👤 Quoc-Dung Tran Huynh

Abdominal aortic aneurysm (AAA) is a serious disease with no effective pharmacological therapy. Although inflammation is recognized as a key regulator of AAA, targeting inflammatory pathways once the disease is established does not improve outcomes. Understanding the earliest molecular indicators could clarify precise biological targets and prognostic markers for AAA. Using ApoE-deficient mice, we performed RNA-Seq on suprarenal abdominal aortas (SRAs) from Ang II- and saline-treated mice 24 h after infusion. We further developed a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) can be conditionally suppressed in vascular smooth muscle cells (VSMCs). RNA-Seq data revealed early IKKβ-dependent cellular anabolic processes in SRAs, including activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, deletion of the Show less

Chemical investigation of the soft coral Sclerophytum humesi led to the discovery of (±)-norsclerohumin A (1), a pair of enantiomeric norsesquiterpenoids possessing an unprecedented oxatricyclo[7.2.1.0 Show less

This pilot randomized controlled trial (RCT) evaluated the efficacy of a behavioral intervention grounded in the Capability-Opportunity-Motivation-Behavior (COM-B) model delivered via online coaching and newsletters for promoting physical activity (PA) in people newly diagnosed with multiple sclerosis (PNDwMS). This unblinded, parallel-group, RCT included 50 PNDwMS (disease duration ≤ 2 years) who were randomized into either PA intervention (n = 25) or waitlist control (WLC) (n = 25) conditions. The intervention was delivered over 16 weeks by a researcher uninvolved in randomization. Data were collected pre- and post-intervention. Primary outcomes included device-measured (steps/day, light PA [LPA], moderate-to-vigorous PA [MVPA]) and self-reported PA (Godin Leisure-Time Exercise Questionnaire [GLTEQ] and International Physical Activity Questionnaire [IPAQ]). Secondary outcomes included fatigue, depression, anxiety, and health-related quality of life (HRQOL). Data were analyzed (intent-to-treat) using condition-by-time mixed-effects ANOVA. There were significant condition-by-time interactions on device-measured (MVPA) and self-reported (IPAQ) PA as well as depression and mental HRQOL (all p ≤ .05). There were moderate and significant improvements in MVPA (Δ11.2 min/day, 95% CI: 8.8, 13.7, d = 0.5) and IPAQ (Δ11.4 units, 95% CI: 10.4, 12.3, d = 0.7), HADS-D (Δ1.4 units, 95% CI: 1.3, 1.5, d = 0.5), and SF-12 MCS (Δ5.6 units, 95% CI: 5.1, 6.1, d = 0.6) scores in the PA intervention condition, but not in the WLC condition. These findings provide preliminary evidence for the efficacy of the COM-B-based behavioral intervention for increasing PA and improving mental health outcomes in PNDwMS. Show less

Lipids are a principal component of drusen and are involved in the pathobiology of age-related macular degeneration (AMD). Nonhuman primates (NHPs) develop macular drusen and may provide insight into circulating or local lipids in AMD. We evaluated aged rhesus macaques by fundus photography, optical coherence tomography (OCT), and fundus autofluorescence, as well as measured fasting plasma glucose, total cholesterol, high- and low-density lipoproteins, triglycerides, and apolipoprotein (Apo) A1, B, CIII, and E. Retinal tissues were collected for electron microscopy and immunostained for oil red O, ApoE, and ApoB. Among 203 adult macaques (mean age 19.1 ± 3.1 years), 25 animals (12.1%) exhibited soft drusen with sub-RPE deposits, while 59 (28.6%) had yellow punctate dots that were mostly hyperautofluorescent without RPE elevation on OCT. Drusen prevalence increased with older age (P = 0.001) but not with plasma lipids (P > 0.05 for all), while the punctate dot phenotype was associated with older age (P = 0.014), higher fasting glucose (P = 0.023), low-density lipoprotein cholesterol (P = 0.022), and ApoB (P = 0.017). Ultrastructure revealed NHP drusen consisting of extracellular sub-RPE lipid particles, whereas punctate dots appeared to correspond to individual RPE cells with intracellular lipid vacuoles. Both sub-RPE and intra-RPE lipids of the two phenotypes contained neutral lipids and ApoE, while ApoE and ApoB appeared to be expressed in RPE. In rhesus macaques, soft drusen are extracellular lipid deposits associated with older age, while punctate dots are intracellular lipids linked to age, hyperglycemia, and hyperlipidemia, suggesting differential dysregulation of lipid transport in these NHP models of AMD. Show less

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of Cln3 Show less

Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease. Show less

Dilated cardiomyopathy (DCM) is an important cause of heart failure and cardiac transplantation. This study determined the prevalence of DCM-associated genes and evaluated the genotype-phenotype correlation in Vietnamese patients. This study analyzed 58 genes from 230 patients. The study cohort consisted of 64.3% men; age at diagnosis 47.9±13.7 years; familial (10.9%) and sporadic DCM (82.2%). The diagnostic yield was 23.5%, 44.0% in familial and 19.6% in sporadic DCM.TTNtruncating variants (TTNtv) were predominant (46.4%), followed byTPM1,DSP,LMNA,MYBPC3,MYH6,MYH7,DES,TNNT2,ACTC1,ACTN2,BAG3,DMD,FKTN,PLN,TBX5,RBM20,TCAP(2-6%). Familial DCM, genotype-positive andTTNtv-positive patients were younger than those with genotype-negative and sporadic DCM. Genotype-positive patients displayed a decreased systolic blood pressure and left ventricular wall thickness compared to genotype-negative patients. Genotype-positive patients, particularly those withTTNtv, had a family history of DCM, higher left atrial volume index and body mass index, and lower right ventricle-fractional area change than genotype-negative patients. Genotype-positive patients reached the combined outcomes more frequently and at a younger age than genotype-negative patients. Major cardiac events occurred more frequently in patients positive with genes other thanTTNtv. The study findings provided an overview of Vietnamese DCM patients' genetic profile and suggested that management of environmental factors may be beneficial for DCM patients. Show less

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h Show less

Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk. Show less

15q24 microdeletion and microduplication syndromes are genetic disorders caused by non-allelic homologous recombination between low-copy repeats (LCRs) in the 15q24 chromosome region. Individuals with 15q24 microdeletion and microduplication syndromes share a common 1.2 Mb critical interval, spanning from LCR15q24B to LCR15q24C. Patients with 15q24 microdeletion syndrome exhibit distinct dysmorphic features, microcephaly, variable developmental delay, multiples congenital anomalies while individuals with reciprocal 15q24 microduplication syndrome show mild developmental delay, facial dysmorphism associated with skeletal and genital abnormalities. We report the first case of a 10 year-old girl presenting mild developmental delay, psychomotor retardation, epilepsy, ventricular arrhythmia, overweight and idiopathic central precocious puberty. 180K array-CGH analysis identified a 1.38 Mb heterozygous interstitial 15q24.1 BP4-BP1 microdeletion including HCN4 combined with a concomitant 2.6 Mb heterozygous distal 15q24.2q24.3 microduplication. FISH analysis showed that both deletion and duplication occurred de novo in the proband. Of note, both copy number imbalances did not involve the 1.2 Mb minimal deletion/duplication critical interval of the 15q24.1q24.2 chromosome region (74.3-75.5 Mb). Sequencing of candidate genes for epilepsy and obesity showed that the proband was hemizygous for paternal A-at risk allele of BBS4 rs7178130 and NPTN rs7171755 predisposing to obesity, epilepsy and intellectual deficits. Our study highlights the complex interaction of functional polymorphisms and/or genetic variants leading to variable clinical manifestations in patients with submicroscopic chromosomal aberrations. Show less

High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943. Show less

Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay. Show less