👤 Alexis T Clark

Annotation of regulatory elements is essential for understanding mechanisms underlying gene regulation, particularly tissue-specific regulation in human and animals. Here, we characterize 274,682 enhancers and 25,975 promoters across 24 tissues from an adult female sheep using ChIP-seq, ATAC-seq, CAGE-seq, RRBS, WGBS, and RNA-seq. We identify seven neural development-related genes with over 10 enhancers in brain tissues, highlighting the role of tissue-specific regulation. Cis-regulatory enhancer-promoter combinations provide insights into tissue-specific enhancers, such as the cerebellum-specific enhancer (chr15: 57390520-57390685) regulating BDNF, which is expressed in both the cerebellum and cerebral cortex. Comparative analysis of enhancer-promoter combinations in human, mouse, pig, cattle, and sheep reveals ruminant-specific pathways, including pentose catabolism and long-chain fatty acid import regulation. A milk fat yield quantitative trait locus (QTL) identified within an enhancer interacts with the fat metabolism-related gene COMMD1, and a birth weight-associated QTL detected within a cerebellum-specific enhancer regulates XKR4. This study provides a robust framework for exploring cis-regulatory mechanisms and tissue-specific regulation, advancing the functional annotation of the sheep reference genome. Show less

Postinfectious olfactory dysfunction (PIOD) is common in COVID-19 patients. This 2-arm double-blinded randomized controlled trial (RCT) aimed to establish proof-of-concept for vitamin A versus placebo as a treatment modality for patients with PIOD. This study compared 9,000 IU daily self-administered vitamin A intranasal drops versus peanut oil drops over 12 wk in COVID-19 patients with PIOD. Outcome measures included: olfactory bulb volume (OBV), olfactory sulcus depth, cerebral functional MRI blood oxygen level dependent (BOLD) signal, Sniffin' Sticks TDI score, SSParoT, olfactory disorder questionnaire (ODQ) score, and brain-derived neurotropic factor (BDNF) levels were collected from participants at baseline and after trial intervention at 12 wk. Fifty-seven PIOD were recruited in the trial and allocated to vitamin A or placebo arm at a 2:1 ratio. After withdrawals and exclusions, 30 participants in the vitamin A arm and 15 in the placebo arm were analyzed. There was no significant difference in the change in OBV between both groups. Aside from an improvement in the quality-of-life component of ODQ questionnaire scores (P = 0.01), there were no significant differences in any of the other secondary outcome measures. This proof-of-concept trial has demonstrated no significant effect of intranasal vitamin A on olfactory function in COVID-19 PIOD patients. Further work is required to identify other therapeutic agents in the management of PIOD or evaluate a different PIOD cohort with non-COVID etiology. Show less

Elevated levels of lipoprotein(a) (Lp[a]) are a causal risk factor for atherosclerotic cardiovascular disease. Similarities between the apolipoprotein(a) (apo[a]) component of Lp(a) and plasminogen suggest that antifibrinolytic properties may account for the pathological effects of Lp(a). However, the antifibrinolytic effects of apo(a) do not appear to be retained by the complete Lp(a) particle. We evaluated the effects of Lp(a), apo(a), and various apo(a) variants on clot formation and lysis times, thrombin generation, plasminogen activation, and fibrin architectures in ex vivo plasma clots. We also constructed predictive protein models to gain insight into the apo(a)-plasminogen interaction. Apo(a) strongly inhibited fibrinolysis, an effect dependent on the presence of the apo(a) protease domain and mediated by Lys216 in this domain. Modeling of apo(a) suggests that Lys216 is blocked from binding to plasminogen in the Lp(a) particle by the presence of the apoB-containing lipoprotein. Lp(a) and apo(a) shortened plasma clot formation times, and accounting for this revealed a small but significant prolongation of fibrinolysis by Lp(a). The procoagulant effects involved the development of lysis-resistant clot architectures and were mediated through the strong lysine-binding site in apo(a) kringle IV type 10. In addition, Lp(a) (but not apo[a]) accelerated thrombin generation. The strong antifibrinolytic effects of apo(a) do not appear to be retained in the complete Lp(a) particle. However, Lp(a) and apo(a) displayed procoagulant effects, in part dependent on the kringle 4-like lysine-binding site. Further analysis is required to determine whether these reported procoagulant effects of Lp(a) impact thrombosis in vivo. Show less

Clarifying relationships between amyloid, tau, and cognition is crucial to understanding dementia risk, but has been mainly performed in non-Hispanic White (NHW) participants. It is unknown whether findings are generalizable to other ethnoracial groups. We evaluated relationships between amyloid-β (Aβ) positivity, apolipoprotein E allele (APOE) ε4, tau-positron emission tomography (PET) Black (β = 0.28, p < 0.001) and Hispanic (β = 0.34, p < 0.001) participants had higher medial temporal lobe (MTL) tau than NHW participants; however, findings were attenuated when accounting for choroid plexus off-target binding. Hispanic participants showed higher tau in lateral temporal regions compared to NHW and Black participants; however, reducing meningeal off-target binding through erosion demonstrated similar lateral temporal tau across groups. Factors other than amyloid and tau may impact cognition in Black participants. PI2620 off-target ethnoracial differences should be investigated. Show less

The apolipoprotein E epsilon 4 (APOE ε4) gene is associated with an increased risk of developing sporadic Alzheimer's disease (AD). Several studies have focused on declarative memory, where episodic memory deficits are reported in ε4 carriers, while semantic memory has received much less attention. To clarify whether the impact of APOE ε4 on declarative memory is specific to episodic memory, we administered a novel measure of autobiographical memory, the Semantic Autobiographical Interview. Thirty-eight healthy older adults were recruited, 19 ε4 carriers and 19 noncarriers, matched in age, education, and gender. The groups did not significantly differ in any neuropsychological tests except for recognition memory, where ε4 carriers showed reduced performance. On the original Autobiographical Interview (AI), results revealed a reduced number of target details in carriers. Together, these results suggest a reduction of episodic specificity in ε4 carriers. In contrast, carriers had very similar semantic production to noncarriers, whether it was for off-task semantic details in the AI, or on-task general and personal semantic details produced in the Semantic Autobiographical Interview. These results suggest that older adults retain the gist of their personal experience and that the semanticization of their autobiographical narratives is robust and less sensitive to risk for AD than episodic memory. (PsycInfo Database Record (c) 2026 APA, all rights reserved). Show less

The genetic basis of sporadic early-onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late-onset Alzheimer's disease (LOAD) polygenic risk in EOAD. A LOAD polygenic score (PGS) was calculated in the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset (p = 0.106) or with cognitive performance (p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal-associated protein 25 (SNAP-25) (p = 2.3 × 10 While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal-associated protein 25 (SNAP-25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD. Show less

Accurate and ongoing assessments of physical activity (PA) and sedentary time (SED) are needed to support public health surveillance, evaluate interventions, and advance the understanding of how movement behaviours relate to health. After six cycles of data collection (2007 to 2019) using the Actical (AC) accelerometer, the Canadian Health Measures Survey (CHMS) transitioned to the ActiGraph wGT3X-BT (AG). To understand how estimates from the AC accelerometer may compare with those from the AG in the context of the CHMS, this study compares AC and AG accelerometer estimates of PA, step counts, and SED using CHMS protocols. A convenience sample of 47 adults (aged 18 to 79 years) and 36 children and youth (aged 3 to 17 years) wore both AC and AG accelerometers on their waist for seven consecutive days. Estimates of PA and SED, step counts, and the percentage of those meeting PA recommendations were compared between the devices using descriptive, correlation, and agreement statistics. Agreement ranged from poor to excellent, with variability across PA intensities and age groups. Significant absolute differences in SED and light PA (LPA) were observed across all age groups, and in step counts among children and youth. Agreement was good to excellent across most age groups for moderate-to-vigorous PA (MVPA), and among adults for step counts. While the percentage of those meeting PA recommendations was higher with the AG, results were not statistically different. Similar comparisons could be made with the AG device when using the normal and low frequency extension filters. The results of the present study provide data users and researchers with an indication of the expected differences between the devices across various movement behaviour outcomes in the context of the CHMS. Results suggest that comparisons between cycles 1 to 6 and Cycle 7 onward of the CHMS for MVPA are acceptable, but they should be carried out with caution. Comparisons of SED, LPA, vigorous PA, and step counts are not recommended. Show less

This study, for the first time, sought to investigate whether the interaction between the GRS consists of three SNPs (CAV-1, CRY-1, MC4R) and fat intake is associated with inflammatory markers among Iranian overweight and obese women. This cross-sectional study was conducted with 246 overweight and obese women, aged 18-48 years. Three SNPs, including CAV-1 rs3807992, CRY-1 rs2287161, and MC4R rs17782313, were genotyped using PCR-RFLP to calculate the genetic risk score (GRS) for each participant. Dietary fat intake was measured using a validated semi-quantitative food frequency questionnaire (FFQ). C-reactive protein (CRP), interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and Galectin-3 (Gal-3) were assessed as the primary outcomes of the study. After controlling for confounding variables, a significant interaction between high total fat intake and high GRS, compared to the reference group, was found for TGF-β level ( Consuming different types of fats can influence the interaction between GRS and inflammatory markers, suggesting further research is needed to fully understand this relationship. The online version contains supplementary material available at 10.1007/s40200-024-01542-z. Show less

Childhood obesity is a global concern and has both nutritional and genetic causative factors. One of the most common monogenic causes of obesity is heterozygous mutations in the Melanocortin 4 receptor (MC4R), which are found in 5.7-8.6% of individuals with early-onset obesity. We report, the effect of semaglutide, a long-acting glucagon-like peptide (GLP-1) analogue, in the treatment of severe obesity in an adolescent boy with a heterozygous mutation in MC4R. A 13-year-old boy with a history of excessive weight gain since infancy was referred to the specialised weight management team. He was born at full term with a birth weight of 3.57 kg (50th centile), but his weight consistently exceeded the 99.6th percentile after the age of 1 year. At the age of 5 years, he was diagnosed with autism spectrum disorder (ASD). Diagnostic investigations revealed insulin resistance and dyslipidaemia, while genetic testing confirmed a heterozygous mutation in MC4R (E61K), inherited from his mother. Managing his condition was challenging due to his rapid weight gain, needle phobia, and behavioural difficulties. Despite intense multidisciplinary lifestyle interventions, he continued to gain weight, reaching a peak weight of 187.5 kg (+16.65 standard deviation score [SDS]), body mass index (BMI) of 56.9 kg/m2 (+4.19 SDS), and body fat of 63.9% at the age of 13 years. Due to severe ASD and needle phobia, he was not keen on daily GLP-1 injections. He was commenced on semaglutide subcutaneous injection at a dose of 0.25 mg weekly, gradually increasing to the maximum dose of 1 mg weekly. Over the course of 12 weeks, his BMI decreased to 52.2 kg/m2 (+4.08 SDS) and weight dropped to 176.8 kg (+14.76 SDS, body fat: 52.7%). At the 3-month and 12-month reviews post-treatment, he achieved weight loss of 5.7% and 11%, respectively. The quality of life questionnaire showed improved scores from 35.95 to 60.36 at 12-month review, indicating enhanced well-being. The continuous glucose monitor demonstrated an improvement in time in range. Semaglutide was approved by the US Food and Drug Administration (FDA) for weight management in adolescents aged 12 years and above in December 2022. A recent case series underscored the benefits of therapy with liraglutide, a short-acting GLP-1 analogue, in rare genetic cases of early-onset obesity. To our knowledge, this is the first case report to highlight the efficacy and safety of semaglutide in an adolescent with heterozygous MC4R mutation. Semaglutide could be a potential treatment option for monogenic obesity and will benefit from further research. Show less

Cardiovascular dysfunction frequently accompanies aging and is often worsened by adverse lifestyle factors and genetic susceptibility. The apolipoprotein E (APOE) gene modulates susceptibility to cardiovascular disease, but how exercise and diet interact with APOE genotype remains insufficiently understood. We investigate the cardioprotective potential of exercise in humanized APOE-targeted replacement mice on control and high-fat diet, using photon-counting computed tomography (PCCT) and deep learning-based image segmentation. This study included 251 male and female mice in mid-to-late life of APOE2, APOE3, and APOE4 genotypes with variation in humanized NOS2 (HN) mediated innate immune response, exercise status (exercised vs. sedentary) and diet (control vs. high-fat). Mice underwent in vivo cine cardiac PCCT imaging following contrast enhancement with liposomal iodine nanoparticles. Stroke volume, ejection fraction, and myocardial mass were derived from automated segmentation of cardiac structures using a 3D U-Net model. We assessed main and interaction effects of genotype, sex, HN status, age, exercise and diet using generalized linear models, while Mann-Whitney U tests assessed effects of exercise within stratified subgroups. Exercise was a significant predictor of improvement in several cardiac functional metrics with a large effect size. The interaction between exercise and diet was a significant predictor of reduced body mass and myocardial mass. Stratified analyses found that exercise improves cardiac functional metrics in APOE4 mice on both diets, and APOE3 mice primarily on control diet, while benefitting HN mice more than non-HN mice. Voluntary exercise can partially rescue cardiac dysfunction induced by high-fat diet in adult APOE-targeted replacement mice, with benefits modulated by genotype, sex, and HN status. APOE4 and HN mice benefitted most from exercise. Contrast-enhanced PCCT combined with deep learning segmentation enables scalable, minimally invasive cardiac phenotyping and reveals interaction effects that are critical for designing precision lifestyle interventions in genetically at-risk populations. Show less

This study evaluates photon-counting CT (PCCT) for the imaging of mouse femurs and investigates how APOE genotype, sex, and humanized nitric oxide synthase (HN) expression influence bone morphology during aging. A custom-built micro-CT system with a photon-counting detector (PCD) was used to acquire dual-energy scans of mouse femur samples. PCCT projections were corrected for tile gain differences, iteratively reconstructed with 20 µm isotropic resolution, and decomposed into calcium and water maps. PCD spatial resolution was benchmarked against an energy-integrating detector (EID) using line profiles through trabecular bone. The contrast-to-noise ratio quantified the effects of iterative reconstruction and material decomposition. Femur features such as mean cortical thickness, mean trabecular spacing (TbSp_mean), and trabecular bone volume fraction (BV/TV) were extracted from calcium maps using BoneJ. The statistical analysis used 57 aged mice representing the APOE22, APOE33, and APOE44 genotypes, including 27 expressing HN. We used generalized linear models (GLMs) to evaluate the main interaction effects of age, sex, genotype, and HN status on femur features and Mann-Whitney U tests for stratified analyses. PCCT outperformed EID-CT in spatial resolution and enabled the effective separation of calcium and water. Female HN mice exhibited reduced BV/TV compared to both male HN and female non-HN mice. While genotype effects were modest, a genotype-by-sex stratified analysis found significant effects of HN status in female APOE22 and APOE44 mice only. Linear regression showed that age significantly decreased cortical thickness and increased TbSp_mean in male mice only. These results demonstrate PCCT's utility for femur analysis and reveal strong effects of sex/HN interaction on trabecular bone health in mice. Show less

This study used whole-genome sequence data on 406 beef cattle (203 Hanwoo and 203 Angus) to detect signatures of selection using four different methods; integrated haplotype score (iHS), Rsb, XP-EHH, and runs of homozygosity (ROH). Based on Rsb and XP-EHH analysis, 36 and 21 genomic regions differed significantly between Angus and Hanwoo breeds. Within breeds, we identified 108 regions (76 in Hanwoo and 32 in Angus) with the ROH analysis and 331 regions with the iHS method (298 in Hanwoo and 33 in Angus). The candidate genes related to meat quality, such as HSPA9 and LPL, were found within Hanwoo, while genes associated with growth and meat quantity traits, including ACTC1 and TMEM68, were identified within Angus. This study can assist in understanding the selection history of these breeds and identifying the genomic regions associated with the traits selected for in the breeding programs for these cattle breeds. Show less

Liver x receptor alpha (LXRα) functions as an intracellular cholesterol sensor that regulates lipid metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, elevated cholesterol in the liver may play a critical role in the development of MASH. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH in LXRα mutant mice suggesting that LXRα normally functions to impede the development of liver disease. Show less

Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation and Show less

Lymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs. How this occurs remains unclear. Here we demonstrate that in small pre-B cells, the lineage and stage-specific epigenetic reader bromodomain and WD repeat-containing protein 1 (BRWD1) reorders three-dimensional chromatin topology to affect the transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters, and coordinated this switch with Igk locus contraction. BRWD1 did so by converting chromatin-bound static to dynamic cohesin competent to mediate long-range looping. ATP-depletion revealed cohesin conversion to be the main energetic mechanism dictating dynamic chromatin looping. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be dictated by lineage contextual mechanisms to facilitate specific cell fate transitions. Show less

The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Show less

The Fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Show less

The objective of the experiment was to determine the effects of supplemental SFA sources, lysophospholipids (LPL), and their interaction on production and nutrient digestibility in lactating dairy cows. The experiment was conducted with 48 cows in a randomized complete block design. Cows were blocked (12 blocks total) by parity and days in milk and randomly assigned to 4 dietary treatments in each block (2 × 2 factorial arrangement), i.e., 2 sources of fat supplements, C16:0 (PA)- or C18:0 (SA)-enriched fat, and with or without LPL. The experiment was conducted for 6 wk to measure daily dry matter intake, milk yield, and weekly milk composition. During the last week of the experiment, spot fecal and urine samples were collected to determine total-tract nutrient digestibility. Milk samples in the last week were also collected to analyze the milk fatty acid (FA) profile. All data were analyzed using the MIXED procedure of SAS, where block was used as a random effect and FA, LPL, and the interaction of FA by LPL were used as fixed effects. Week and interactions of week by FA or LPL were included for production measures. Different sources of SFA did not affect dry matter intake and milk yield. However, the PA treatment increased (39.7 vs. 36.8 kg) energy-corrected milk compared with SA due to increased milk fat yield. No effect of LPL on production measures was observed. Total-tract digestibilities of dry matter, organic matter, crude protein, and total FA were not different between the PA and SA groups, but PA increased (41.4% vs. 38.8%) neutral detergent fiber digestibility compared with SA. Supplementation of LPL increased (64.7% vs. 60.5%) total FA digestibility, especially 18-carbon FA (74.1% vs. 68.2%). An interaction of SFA by LPL was found for 16-carbon FA digestibility. The PA diet increased the concentration of 16-carbon FA in milk fat and SA increased the concentration of preformed FA (≥18 carbons). Supplementation of LPL decreased the concentration of trans-10 C18:1. No difference in N utilization and excretion among treatments was observed. In conclusion, the PA diet was more effective in improving milk fat yield of lactating cows compared with SA. Supplementation of LPL increased digestibility of total FA, especially 18-carbon FA but did not affect production. Show less

Liver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease. Show less

Previous studies have shown that the minor allele (C allele) for melanocortin 4 receptor (MC4R) rs17782313 may be associated with depressed mood. Moreover, dietary patterns have potentially adverse effects on depression. This study investigates the interactions between the MC4R gene variant (rs17782313) and dietary patterns on depression among Iranian obese and overweight women. A total of 289 Iranian overweight and obese women, aged 18-50 years, were enrolled in this cross-sectional study. Biochemical, anthropometric, and body composition indices were assessed in all participants. Moreover, MC4R rs17782313, by the restriction fragment length polymorphism (PCR-RFLP) method, and depression, using the 21-item Depression Anxiety Stress Scales (DASS) questionnaire, were assessed. Food intakes were assessed by completing a 147-item semi-quantitative food frequency questionnaire (FFQ). By the use of factor analysis, 2 major dietary patterns were extracted: healthy dietary pattern (HDP) and unhealthy dietary pattern (UDP). Binary logistic analysis showed that individuals with minor allele risk (CC) with high adherence to the unhealthy pattern increased odds for depression (OR: 8.77, 95%CI: -0.86-18.40, P: 0.07), after controlling for confounders. Also, a logical inverse relationship was observed between CT genotype and HDP on depression in the crude and adjusted models (OR: -0.56, 95% CI: -3.69-2.57, P: 0.72) (OR: -4.17, 95% CI: -9.28-0.94, P: 0.11), although this interaction was not statistically significant. According to the above findings, adherence to unhealthy food intake pattern increases odds of depression in MC4R risk allele (C allele) carriers. To confirm these findings, more studies are needed in the form of clinical trials and prospective studies with higher sample sizes. Show less

The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation of unknown physiological BACE1 substrates. To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans. Show less

Cardiovascular disease (CVD) is the leading cause of death in women globally. Recent studies have reported that the minor allele (C allele) for melanocortin 4 receptor (MC4R) rs17782313 may be related to the incidence of obesity and the risk of CVD. Therefore, the present study aimed to investigate the interactions between the modified Nordic-style diet score (MND) and MC4R gene variant on markers of CVD. The current cross-sectional study was conducted on 282 Iranian women, aged 18-48 years, with a body mass index (BMI) ≥ 25. MND score was assessed using a 147 items food frequency questionnaire (FFQ). Genotyping of the MC4R (rs17782313) was conducted by the PCR method. The anthropometric measurements and serum profiles were assessed by standard protocols. The means and standard deviation (SD) of age, weight, and BMI of individuals were 36.67 ± 9.10 years, 81.29 ± 12.43 kg, and 31.26 ± 4.29 kg/m In conclusion, the results of the present study suggest that diet, gene variants, and their interaction should be considered in metabolic disease risk assessment. Further studies are needed to confirm these data and better elucidate the interaction. Show less

Currently, no standardized system exists for evaluating and testing at-risk family members of decedents with abnormal post-mortem genetic testing in cases of sudden unexpected death (SUD). The goal of this study was to evaluate the outcomes of referrals made by an urban medical examiner's office to a multi-disciplinary cardiogenetics clinic. Relatives of decedents with pathogenic/likely pathogenic (P/LP) variants or variants of unknown significance (VUS) in genes known to be associated with cardiomyopathies and/or arrhythmias were identified by the New York City Office of Chief Medical Examiner and referred to the Cardiogenetics Clinic at Montefiore Medical Center. Familial referrals of 15 decedents (median 15 years, range 2 days to 57 years) were evaluated. Variants in 13 genes were identified among decedents (9 arrhythmia, 5 cardiomyopathy). P/LP variants were identified in both arrhythmia (RYR2, SCN5A) and cardiomyopathy syndrome (MYBPC3 (2), MYH7) genes. Thirty-two family members were referred, and 14 variants were detected. One pathogenic (MYBPC3) and two likely pathogenic (RYR2, MYH7) mutations were identified. Referral of at-risk family members of decedents who experienced SUD based on informative post-mortem genetic testing for cardiac and genetic evaluation is warranted, as family studies help to reclassify variants and prevent additional sudden death. Show less

Previous studies have shown that the minor allele (C allele) for melanocortin 4 receptor (MC4R) rs17782313, may be associated with incidence of obesity and the risk of cardiovascular diseases (CVDs). Moreover, inflammation caused by the diet has been shown to have, potentially, unfavorable effects on CVD risk. This study used a linear regression model to investigate the interactions between the dietary inflammatory index (DII) and MC4R gene variants on markers of CVD. This comparative cross-sectional study was conducted on 266 Iranian women with overweight and obesity. A food frequency questionnaire (FFQ) with 147 items was used to assess dietary intakes. Individuals were categorized into three groups based on rs17782313 genotype. Participants were also divided into four groups based on DII score. Higher quartiles of DII were associated with lower levels of high density lipoproteins (HDL) (p = 0.01) and higher levels of triglycerides (TG) (p = 0.04). There was a significant difference between genotypes for insulin (p < 0.001), HOMA index (p < 0.001), total body mineral content (p = 0.03), and bone mineral content (BMC) (p = 0.04). Our findings also showed significant interactions between DII score and rs17782313 polymorphism on total cholesterol, total body mineral content, BMC, soft lean mass (SLM), fat free mass (FFM) (p = 0.03), skeletal muscle mass (SMM), and basal metabolic rate (BMR). Higher DII scores were associated with lower HDL levels and higher TG levels, respectively; whilst significant differences were observed between the genotypes of rs17782313 for insulin and HOMA index, total body mineral content, and BMC. These results highlight that dietary compositions, gene variants, and their interaction, should be considered in CVD risk assessment. Show less

Major depressive disorder (MDD) is more common in women than in men, and evidence of gender-related subtypes of depression is emerging. Previously identified blood-based transcriptomic biomarkers distinguished male and female subjects with MDD from those without the disorder. In the present pilot study, we investigated the performance of these biomarkers in pregnant and postpartum women with prior major depressive episodes, some of whom had current symptomatology. The symptom scores of 13 pregnant and 15 postpartum women were identified by the Inventory of Depressive Symptoms (IDS-SR-30) at the time of blood sampling. Blood levels of the 20 transcriptomic biomarkers and that of estrogen receptor 2 (ESR2), membrane progesterone receptor alpha and beta (mPRα, mPRβ) were measured. In pregnant women, transcript levels of ADCY3, ASAH1, ATP11C, CDR2, ESR2, FAM46A, mPRβ, NAGA, RAPH1, TLR7, and ZNF291/SCAPER showed significant association with IDS-SR-30 scores, of which ADCY3, FAM46A, RAPH1, and TLR7 were identified in previous studies for their diagnostic potential for major depression. ASAH1 and ATP11C were previously also identified as potential markers of treatment efficacy. In postpartum women, transcript levels of CAT, CD59, and RAPH1 demonstrated a trend of association with IDS-SR-30 scores. Transcript levels of ADCY3, ATP11C, FAM46A, RAPH1, and ZNF291/SCAPER correlated with ESR2 and mPRβ expressions in pregnant women, whereas these associations only existed for mPRβ in postpartum women. These results suggest that a blood biomarker panel can identify depression symptomatology in pregnant women and that expression of these biomarker genes are affected by estrogen and/or progesterone binding differently during pregnancy and postpartum. Show less

Prospective cohort studies question the value of HDL-C (high-density lipoprotein cholesterol) for stroke risk prediction. Investigate the relationship between long-term functional recovery and HDL proteome and function. Changes in HDL protein composition and function (cholesterol efflux capacity) in patients after acute ischemic stroke at 2 time points (24 hours, 35 patients; 96 hours, 20 patients) and in 35 control subjects were measured. The recovery from stroke was assessed by 3 months, the National Institutes of Health Stroke Scale and modified Rankin scale scores. When compared with control subject after adjustments for sex and HDL-C levels, 12 proteins some of which participate in acute phase response and platelet activation (APMAP [adipocyte plasma membrane-associated protein], GPLD1 [phosphate inositol-glycan specific phospholipase D], APOE [apolipoprotein E], IHH [Indian hedgehog protein], ITIH4 [inter-alpha-trypsin inhibitor chain H4], SAA2 [serum amyloid A2], APOA4 [apolipoprotein A-IV], CLU [clusterin], ANTRX2 [anthrax toxin receptor 2], PON1 [serum paraoxonase/arylesterase], SERPINA1 [alpha-1-antitrypsin], and APOF [apolipoprotein F]) were significantly (adjusted Changes in HDL proteins during early acute phase of stroke associate with recovery. Monitoring HDL proteins may provide clinical biomarkers that inform on stroke recuperation. Show less

To elucidate the genetic cause of a large 5 generation South Indian family with multiple individuals with predominantly an upper limb postural tremor and posturing in keeping with another form of tremor, namely, dystonic tremor. Whole-genome single nucleotide polymorphism (SNP) microarray analysis was undertaken to look for copy number variants in the affected individuals. Whole-genome SNP microarray studies identified a tandem duplicated genomic segment of chromosome 15q24 present in all affected family members. Whole-genome sequencing demonstrated that it comprised a ∼550-kb tandem duplication encompassing the entire The identification of a genomic duplication as the likely molecular cause of this condition, resulting in an additional Show less