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Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

Improving the development of the social, emotional, and physical domains during early childhood impacts the overall trajectory of a child's well-being. However, researchers often address these independently, leaving a gap for a more integrated approach to promoting development. This study explores the effects of a dual-component intervention on changes in preschool-aged boys' and girls' gross motor and social-emotional skills. Preschoolers (N = 475; girls = 220 and boys = 255) ages 3-6 years completed the 9-month dual-component intervention and were randomized into control (n = 148) or intervention (n = 327) groups by classroom. Significant improvements were observed in social skills, locomotor, and total Test of Gross Motor Development-3. Additionally, boys and girls improved at the same rate in ball skills, locomotor, and total Test of Gross Motor Development-3. These results suggest that the dual-component intervention can improve preschoolers' social skills and motor skills with no differential effects.

In the marine environment, dynamic physical processes shape biological productivity and predator-prey interactions across multiple scales. Identifying pathways of physical-biological coupling is fundamental to understand the functioning of marine ecosystems yet it is challenging because the interactions are difficult to measure. We examined submesoscale (less than 100 km) surface current features using remote sensing techniques alongside ship-based surveys of krill and baleen whale distributions in the California Current System. We found that aggregative surface current features, represented by Lagrangian coherent structures (LCS) integrated over temporal scales between 2 and 10 days, were associated with increased (a) krill density (up to 2.6 times more dense), (b) baleen whale presence (up to 8.3 times more likely) and (c) subsurface seawater density (at depths up to 10 m). The link between physical oceanography, krill density and krill-predator distributions suggests that LCS are important features that drive the flux of energy and nutrients across trophic levels. Our results may help inform dynamic management strategies aimed at reducing large whales ship strikes and help assess the potential impacts of environmental change on this critical ecosystem.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Abstract Myocardial ischemia causes the release of bradykinin, which activates afferent nerve endings in the ventricular epicardium. This elicits a sympathetically mediated increase in arterial pressure and heart rate, referred to as the cardiogenic sympathetic afferent reflex. The rostroventrolateral medulla (RVLM) is a key sympathetic brain stem site for regulating cardiovascular activity. This study aimed to determine the importance of non‐barosensitive nociception sympathetic activity and the role of glutamate receptor activation of RVLM neurons in the cardiogenic sympathetic afferent reflex. We tested the hypothesis that inhibition of barosensitive sympathetic activity attenuates but does not abolish the reflex response to cardiac visceral afferents. Renal sympathetic nerve activity (RSNA), arterial pressure, and heart rate responses to epicardial bradykinin application were recorded in anesthetized rats before and after bilateral RVLM microinjection of either GABAA agonist muscimol, ionotropic glutamate receptor antagonist kynurenic acid, N‐methyl‐d‐aspartate (NMDA) receptor antagonist 2‐amino‐5‐ phosphonopentanoic acid (AP5), or non‐NMDA antagonist 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX). Baroreceptor loading‐induced inhibition of barosensitive activity attenuated the bradykinin‐induced RSNA response (93 ± 14% increase) and tachycardia (18 ± 3 bpm). While RVLM muscimol microinjection abolished the RSNA response (1.6 ± 4.2% from baseline, 0.49 ± 0.38 μV*s), surprisingly, it did not abolish the tachycardia (27 ± 4 bpm). Kynurenic acid microinjection blocked the arterial pressure and RSNA responses, while AP5 or CNQX only attenuated the responses. These data suggest that nociception‐sensitive sympathetic activity that does not appear to be barosensitive is also involved in the cardiogenic sympathetic afferent reflex. Importantly, while muscimol and kynurenic acid abolished the arterial pressure and RSNA response, neither affected the tachycardia, suggesting an alternate cardiac pathway independent of RVLM.

Abstract Individuals living and working in dangerous settings (e.g., first responders and military personnel) make complex decisions amidst serious threats. However, controlled studies on decision-making under threat are limited given obvious ethical concerns. Here, we embed a complex decision-making task within a threatening, immersive virtual environment. Based on the Iowa Gambling Task (IGT), a paradigm widely used to study complex decision-making, the task requires participants to make a series of choices to escape a collapsing building. In Study 1 we demonstrate that, as with the traditional IGT, participants learn to make advantageous decisions over time and that their behavioural data can be described by reinforcement-learning based computational models. In Study 2 we created threatening and neutral versions of the environment. In the threat condition, participants performed worse, taking longer to improve from baseline and scoring lower through the final trials. Computational modelling further revealed that participants in the threat condition were more responsive to short term rewards and less likely to perseverate on a given choice. These findings suggest that when threat is integral to decision-making, individuals make more erratic choices and focus on short term gains. They furthermore demonstrate the utility of virtual environments for making threat integral to cognitive tasks.

The study described in this paper investigated a unique collaboration among a special education and two general educators that sought to prepare students for success in the general education mathematics curriculum and that consisted of coordinated, reform-based instructional design across classroom and pull-out services provided by the special educator including preteaching. During preteaching, the special educator delivered instruction on key mathematics and collaboration skills that special education students would need a few days before they would receive instruction on the same content in their general education classrooms. Their collaboration produced high levels of teacher satisfaction, substantive teacher change, and increases in student engagement, self-efficacy, and achievement.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

Abstract Background The associations of vegetarian diets with risks for site-specific cancers have not been estimated reliably due to the low number of vegetarians in previous studies. Therefore, the Cancer Risk in Vegetarians Consortium was established. The aim is to describe and compare the baseline characteristics between non-vegetarian and vegetarian diet groups and between the collaborating studies. Methods We harmonised individual-level data from 11 prospective cohort studies from Western Europe, North America, South Asia and East Asia. Comparisons of food intakes, sociodemographic and lifestyle factors were made between diet groups and between cohorts using descriptive statistics. Results 2.3 million participants were included; 66% women and 34% men, with mean ages at recruitment of 57 (SD: 7.8) and 57 (8.6) years, respectively. There were 2.1 million meat eaters, 60,903 poultry eaters, 44,780 pescatarians, 81,165 vegetarians, and 14,167 vegans. Food intake differences between the diet groups varied across the cohorts; for example, fruit and vegetable intakes were generally higher in vegetarians than in meat eaters in all the cohorts except in China. BMI was generally lower in vegetarians, particularly vegans, except for the cohorts in India and China. In general, but with some exceptions, vegetarians were also more likely to be highly educated and physically active and less likely to smoke. In the available resurveys, stability of diet groups was high in all the cohorts except in China. Conclusions Food intakes and lifestyle factors of both non-vegetarians and vegetarians varied markedly across the individual cohorts, which may be due to differences in both culture and socioeconomic status, as well as differences in questionnaire design. Therefore, care is needed in the interpretation of the impacts of vegetarian diets on cancer risk.

Abstract Wolbachia is an obligate intracellular α-proteobacterium, which commonly infects arthropods and filarial nematodes. Different strains of Wolbachia are capable of a wide range of regulatory manipulations in their diverse hosts, including the modulation of host cellular differentiation to influence host reproduction. The genetic basis for the majority of these phenotypes is unknown. The wWil strain from the neotropical fruit fly, Drosophila willistoni, exhibits a remarkably high affinity for host germline-derived cells relative to the somatic cells. This trait could be leveraged for understanding how Wolbachia influences the host germline and for controlling host populations in the field. To further the use of this strain in biological and biomedical research, we sequenced the genome of the wWil strain isolated from host cell culture cells. Here, we present the first high quality Nanopore assembly of wWil, the Wolbachia endosymbiont of D. willistoni. Our assembly resulted in a circular genome of 1.27 Mb with a BUSCO completeness score of 99.7%. Consistent with other insect-associated Wolbachia strains, comparative genomic analysis revealed that wWil has a highly mosaic genome relative to the closely related wMel and wAu strains from Drosophila melanogaster and Drosophila simulans, respectively.

Abstract Kaposi’s sarcoma (KS) is a cancer affecting skin and internal organs for which the Kaposi’s sarcoma associated herpesvirus (KSHV) is a necessary cause. Previous work has pursued KS diagnosis by quantifying KSHV DNA in skin biopsies using a point-of-care (POC) device which performs quantitative loop-mediated isothermal amplification (LAMP). These previous studies revealed that extracting DNA from patient biopsies was the rate limiting step in an otherwise rapid process. In this study, a simplified, POC-compatible alkaline DNA extraction, ColdSHOT, was optimized for 0.75 mm human skin punch biopsies. The optimized ColdSHOT extraction consistently produced 40,000+ copies of DNA per 5 µl reaction from 3 mg samples—a yield comparable to standard spin column extractions—within 1 h without significant equipment. The DNA yield was estimated sufficient for KSHV detection from KS-positive patient biopsies, and the LAMP assay was not affected by non-target tissue in the unpurified samples. Furthermore, the yields achieved via ColdSHOT were robust to sample storage in phosphate-buffered saline (PBS) or Tris-EDTA (TE) buffer prior to DNA extraction, and the DNA sample was stable after extraction. The results presented in this study indicate that the ColdSHOT DNA extraction could be implemented to simplify and accelerate the LAMP-based diagnosis of Kaposi’s sarcoma using submillimeter biopsy samples.

Abstract Aim Receiving a diagnosis of brain stem death poses significant challenges for families. While much research focuses on organ donation in the context of brain stem death, there is a notable dearth of studies examining the experiences of families themselves. The aim of this review is to explore the experiences of families facing brain stem death. Design Systematic review. Method A narrative synthesis was conducted, drawing on 11 studies that employed both qualitative and quantitative methodologies. The search encompassed four electronic databases: AHMED (Allied and Complementary Medicine), Emcare (1995-present), MEDLINE (Ovid), and APA PsycInfo (Ovid). Due to the limited research on this topic, no restrictions were placed on the publication dates. Results The synthesis revealed five main themes: The Unexpected Prognosis, Coming to Terms with Brain Stem Death—Grieving Process, Observing Brain Stem Death Testing, The Impact of Staff on Families’ Experience, and The Lasting Impact. Conclusion The review underscores the pervasive lack of understanding among families regarding the diagnosis and process of brain stem death, as well as the short- and long-term distress it can engender. There is a clear imperative to establish national or international protocols for brain stem death, ensuring more effective and consistent support for affected families.

Abstract Accurate, and objective diagnosis of brain injury remains challenging. This study evaluated useability and reliability of computerized eye-tracker assessments (CEAs) designed to assess oculomotor function, visual attention/processing, and selective attention in recent mild traumatic brain injury (mTBI), persistent post-concussion syndrome (PPCS), and controls. Tests included egocentric localisation, fixation-stability, smooth-pursuit, saccades, Stroop, and the vestibulo-ocular reflex (VOR). Thirty-five healthy adults performed the CEA battery twice to assess useability and test–retest reliability. In separate experiments, CEA data from 55 healthy, 20 mTBI, and 40 PPCS adults were used to train a machine learning model to categorize participants into control, mTBI, or PPCS classes. Intraclass correlation coefficients demonstrated moderate (ICC > .50) to excellent (ICC > .98) reliability (p

Social engagement is critical to the personal and social development of children. Individuals with Autism Spectrum Disorder (ASD) often exhibit low levels of social engagement with peers and adults, with clearly fewer instances of eye contact, initiation, joint attention, and empathy. Given the pivotal role of social engagement, procedures that naturally evoke higher rates of social engagement may be critical. Prior research suggests that cartoons and other animated characters are more appealing to children with ASD than traditional face-to-face interactions with adults. However, this assertion lacks consistent empirical support. In this study, five elementary age students with ASD participated in a series of interactions with adults and live animation avatars. An alternating treatments design was used to evaluate participants' social engagement comparing their interactions with avatars to those with humans. Data show all five participants were consistently more attentive to the avatar than to human interventionists. In addition, all participants and their parents indicated the procedures were socially valid (i.e., preferred, feasible, and effective).

Dietary modifications such as caloric restriction (CR) and intermittent fasting (IF) have gained popularity due to their proven health benefits in aged populations. In time restricted feeding (TRF), a form of intermittent fasting, the amount of time for food intake is regulated without restricting the caloric intake. TRF is beneficial for the central nervous system to support brain health in the context of aging. Therefore, we here ask whether TRF also exerts beneficial effects in the aged retina. We compared aged mice (24 months) on a TRF paradigm (access to food for six hours per day) for either 6 or 12 months against young control mice (8 months) and aged control mice on an ad libitum diet. We examined changes in the retina at the functional (electroretinography), structural (histology and fluorescein angiograms) and molecular (gene expression) level. TRF treatment showed amelioration of age-related reductions in both scotopic and photopic b-wave amplitudes suggesting benefits for retinal interneuron signaling. TRF did not affect age-related signs of retinal inflammation or microglial activation at either the molecular or histological level. Our data indicate that TRF helps preserve some aspects of retinal function that are decreased with aging, adding to our understanding of the health benefits that altered feeding patterns may confer.