👤 Jennifer E Ho

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Show less

Apolipoprotein B (APOB) containing lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB, comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1 mediated uptake of APOB100 containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease. Show less

Multiple studies show conflicting association between APOE polymorphisms and the risk of PDD, yielding inconsistent results. To elucidate, a meta-analysis was conducted using existing articles from Web of Science, PubMed, Cochrane, Google Scholar, Embase, WanFang, and CNKI databases, including case-control studies published up to January 31, 2025. A total of 27 studies (3,115 PD controls and 1,338 PDD cases) were included, with pooled Odds Ratio (ORs) and 95% confidence intervals (CIs) calculated using CMA, Biostat, United States. To assess APOE genotypes and PDD risk, three comparisons were examined: 5 genotypes vs. ε3/3, ε2+/ε4 + vs. ε3/3, and ε4 + vs. ε4-. The ε3/4 (OR = 1.56, 95% CI: 1.25-1.95); ε4 + vs. ε3/3 (OR = 1.52, 95% CI: 1.20-1.93) and ε4 + vs. ε4- (OR = 1.62, 95% CI: 1.39-1.90) genotypes were associated with an increased PDD risk, while ε2 + showed no significant effect (OR = 1.21, 95% CI: 0.88-1.65, Show less

N6-methyladenosine (m6A) RNA modification can govern cell fate by co- or post-transcriptionally regulating gene expression. VSMCs can undergo phenotypic switching, contributing to other cells within atherosclerotic plaques, including foam cell- and macrophage-like cells. However, the role of VSMC m6A in atherosclerosis development remains unclear. While PPAR-α and PPAR-γ have been extensively studied in macrophages for their roles in atherosclerosis, the epigenetic regulation of these nuclear receptors under high cholesterol conditions remains poorly understood. We utilized murine and human atherosclerotic aortas, along with VSMC-specific Mettl3 and Mettl14 knockout mice, to evaluate the role of VSMC m6A in atherosclerosis. Lineage tracing was used to assess macrophage-like VSMCs. The epigenetic regulation of Ppara and Pparg transcription by Methyltransferase-like 14 (METTL14) was investigated through a variety of methods, including histological, cellular, genomic, transcriptomic, metabolomic, lipidomic, computational, and pharmacological approaches. The therapeutic potential of VSMC Mettl14 in atherosclerosis was analyzed using adeno-associated virus-mediated expression in ApoE-/- mice.We showed that the METTL3/METTL14 methyltransferase complex was reduced in both murine and human atherosclerotic VSMCs. The levels of METTL3, and consequently m6A, were regulated by METTL14, which was in turn influenced by ox-LDL. Notably, while VSMC METTL3 or m6A did not contribute to atherosclerosis, VSMC-specific Mettl14 knockout mice exhibited accelerated foam cell formation, enhanced vascular inflammation, and exacerbated atherosclerosis. These effects were driven by impaired beta-oxidation and reduced mitochondrial oxidative phosphorylation (OXPHOS). Replenishment of Mettl14 significantly attenuated these adverse effects. Specifically, METTL14 regulated phenotypic switching of VSMCs and modulated the number of VSMC-derived macrophage-like cells, rather than infiltrating macrophages, within atherosclerotic plaques. Furthermore, we demonstrated that METTL14 regulates the transcription of Ppara and Pparg, master regulators of lipid metabolism that promote cholesterol efflux, by enhancing SETD1A-mediated H3K4 trimethylation in an m6A-independent manner. Activation of PPAR-γ with rosiglitazone restored impaired mitochondrial OXPHOS in Mettl14-deficient VSMCs, leading to reduced lipid accumulation. Lastly, recapitulating Mettl14 expression in atherosclerotic vessels through AAV gene therapy effectively inhibited atherosclerosis progression without compromising liver function. We have unveiled that METTL14 promotes lipid metabolism and inhibits atherogenesis through activating PPAR-α/γ expression. These experiments highlight the therapeutic potential of the endogenous METTL14/PPAR-α/γ axis for treating atherosclerotic and metabolic diseases. Show less

CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort. Show less

Manganese and iron are essential trace elements involved in critical neuronal processes; however, excessive exposure to these metals is a significant risk factor for Alzheimer's disease (AD). While most previous studies have focused on single-metal neurotoxicity, the mechanisms underlying combined manganese and iron exposure remain unclear. In this study, we investigated the effects of manganese and iron exposure, both individually and in combination, on tau hyperphosphorylation, β-amyloid (Aβ) accumulation (particularly Aβ Show less

Despite of the highly potent antiretroviral therapies, HIV-1 establishes persistent infection and causes chronic inflammation in AIDS patients. Beyond CD4+ T cells, HIV-1 infects myeloid cells, including circulating monocytes and tissue-resident macrophages, and integrates with host genomes to form stable viral reservoirs. To achieve a functional HIV cure, latency-promoting agents (LPAs) have been developed for the "block-and-lock" strategy to reinforce deep HIV-1 latency and permanently silence proviruses. However, most LPAs have been tested mainly in CD4 Show less

Drug resistance is a major challenge in colorectal cancer (CRC) treatment. Overcoming drug resistance and improving therapeutic outcomes are crucial issues for patients with drug-resistant CRC. Crassocephalum rabens (Benth.) S. Moore (CR) is an edible plant and a folk medicine. Its galactolipids have anti-inflammatory and antitumor potential. This study explored the pharmacological mechanism and therapeutic efficacy of galactolipids isolated from CR (designated CRA) for treating drug-resistant CRC in vitro and in vivo. The antitumor activity and molecular mechanisms of CRA were investigated using cytotoxicity, reactive oxygen species (ROS) production, RNA sequencing, quantitative PCR (qPCR), Western blotting, and LPA concentration assays. Virtual molecular docking was conducted to identify CRA's action site on the target protein. The therapeutic effectiveness of CRA was evaluated using HT-29 xenograft mice. CRA induced ROS-mediated cytotoxicity by inhibiting the expression of interferon-α-induced protein 6 (IFI6). IFI6 suppression by CRA led to ROS accumulation and oxidative DNA damage, ultimately resulting in cell death. CRA antagonistically targeted lysophosphatidic acid receptors (LPAR), specifically LPAR2, and blocked their downstream signaling pathways, including PI3K/AKT/mTOR, Ras/Raf/p38, PLC/PKC, Rho/PKA, and NF-κB, which inhibited cell survival. Furthermore, CRA also inhibited the intracellular synthesis of LPA. In HT-29 tumor-bearing mice, CRA significantly reduced tumor growth. The antitumor activity of CRA, through inhibiting LPAR2 expression and inducing IFI6-mediated oxidative stress, was also observed in tumors. CR galactolipids directly targeted LPAR2, inhibited the LPAR2 signaling pathways, and induced IFI6-mediated ROS accumulation to combat drug-resistant CRC. Show less

The genetic influences on normal aortic valve function and their impact on aortic stenosis risk are of substantial interest. We used deep learning to measure peak velocity, mean gradient and aortic valve area from magnetic resonance imaging and conducted genome-wide association studies (GWAS) in 59,571 participants in the UK Biobank. Incorporating the aortic valve measurement GWAS with aortic stenosis GWAS using multitrait analysis of GWAS (MTAG), we identified 166 distinct loci (134 with aortic valve traits, 134 with aortic stenosis and 166 unique loci across all GWAS), including PCSK9 and LDLR. The MTAG aortic stenosis PGS was associated with aortic stenosis in All of Us (hazard ratio (HR) = 3.32 for top 5% versus all others, P = 8.8 × 10 Show less

Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) is critical for transporting lipoprotein lipase (LPL) to the capillary lumen, where LPL breaks down triglycerides in triglyceride-rich lipoproteins. We herein report a 12-year-old Chinese girl who presented with severe hypertriglyceridemia and a recent diagnosis of systemic lupus erythematosus (SLE). She was first noted to have severe hypertriglyceridemia at 8.5 years old, complicated by three episodes of acute pancreatitis within 2 years. Between these episodes, her plasma triglycerides remained elevated, but at lower levels. Next-generation sequencing for primary hypertriglyceridemia yielded no significant findings. Investigations for secondary causes, to include fasting glucose, HbA1c, and thyroid function testing, were unrevealing. Given the fluctuating triglyceride levels and negative genetic testing for primary hypertriglyceridemia in the background of SLE, autoimmune hypertriglyceridemia was suspected. The diagnosis of GPIHBP1 autoantibody syndrome was confirmed by an elevated GPIHBP1 autoantibody titer and a low LPL mass in her serum. Her SLE was well controlled with immunosuppressants and belimumab. Fenofibrate and omega-3 fatty acids, which were initially prescribed for her hypertriglyceridemia, were later discontinued. The GPIHBP1 autoantibody and LPL mass normalized 2 years after diagnosis. This case illustrates hypertriglyceridemia caused by a rare disease entity associated with autoantibodies against the GPIHBP1 protein. This entity is worth considering after excluding genetic and common secondary causes of hypertriglyceridemia, particularly in a patient with a history of autoimmune disease. Show less

Adherence to antiretroviral therapy is essential for achieving viral suppression. Plasma separation cards (HemaSep; HS-DBS) provide advantages for pharmacokinetic (PK) analysis and adherence monitoring, including simplified sample collection. This study compared the PK of dolutegravir (DTG), nucleoside reverse transcriptase inhibitors (NRTIs), and their intracellular metabolites in the dried plasma and cellular fractions of HS-DBS against the appropriate gold-standard matrices: liquid plasma for parent drugs and Whatman DBS (WM-DBS) for NRTI metabolites. The APT-POCT-01 clinical trial (NCT04302896) is an open-label study assessing drug concentrations following cessation in healthy volunteers. Participants were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Paired liquid plasma (L-pL), HS-DBS, and WM-DBS samples were collected on Day 15 and following treatment cessation (0-336 hours post-final dose). 29 individuals were included in the PK analysis (15-TDF/14-TAF). Tenofovir diphosphate (TFV-DP) was quantifiable up to 14 days post-cessation in HS-DBS (TAF/TDF) and WM-DBS (TDF) (HS-DBS t½ > 17 days, WM-DBS t½ = 15 days). 3TC-TP and FTC-TP were eliminated more rapidly. Nucleoside di/triphosphate concentrations were 3-7-fold higher, with prolonged half-lives (TFV-DP, FTC-TP), compared with WM-DBS. TFV-DP levels were ~12-fold higher with TDF compared to TAF. For NRTI and DTG, HS-plasma resulted in 1.8-fold higher exposures compared to L-pL. Measurable HS-DBS concentrations were correlated with L-pL and WM-DBS, with Bland-Altman analysis indicating agreement between methods. This study provides important insights into the elimination kinetics of NRTI, their intracellular metabolites and DTG. Plasma separation cards are a promising alternative for adherence monitoring, enabling simultaneous quantification of parent and intracellular moieties from a single sample. Differences in TFV-DP levels between TDF and TAF regimens, and DBS sampling method, underscore the need for matrix and regimen-specific interpretation to validate adherence benchmarks. Show less

Increased fasting and postprandial triglyceride levels are risk factors for cardiovascular disease (CVD). Partially metabolized triglyceride-rich lipoproteins (TRLs) termed remnants are created when intestinally-derived chylomicrons and liver secreted very low density lipoproteins (VLDLs) interact with lipoprotein lipase (LpL) situated on the luminal surface of capillary endothelial cells. Higher circulating remnant levels have been implicated as the reason for the relationship between TRL levels and CVD. We hypothesized that nascent lipoproteins not only remnants are atherogenic. To test this, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl Show less

Prostate cancer (PCa) is the most general cancer in men and is often linked with distant metastasis in its later stages. The caffeic acid (CA) derivative, N-(4-methoxyphenyl)methylcaffeamide (MPMCA), demonstrates superior liver-protective effects compared to CA. Nevertheless, the functions of MPMCA on prostate cancer metastasis remain unclear. Here, we demonstrate that MPMCA blocks migration and invasion in prostate cancer cells without affecting cell viability. By suppressing the production of mesenchymal markers Vimentin, N-cadherin and β-catenin and upregulating the production of the epithelial marker Zonula Occludens-1 (ZO-1), MPMCA also controls Epithelial-Mesenchymal Transition (EMT). The Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) pathway has been documented to regulate MPMCA-inhibited cell motility. Transfection with Snail and Slug cDNA reverses MPMCA's suppression of EMT, migration, and invasion in prostate cancer cells. Importantly, our in vivo data indicates that MPMCA reduces Snail and Slug expression and prostate cancer metastasis. Our evidence suggests that MPMCA is a novel therapeutic candidate for treating metastatic prostate cancer. Show less

While the benefits of almond consumption in reducing levels of TC and LDL-C are well established, the effects on additional lipids that have emerged as important predictors of cardiovascular disease, such as ApoB and the ratio of ApoB:ApoA, are not well characterized. In this systematic review and meta-analysis, the effects of almond consumption on blood lipids were comprehensively assessed. On 12 May 2025, ProQuest Dialog™ was used to search ten literature databases (AdisInsight: Trials; Allied & Complementary Medicine™; BIOSIS Previews 36 publications (48 almond-control datasets) representing 2485 participants were included. Almond consumption significantly reduced LDL-C (-0.132 mmol/L; 95% CI: -0.190, -0.075 mmol/L; Almond consumption improves levels of LDL-C, TC, non-HDL-C, TC:HDL-C, LDL-C:HDL-C, ApoB, and ApoB:ApoA, though dedicated clinical trials are needed to better understand effects on TG levels. Show less

Familial hypercholesterolaemia (FH) is a hereditary disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels, substantially increasing the risk of atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting therapies, including monoclonal antibodies and small interfering RNA (siRNA) agents, have emerged as effective lipid lowering therapies. To assess the efficacy and safety of PCSK9-targeting therapy on lipid biomarkers and adverse events in patients with FH, compared with placebo on the background of standard lipid-lowering therapy. A systematic review and meta-analysis were conducted, incorporating data from 23 randomised controlled trials involving adult and paediatric FH patients treated with PCSK9 inhibitors (PCSK9i) or siRNA, including alirocumab, bococizumab, evolocumab, tafolecimab and inclisiran. Eligible studies reported changes in LDL-C, apolipoprotein B (ApoB), lipoprotein a (Lp(a)), triglycerides (TGL) and adverse effects. Pooled mean differences (MDs) and ORs with 95% CIs were calculated using random-effects models, and heterogeneity was assessed with I² statistic. This meta-analysis was registered on PROSPERO (CRD42025631510). A total of 4282 patients were included. PCSK9-targeting therapies significantly reduced LDL-C levels compared with control therapies (MD=-46.64%; 95% CI -50.77% to -42.52%; p<0.00001) and TGL (MD=-15.18%; 95% CI -19.34% to -11.03%; p<0.00001). Significant reductions were also observed for ApoB (MD=-34.94%; 95% CI -40.89% to -28.99%; p<0.00001) and Lp(a) (MD=-22.7%; 95% CI -25.95% to -19.44%; p<0.00001). LDL-C, TGL and ApoB reduction were more significant in heterozygous FH patients than in homozygous patients. The safety profile of these therapies was favourable, with adverse event rates comparable to those of the controls. PCSK9i and Inclisiran demonstrate significant and sustained reductions in LDL-C, ApoB, Lp(a) and TGL in FH patients, especially in heterozygous FH patients. These agents are generally well-tolerated and represent effective treatment options for FH patients inadequately controlled by standard lipid-lowering therapies. Show less

This study aims to explore whether conventional and emerging biomarkers could improve risk discrimination and calibration in the secondary prevention of recurrent atherosclerotic cardiovascular disease (ASCVD), based on a model using predictors from SMART2 (Secondary Manifestations of ARTerial Disease). In a cohort of 20 658 UK Biobank participants with medical history of ASCVD, we analysed any improvement in C indices and net reclassification index (NRI) for future ASCVD events, following addition of lipoprotein A (LP-a), apolipoprotein B, Cystatin C, Hemoglobin A1c (HbA1c), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase, and alkaline phosphatase (ALP), to a model with predictors used in SMART2 for the outcome of recurrent major cardiovascular event. We also examined any improvement in C indices and NRIs replacing creatinine-based estimated glomerular filtration rate (eGFR) with Cystatin C-based estimates. Calibration plots between different models were also compared. Compared with the baseline model (C index = 0.663), modest increments in C indices were observed when adding HbA1c (ΔC = 0.0064, P < 0.001), Cystatin C (ΔC = 0.0037, P < 0.001), GGT (ΔC = 0.0023, P < 0.001), AST (ΔC = 0.0007, P < 0.005) or ALP (ΔC = 0.0010, P < 0.001) or replacing eGFRCr with eGFRCysC (ΔC = 0.0036, P < 0.001) or eGFRCr-CysC (ΔC = 0.00336, P < 0.001). Similarly, the strongest improvements in NRI were observed with the addition of HbA1c (NRI = 0.014) or Cystatin C (NRI = 0.006) or replacing eGFRCr with eGFRCr-CysC (NRI = 0.001) or eGFRCysC (NRI = 0.002). There was no evidence that adding biomarkers modified calibration. Adding several biomarkers, most notably Cystatin C and HbA1c, but not LP-a, in a model using SMART2 predictors modestly improved discrimination. Show less

Aberrant aggregation of amyloid-β (Aβ) peptides is a hallmark of Alzheimer's disease (AD), contributing to synaptic dysfunction and cognitive decline. Recently, pyroglutamate-modified Aβ (pE3-Aβ) has emerged as a key contributor to Aβ pathology, as it is a highly aggregation-prone variant that enhances amyloid seeding and accelerates plaque propagation. β-Secretase (BACE1) and glutaminyl cyclase (QC) are essential enzymes for generating Aβ and pE3-Aβ, respectively, and represent key therapeutic targets. This study evaluated fucoxanthin, a marine carotenoid found in brown algae for its potential to modulate Aβ pathology and cognitive function. In SweAPP N2a cells, fucoxanthin (0.1-5 μM) significantly decreased BACE1 and QC expression, accompanied by reduced levels of Aβ Show less

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management. Show less

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Lipoprotein (a) [Lp(a)] has emerged as an independent risk factor for CAD, but its role in predicting coronary severity in Vietnamese populations remains unclear. To evaluate the value of Lp(a) in predicting the severity of coronary artery stenosis in chronic CAD. This cross-sectional study was conducted at Tam Anh General Hospital from June 2024 to June 2025, including 138 patients diagnosed with chronic CAD. Demographic, clinical, laboratory, and coronary angiographic data were collected. CAD severity was assessed using the Gensini score. Logistic regression and ROC analysis were employed to evaluate the predicting value of Lp(a). Severe CAD (Gensini score >40) was present in 31.9% of the cohort. Patients with Lp(a) ≥30 mg/dL exhibited a significantly higher prevalence of severe CAD (72.5% vs. 8.0%). Lp(a) levels correlated strongly with the Gensini score. The optimal cut-off for predicting severe CAD was 30.6 mg/dL (AUC = 0.869). Multivariate analysis confirmed Lp(a) as an independent predictor. Lp(a) ≥30 mg/dL is strongly associated with severe coronary artery stenosis. Lp(a) is a valuable independent predictor of CAD severity and may serve as an essential tool for risk stratification in clinical practice. Show less

Hypertrophic cardiomyopathy (HCM) is an inherited cardiomyopathy often caused by pathogenic variants in MYBPC3 and MYH7, encoding myosin-binding protein C3 and myosin heavy chain 7, respectively. These variants can cause increased actin-myosin crossbridge cycling, resulting in ventricular hypercontractility, but mice lacking Mybpc3 exhibited reduced left ventricular ejection time (LVET) as a sign of systolic dysfunction. In this study, we tested whether LVET is specifically altered in patients carrying MYBPC3 variants by retrospective echocardiographic analysis in two genotype-defined HCM cohorts. LVET was measured by echocardiography and adjusted for heart rate [LVET index (LVETI)] in 166 patients. Variant carriers were stratified for the presence (LVH+) or absence of left ventricular hypertrophy with septal thickness of ≥13 mm (LVH-). Multivariate analysis of variance (MANOVA) was used to identify differences in LVETI between variant carriers and controls with LVETI as the dependent variable, adjusted for sex, age, left ventricular ejection fraction (LVEF), interventricular septal diameter in diastole (IVSd), diastolic dysfunction, left ventricular outflow tract (LVOT) gradient at rest and medication history as confounders. In a total of 166 patients carrying MYBPC3 or MYH7 pathogenic variants (38 ± 3 years, 45% female), we compared the discovery cohort (40 MYBPC3 and 31 MYH7) and the validation cohort ('Valsartan in Attenuating Disease Evolution in Early Sarcomeric HCM'; 54 MYBPC3 and 41 MYH7) with 44 healthy controls. LVETI was lower in MYBPC3 and higher in MYH7 LVH+ patients than in controls in the discovery, validation and pooled cohorts (pooled: MYBPC3 381 ± 19 ms vs. MYH7 437 ± 38 ms, P < 0.001; MYBPC3 vs. controls 411 ± 15 ms, P < 0.001; and MYH7 vs. controls, P < 0.001). Similar findings were seen in LVH- (pooled: MYBPC3 380 ± 16 ms vs. MYH7 437 ± 39 ms, P < 0.001; MYBPC3 vs. controls, P < 0.001). While MYH7 variants were all missense as expected, 87% of the MYBPC3 variants were truncating (including nonsense variants, out-of-frame deletion and splice site variants) and 13% were non-truncating (missense and in-frame deletion). LVETI did not differ between the groups and was significantly lower than the control in both. The data suggest that variants in MYBPC3 and MYH7 result in distinct biophysical consequences, which can be detected by measuring LVETI in patients. The findings may have implications for potential genotype-specific differences in response to therapies targeting sarcomere function. Show less

Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM, with the majority of mutations resulting in haploinsufficiency. To restore cardiac MYBPC3, we use an adeno-associated virus (AAV9) vector and engineer an optimized expression cassette with a minimal promoter and cis-regulatory elements (TN-201) to enhance packaging efficiency and cardiomyocyte expression. Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival. Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. These findings suggest that TN-201 may offer therapeutic benefits in MYBPC3-associated cardiomyopathy, pending further validation in clinical settings. Show less

Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry. Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for females and males to find the sex-specific hazard ratio (HR). After a mean follow-up of 6.4 years, females had a higher risk of heart failure (HR, 1.51 [95% CI, 1.21-1.88]; We found that clinical and genetic factors contributing to adverse outcomes in hypertrophic cardiomyopathy affect females and males differently. Thus, research to inform sex-specific management of hypertrophic cardiomyopathy could improve outcomes for both sexes. Show less

Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10 Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM. Show less

Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration. Show less

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10 Show less

Although molecular tests developed for a growing list of oncogenic alterations have significantly aided in the classification of head and neck carcinomas, tumours in which prototypical histologic and immunophenotypic features are lacking or only partially developed continue to pose diagnostic challenges. Searching for known diagnostic and therapeutic targets by clinical next-generation sequencing (NGS) assays can often lead to new discoveries. We present our institutional experience in applying targeted RNA NGS in 36 head and neck carcinomas that were morphologically difficult to classify between 2016 and 2023. The patients ranged in age from 5 to 83 years (median, 64), with the majority of tumors occurring in the major salivary glands and the sinonasal tract. Overall, seven (19%) cases showed unusual gene rearrangements, including five novel alterations: MON2::STAT6 in a hard palate adenocarcinoma with mucinous features, POC5::RAF1 in apocrine intraductal carcinoma of the lacrimal gland, EWSR1::CDADC1 fusion in a basaloid carcinoma of the submandibular gland, NFATC2::NUTM2B in myoepithelial carcinoma, and NSD3::NCOA2 fusion in a peculiar high-grade carcinoma with a peritheliomatous growth pattern, and focal myogenic differentiation. Potential therapeutic actionability was identified in three cases (RAF1 and FGFR2 fusions). These findings broaden the current spectrum of gene rearrangements in head and neck carcinomas and support the utility of clinical NGS in identifying unusual, actionable alterations in diagnostically challenging cases. Show less

The intricate involvement of the histaminergic system, encompassing histamine and histamine receptors, in the progression of diverse neoplasias has attracted considerable scrutiny. Histamine receptor H1 (HRH1) was reported to be overexpressed in several cancer types, but its specific functional implications in oral squamous cell carcinoma (OSCC) predominantly remain unexplored. Our findings indicate that dysregulated high levels of HRH1 were correlated with lymph node (LN) metastasis and poor prognoses in OSCC patients. We identified a disintegrin and metalloprotease 9 (ADAM9) as a critical downstream target of HRH1, promoting protumorigenic and prometastatic characteristics both in vitro and in vivo. Molecular investigations revealed that the cyclic increase in the HRH1-ADAM9-Snail/Slug axis promoted progression of the epithelial-to-mesenchymal transition (EMT). Clinical analyses demonstrated significant correlations of HRH1 expression with ADAM9 and with EMT-related markers, with elevated ADAM9 also associated with LN metastasis in OSCC patients. Regarding therapeutic aspects, we discovered that activated STAT3 acts as a compensatory pathway for the long-term HRH1 signaling blockade in OSCC cells. Combining inhibition of HRH1 and STAT3 using their respective inhibitors or short hairpin (sh)RNAs enhanced the tumor-suppressive effects compared to HRH1 inhibition/depletion alone in OSCC cells and a xenograft model. In summary, HRH1 has emerged as a valuable biomarker for predicting OSCC progression, and combined targeting of HRH1 and STAT3 may represent a promising strategy for preventing OSCC progression. Show less

Palmitoylation, a lipid-based posttranslational protein modification, plays a crucial role in regulating various aspects of neuronal function through altering protein membrane-targeting, stabilities, and protein-protein interaction profiles. Disruption of palmitoylation has recently garnered attention as disease mechanism in neurodegeneration. Many proteins implicated in neurodegenerative diseases and associated neuronal dysfunction, including but not limited to amyloid precursor protein, β-secretase (BACE1), postsynaptic density protein 95, Fyn, synaptotagmin-11, mutant huntingtin, and mutant superoxide dismutase 1, undergo palmitoylation, and recent evidence suggests that altered palmitoylation contributes to the pathological characteristics of these proteins and associated disruption of cellular processes. In addition, dysfunction of enzymes that catalyze palmitoylation and depalmitoylation has been connected to the development of neurological disorders. This review highlights some of the latest advances in our understanding of palmitoylation regulation in neurodegenerative diseases and explores potential therapeutic implications. Show less

Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. We generated LDL receptor-deficient ( Diabetic Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux. Show less