisms of adaptation to the changing levels of iron are not well known in this group of bacteria. We defined the iron stimulon of Bacteroidetes by examination of the transcriptomic response of Porphyromonas gingivalis and Prevotella intermedia (both belong to the oral microbiome) and Bacteroidetes thetaiotaomicron (belongs to the gut microbiome). Our results indicate that many of the iron-regulated operons are shared among the three genera. Furthermore, using bioinformatics analysis, we identified a significant overlap between our in vitro studies and transcriptomic data derived from a colitis study, thus underscoring the biological significance of our work. Defining the iron-dependent stimulon of Bacteroidetes can help to identify the molecular mechanisms of iron-dependent regulation as well as better understand the persistence of the anaerobes in the human host., Competing Interests: The authors declare no conflict of interest.

Indigenous research posits that practice-based evidence is fundamental to culturally grounded, multifaceted methods. The objective is to outline the key tenets and characteristics of Elder-centered research and relevant methodology using an interconnected progression of Alaska Native studies. Semi-structured interviews were conducted with 12 Alaska Native Elders, 21 Alaska Native caregivers, and 12 Alaska Native and non-Native caregivers in two studies exploring cultural understandings of memory and successful aging. The design and implementation of these studies employed Elders at every level, ensuring cultural relevance, outcomes, and dissemination. Results reflect the benefits of engaging Alaska Native Elders in research and reveal methods for best practices: (a) creating advisory councils, (b) identifying stakeholders, (c) weaving together Elder and western knowledge systems, and (d) the reciprocal nature of Elder engagement and well-being. This research centers Indigenous values and research for an Elder-centered methodology that encourages engagement of older adults in applicable, meaningful, restorative, and enculturated ways., Competing Interests: Declaration of conflicting interests The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

Background: In recent years public health research has shifted to more strengths or asset-based approaches to health research but there is little understanding of what this concept means to Indigenous researchers. Therefore our purpose was to define an Indigenous strengths-based approach to health and well-being research., Methods: Using Group Concept Mapping, Indigenous health researchers (N = 27) participated in three-phases. Phase 1: Participants provided 218 unique responses to the focus prompt "Indigenous Strengths-Based Health and Wellness Research…" Redundancies and irrelevant statements were removed using content analysis, resulting in a final set of 94 statements. Phase 2: Participants sorted statements into groupings and named these groupings. Participants rated each statement based on importance using a 4-point scale. Hierarchical cluster analysis was used to create clusters based on how statements were grouped by participants. Phase 3: Two virtual meetings were held to share and invite researchers to collaboratively interpret results., Results: A six-cluster map representing the meaning of Indigenous strengths-based health and wellness research was created. Results of mean rating analysis showed all six clusters were rated on average as moderately important., Conclusions: The definition of Indigenous strengths-based health research, created through collaboration with leading AI/AN health researchers, centers Indigenous knowledges and cultures while shifting the research narrative from one of illness to one of flourishing and relationality. This framework offers actionable steps to researchers, public health practitioners, funders, and institutions to promote relational, strengths-based research that has the potential to promote Indigenous health and wellness at individual, family, community, and population levels., (© 2023. The Author(s).)

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis 1 . These lesions are precursors for blood cancers 2-6 , but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: In many families, multiple caregivers support older adults living with dementia. Studying collaboration among caregivers requires consideration of conceptual and methodological issues that have not been fully explored. This study presents a framework for conceptualizing caregiver collaboration and an index that captures variation in collaboration among multiple caregivers within care networks., Methods: We used data from the 2015 waves of the National Health and Aging Trends Study and National Study of Caregiving (NSOC) to operationalize collaboration among multiple caregivers (N = 1,298) of 552 care recipients (Mage = 83.69, SD = 7.73; 71.6% women; 47.9% possible/probable dementia; 38.9% people of color)., Results: The care collaboration index considered individual and overlapping contributions while controlling for the size of the care network (caregivers in network responding to NSOC survey) and total network size (number of caregivers in network) in the statistical model. Larger care networks enabled more collaboration, both in general and across most types of tasks (βs > 0.38). Collaboration was greater among those caring for a Black or Hispanic care recipient, both in general and for household and medical/health tasks specifically (βs > 0.11). Collaboration was also greater among those caring for recipients with probable dementia, both in general and for most tasks (βs > 0.11) but not transportation-related tasks (p = .219)., Discussion: Results are examined in the context of care network dynamics and proposed mechanisms linking care collaboration to outcomes for caregivers and recipients. Strengths and limitations of our conceptualization and operationalization of collaboration are discussed., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Ferroportin (FPN), the only identified eukaryotic iron efflux channel, plays an important role in iron homeostasis and is downregulated in many cancers. To determine if iron related pathways are important for Head and Neck Squamous Cell Carcinoma (HNSCC) progression and proliferation, we utilize a model of FPN over-expression to simulate iron depletion and probe associated molecular pathways., Methods: The state of iron related proteins and ferroptosis sensitivity was assessed in a panel of metastatic HNSCC cell lines. Stable, inducible expression of FPN was confirmed in the metastatic HNSCC lines HN12 and JHU-022 as well as the non-transformed normal oral keratinocyte (NOK) cell line and the effect of FPN mediated iron depletion was assessed in these cell lines., Results: HNSCC cells are sensitive to iron chelation and ferroptosis, but the non-transformed NOK cell line is not. We found that FPN expression inhibits HNSCC cell proliferation and colony formation but NOK cells are unaffected. Inhibition of cell proliferation is rescued by the addition of hepcidin. Decreases in proliferation are due to the disruption of iron homeostasis via loss of labile iron caused by elevated FPN levels. This in turn protects HNSCC cells from ferroptotic cell death. Expression of FPN induces DNA damage, activates p21, and reduces levels of cyclin proteins thereby inhibiting cell cycle progression of HNSCC cells, arresting cells in the S-phase. Induction of FPN severely inhibits Edu incorporation and increased β-galactosidase activity, indicating cells have entered senescence. Finally, in an oral orthotopic mouse xenograft model, FPN induction yields a significant decrease in tumor growth., Conclusions: Our results indicate that iron plays a role in HNSCC cell proliferation and growth and is important for cell cycle progression. Iron based interventional strategies such as ferroptosis or iron chelation may have potential therapeutic benefits in advanced HNSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Belvin and Lewis.)

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression., (© 2022. The Author(s).)

aged well, yet today they experience high rates of illness and lower access to care because of colonisation. Aand this research explores successful ageing from an AN perspective or what it means to achieve "Eldership" in the rural Northwest Alaska. A community-based participatory research approach was used to engage participants at every stage of the research process. Semi-structured interviews were conducted with 16 AN men and 25 women and the interviews were professionally transcribed. Kleinman's explanatory model served as the foundation of the questionnaire to gain a sense of the beliefs about ageing and guide the thematic analysis to establish an AN understanding of successful ageing. The foundation of the Norton Sound southern sub-region Model of Successful Ageing is the reciprocal relationship between Elders and family which enables Elders to access meaningful activities, including Native ways of life, physical health, spirituality, and emotional well-being. Community-based interventions should foster opportunities for Elders to share their Native way of life alongside family and community members, which will enable them to remain physically active, maintain healthy emotional well-being, continue engaging in spiritual practices, and contribute to the health and well-being of families.

Background and Objectives: Physical activity (PA) is a powerful protective factor known to reduce risk for chronic conditions across the life span. PA levels are lower among American Indians and Alaska Natives (AIANs) when compared with other racial/ethnic groups and decrease with age. This evidence justifies a synthesis of current intervention research to increase PA levels among AIANs. This systematic review examines completed interventions to increase PA among AIAN older adults and considers recommended practices for research with Indigenous communities., Research Design and Methods: The systematic review was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for systematic review protocols and reporting guidelines. Three electronic databases, PubMed, Web of Science, and PsycINFO, were searched for academic literature. Trials investigating interventions to increase PA among AIAN adults older than 50 years were eligible. The Quality Assessment Tool for Quantitative Studies was used to evaluate the quality of evidence., Results: Three published trials were identified, including one group-level, clinic-based and two individual-level, home-based interventions. All were 6 weeks in duration, took place in urban areas, and used self-report PA measures. Findings indicated an overall increase in PA levels, improved PA-related outcomes, and improved psychosocial health among participants. None described community-engaged or culture-centered research strategies., Discussion and Implications: The narrow yet promising evidence represents a need for expanded research and a call to action for using culture-centered strategies. An advanced understanding of cultural and contextual aspects of PA may produce more impactful interventions, supporting health and mobility across the life span., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The adsorption-induced flip of electron spin at interfaces is an important but poorly understood phenomenon for magnetic devices, sensors, and heterogeneous catalysis, due to the difficulties in determining the surface spins at atomic resolution. We present an evolutionary magnetic order searching method that allows efficient identification of the ground state spin configuration of magnetic bulk and surfaces. Using this approach, we have discovered for the first time a set of adsorption-induced near-degenerate surface magnetic states on the Fe 3 O 4 (111) surface. Molecular adsorption of CO causes a destabilization of the magnetic states of the clean surface leading to a set of near-degenerate surface magnetic states at medium coverage, which causes an abrupt increase of the magnetic entropy on the surface. The empty 2π* orbital of CO, which could accommodate the back donation of the spin density in the Fe d orbitals, plays a key role for the CO adsorption-induced spin transition., (© 2022 Wiley-VCH GmbH.)

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Periodontitis is an inflammatory condition triggered by selected oral microbiota; thus treatment strategies should be aimed at reducing the abundance of the pathogenic bacteria. An obstacle to preclinical testing of such strategies is the availability of reliable animal models. Here, a non-human primate (NHP), Macaca mulatta , was used to examine the effectiveness of a novel antimicrobial, amixicile, which inhibits pyruvate-ferredoxin oxidoreductase (PFOR) present in anaerobic bacteria. Animals were assessed for their periodontal health, including radiography, clinical attachment loss (CAL), presence of plaque (PI), bleeding on probing (BOP) and pocket depth (PD), and sampled for saliva, gingival crevicular fluid (GCF), and subgingival plaque to determine their baseline clinical status. Amixicile was then administered for 2 weeks (40 mg/kg/day) and the animals were monitored for periodontal health immediately after the antibiotic treatment, then at 1 month-, 3 months-, and 6-months posttreatment. Microbial species present in plaque and saliva were determined through 16S rDNA sequencing. Baseline assessment of the microbiome has shown a significant proportion of bacteria belonging to the Streptococcus, Haemophilus, Porphyromonas, Gemella , and Fusobacterium genera. The abundance of Porphyromonas and Fusobacterium was reduced following treatment with amixicile, whereas that of Escherichia, Haemophilus , and Gemella were elevated. CAL, PD, and BOP were also significantly reduced following the treatment. In conclusion, the NHP model proves useful for preclinical studies of strategies targeting selected members of the oral microbiome. We show that amixicile reduces the levels of anaerobic bacteria under in vivo conditions, correlating with a reduction in CAL, PD, and BOP, thus validating its usefulness as an antimicrobial strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gui, Lyons, Deeb, Belvin, Hoffman and Lewis.)

Artificial intelligence (AI) coupled with promising machine learning (ML) techniques well known from computer science is broadly affecting many aspects of various fields including science and technology, industry, and even our day-to-day life. The ML techniques have been developed to analyze high-throughput data with a view to obtaining useful insights, categorizing, predicting, and making evidence-based decisions in novel ways, which will promote the growth of novel applications and fuel the sustainable booming of AI. This paper undertakes a comprehensive survey on the development and application of AI in different aspects of fundamental sciences, including information science, mathematics, medical science, materials science, geoscience, life science, physics, and chemistry. The challenges that each discipline of science meets, and the potentials of AI techniques to handle these challenges, are discussed in detail. Moreover, we shed light on new research trends entailing the integration of AI into each scientific discipline. The aim of this paper is to provide a broad research guideline on fundamental sciences with potential infusion of AI, to help motivate researchers to deeply understand the state-of-the-art applications of AI-based fundamental sciences, and thereby to help promote the continuous development of these fundamental sciences., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)