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Impaired decidualization is associated with recurrent implantation failure (RIF) and lysophosphatidic acid (LPA) is known to play an important role in decidua formation. However, the specific impact of LPA in endometrial decidualization during RIF remains unclear. Metabolomics analysis was performed to identify differentially expressed metabolites (DEMs) in RIF patients Expression of the LPA receptor subtypes, LPAR1-6, was detected in both GEO datasets and clinical endometrial samples. An LPA was identified as a pivotal metabolite in RIF. Among the LPA receptors, LPAR1 and LPAR6 were highly expressed during LPA plays a significant role in the decidualization process of hESCs by regulating LPAR6, rather than LPAR1, providing insights into potential therapeutic target for RIF. Show less

Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21 Show less

Hepatoblastoma (HB) is a rare embryonal liver tumor, with an increasing global incidence that underscores the need to understand its genetic etiology. Utilizing the ancestry-matched expression quantitative loci data, we performed a HB transcriptome-wide association study (TWAS) on 4,539 Europeans, 1,047 Latinos, and 378 African Americans (∼1:10 case-control ratio). We conducted a meta-analysis of multiancestry transcriptome-wide analysis (METRO), followed by METRO-Egger sensitivity analysis and ancestry-specific gene set enrichment analyses. We further explored genes with additional evidence gathered from independent cohorts and databases. Across the three ancestries, the discovered genes shared the same effect direction across ancestries. A meta-analysis of the three ancestries identified 28 genes significantly associated with HB risk, and 15 were nominally significant for at least two ancestries. Our post-TWAS analyses highlighted 8 genes among these 28, including OXER1 (meta-analysis P value = 7.34 × 10-6), FADS1 (P value = 4.01 × 10-6), and UGDH (P value = 5.29 × 10-8), which were expressed in fetal liver hepatoblast cells and were differentially expressed in tumor and normal tissues in an independent Japanese HB study (P values = 2.61 × 10-13, 3.62 × 10-3, and 1.95 × 10-9, respectively). We pinpointed eight potential genes associated with HB using data from an ongoing multiancestry genome-wide association study. We conducted the largest HB TWAS to date, prompting further exploration of genes. 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

To investigate the causal relationship between various lipid-modifying drugs and new-onset diabetes, as well as the mediators contributing to this relationship. Mediation Mendelian randomization was performed to investigate the causal effect of lipid-modifying drug targets on type 2 diabetes (T2D) outcomes and the proportion of this association that is mediated through ectopic fat accumulation traits. Specific sets of variants in or near genes that encode 11 lipid-modifying drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, ABCG5/ABCG8, LPL, PPARA, ANGPTL3, APOC3, and CETP; for expansion of gene symbols, use search tool at www.genenames.org) were extracted. Random effects inverse variance weighted were performed to evaluate the causal effects among outcomes. Mediation analyses were performed to identify the mediators of the association between lipid-modifying drugs and T2D. The study was conducted from November 10, 2023, to April 2, 2024 RESULTS: The genetic mimicry of HMGCR and APOB inhibition was associated with an increased T2D risk, whereas the genetic mimicry of LPL enhancement was linked to a lower T2D risk. Gluteofemoral adipose tissue volume was a mediator for explaining 9.52% (P=.002), 16.90% (P=.03), and 10.50% (P=.003) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Liver fat was a mediator for explaining 21.12% (P=.005), 12.28% (P=.03), and 9.84% (P=.005) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Our findings support the hypothesis that liver fat and gluteofemoral adipose tissue play a mediating role in the prodiabetic effects of HMGCR and APOB inhibition, as well as in the antidiabetic effects of LPL enhancement. Show less

This study aimed to assess the extent to which human participants co-represent the lexico-semantic processing of a humanoid robot partner. Specifically, we investigated whether participants would engage their speech production system to predict the robot's upcoming words, and how they would progressively adapt to the robot's verbal behaviour. In the experiment, a human participant and a robot alternated in naming pictures of objects from 15 semantic categories, while the participant's electrophysiological activity was recorded. We manipulated word frequency as a measure of lexical access, with half of the pictures associated with high-frequency names and the other half with low-frequency names. In addition, the robot was programmed to provide semantic category labels (e.g., "tool" for the picture of a hammer) instead of the more typical basic-level names (e.g., "hammer") for items in five categories. Analysis of the stimulus-locked activity revealed a comparable event-related potential (ERP) associated with word frequency both when it was the participant's and the robot's turn to speak. Analysis of the response-locked activity showed a different pattern for the category and basic-level responses in the first but not in the second part of the experiment, suggesting that participants adapted to the robot's lexico-semantic patterns over time. These findings provide empirical evidence for two key points: (1) participants engage their speech production system to predict the robot's upcoming words and (2) partner-adaptive behaviour facilitates comprehension of the robot's speech. Show less

PARP-inhibitors (PARPi) are an integral part of ovarian cancer treatment. However, overcoming acquired PARPi resistance or increasing the benefit of PARPi in patients without homologous recombination deficiency (HRD) remains an unmet clinical need. We sought to identify genetic modulators of PARPi response, guiding pharmacological PARPi sensitization. CRISPR-Cas9 mediated loss-of-function screen with a focused sgRNA library revealed that DNA-demethylases JMJD1B/JMJD1C, targetable by the small inhibitor methylstat, promote PARPi resistance. Methylstat synergistically interacted with olaparib, and (re-)sensitized ovarian cancer cells to PARPi treatment, surpassing the efficacy of common demethylase inhibitors. Genetic knockout of JMJD1B and/or JMJD1C phenocopied the effect of methylstat in an additive manner. Validation studies revealed methylstat to be a universal PARPi-sensitizing drug, effective, regardless of PARPi resistance status or BRCA1 mutational background. Methylstat modulated clonal cancer dynamics by mitigating positive selection of PARPi-resistant or BRCA1-proficient cells under olaparib treatment. Using a model of PARPi-induced cellular toxicity, we showed that methylstat impairs cellular DNA repair, indicated by an increased susceptibility of ovarian cancer cells to olaparib-induced DNA double strand breaks after methylstat exposure. This study proposes the histone demethylase inhibitor methylstat as an epigenetic drug for overcoming PARPi-resistance or for increasing efficacy of PARPi beyond HRD in ovarian cancer patients. Show less

Aberrant fibroblast growth factor receptor (FGFR)-driven signaling, predominantly arising from FGFR2 amplification, plays a key role in gastric cancer pathogenesis. This open-label, phase 2 study evaluated the efficacy and safety of futibatinib, an irreversible FGFR1-4 inhibitor, in patients with gastric or gastroesophageal junction (GEJ) cancer harboring FGFR2 amplifications. Patients were treated with futibatinib 20 mg orally once daily in a 28-day cycle. The primary endpoint was objective response rate (ORR) per independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Among 28 treated patients, the ORR per independent central review was 17.9 %, comprising five patients with a partial response (median duration of response, 3.9 months), and an additional nine patients with stable disease for a disease control rate of 50.0 %. Median PFS per independent central review and median OS were 2.9 and 5.9 months, respectively. The most common treatment-related adverse events (any grade) were hyperphosphatemia (89.3 %), decreased appetite (32.1 %), and increased aspartate aminotransferase (21.4 %). Only one (3.6 %) patient discontinued study treatment due to an adverse event. Futibatinib demonstrated modest antitumor activity with a safety profile consistent with previous reports in patients with gastric or GEJ cancer harboring FGFR2 amplifications, potentially warranting further investigation. Show less

Obesity-related genetic disorders are marked by severe, early-onset obesity caused by mutations that disrupt key biological mechanisms regulating hunger, energy balance, and fat storage. These disorders commonly impact systems such as the hypothalamic leptin-melanocortin signaling network, which plays a crucial role in controlling appetite and body weight, mainly through the melanocortin-4 receptor (MC4R) pathway. This review explores current management strategies and emerging therapies for genetic obesity disorders, highlighting the importance of treatment approaches and expanded genetic diagnostics to improve outcomes for affected individuals. Show less

The Rare Gynecologic Sarcoma study involved 23 institutions from 10 countries focusing on myxoid leiomyosarcoma and non-smooth muscle uterine sarcomas. Here, we present the main results of the study, including the comparison between the original and final diagnosis, the frequency and type of molecular aberrations, and the clinicopathologic outcomes. A total of 379 cases were included, with available results for next-generation sequencing (NGS) RNA in 338 of 379 cases and NGS DNA in 335 of 379 cases. According to the original diagnoses, the study included 204 cases of low-grade endometrial stromal sarcoma (LG-ESS), 75 cases of high-grade endometrial stromal sarcoma (HG-ESS), 74 cases of undifferentiated uterine sarcoma (UUS), 17 cases of myxoid leiomyosarcoma, and 9 cases of unclassifiable sarcoma. The results of our second reading showed that 29% (110/379) of all the tumors had been originally misdiagnosed. After the reclassification, the final diagnoses were 147 cases of LG-ESS, 69 cases of HG-ESS, 58 cases of UUS, 3 cases of LG-ESS with high-grade transformation, 7 cases of perivascular epithelioid cell tumor, 9 cases of uterine tumor resembling ovarian sex cord tumor, 8 cases of tumors with a KAT6B/A::KANSL1 fusion, 2 cases of tumors with an NTRK fusion, 29 cases of undifferentiated carcinoma, and 47 tumors with smooth muscle differentiation. The molecular testing showed that LG-ESS harbor a recurrent fusion in 75.9% and HG-ESS in 43.7% of cases. The results of our study emphasize the diagnostic, prognostic, and predictive significance of molecular testing in mesenchymal uterine tumors. Show less

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk. Show less

Gastric cancer (GC) is a common malignant tumor, which originated from the epithelial cells of the stomach. It has the characteristics of high incidence and poor prognosis. Therefore, it is urgent to find new prognostic markers for the diagnosis and treatment of GC. Download gene expression matrix and clinical data from TCGA database and GSE84437 dataset. Through independent prognostic analysis and clinical correlation analysis, 74 prognostic related genes (PRG) were screened out. A PPI network was established for PRG to identify four key genes (KG), namely LMOD1, CRYAB, VCL and MYL9. Survival analysis showed that patients with high expression of KG had poor prognosis. Multivariate Cox regression analysis showed that KG was an independent prognostic factor. TCGA database verifies the importance and significance of KG as a prognostic indicator. Functional enrichment analysis showed that KG was mainly involved in cell adhesion molecules, adhesion spots and PI3K/AKT signaling pathway. KG may be a potential therapeutic target for gastric cancer. Show less

Calcific aortic valve disease (CAVD) is characterized by progressive leaflet thickening and calcification, with no available pharmacological treatments. Plasma proteins play a pivotal role in disease regulation. This study aimed to uncover novel therapeutic targets for CAVD using Mendelian randomization (MR) integrated with transcriptomic analysis. Protein quantitative trait loci (pQTL) from the deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) plasma protein databases were used as exposure data. The FinnGen cohort (9870 cases, 402,311 controls) served as the discovery set, while the TARGET cohort (13,765 cases, 640,102 controls) provided validation. MR and summary data-based Mendelian randomization (SMR) were employed to screen for potential causal targets of CAVD. Colocalization analysis was conducted to assess whether CAVD and target proteins shared common causal SNPs. Additional analyses included trancriptomic profiling at multiple RNA levels. Protein-level validation was conducted via Western blot and immunostaining. Six proteins (ANGPTL4, PCSK9, ITGAV, CTSB, GNPTG, and FURIN) with strong genetic colocalization were identified by MR and SMR analysis. Among these, cellular trancriptomic analysis revealed ANGPTL4 and ITGAV with significantly greater expression in osteogenic group, which was further validated in calcified aortic valves and osteogenic valvular interstitial cells in protein level. This study identified six causal proteins with strong genetic colocalization for CAVD, with ANGPTL4 and ITGAV emerging as the most promising targets for further investigation. Show less

Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived N-amidinopyrrolidine scaffold. The initially synthesized derivative 7a showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure-activity relationship studies showed that introducing a substituent at the meta position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative 12f. In contrast, substituents at the para position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2S,4R)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors. Show less

Emerging evidences suggest that autophagy, a key cellular process responsible for degrading and recycling damaged organelles and proteins, plays a crucial role in maintaining neuronal health. Dysfunctional autophagy has been linked to the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of misfolded proteins and cellular debris. Molecular mechanisms underlying autophagy dysfunction in AD involve amyloid-beta (Aβ) and tau accumulation, neuroinflammation, mitochondrial dysfunction, oxidative stress and endoplasmic reticulum stress. Disrupted signaling pathways such as TRIB3, Nmnat and BAG3 that regulate key processes like autophagosome initiation, lysosome function, and protein homeostasis also play a crucial role in the pathogenesis. Restoration of autophagy by modulating these molecular and signaling pathways may be an effective therapeutic strategy for AD. Studies have found few drugs targeting autophagy dysregulation in AD. These drugs include metformin that has been found to modulate the expression of TRIB3 for autophagy regulation. Another drug, resveratrol has been reported to augment the activity of Nmnat thus, increases autophagy flux. BACE1 and mTOR inhibitors like arctigenin, nilvadipine and dapagliflozin were also found to restore autophagy. This study elaborates recent advances in signaling and molecular pathways and discusses current and emerging therapeutic interventions targeting autophagy dysfunction in AD. Show less

The development of cerebral infarction is multifactorial, including both environmental and genetic factors. This study assessed the association between fibroblast growth factor (FGF)-related gene polymorphisms and the incidence of cerebral infarction among patients on direct oral anticoagulants (DOACs). Patients over 18 years old with atrial fibrillation who were receiving DOACs for cerebral infarction prevention at Ewha Womans University Mokdong Hospital and Ewha Womans University Seoul Hospital were enrolled in this analysis. Twenty-one single nucleotide polymorphisms (SNPs) from FGF1, FGF2, and FGFR1 were examined. In multivariable logistic regression analysis, three models (Model I: demographic factors only, Model II: demographic factors and genetic factors, and Model III: genetic factors and the CHA Among the 536 candidate patients, 21 (3.9 %) experienced cerebral infarction while taking DOACs. From Model I and Model II, age ≥ 75 years and previous thromboembolic event history increased the risk of cerebral infarction. For genetic factors in Model II and III, FGF1 rs1596776 GG, FGFR1 rs6996321 AA, and FGFR1 rs7012413 TT genotypes were associated with a higher risk of cerebral infarction. The area under the receiver operating curve increased from 0.747 (Model I) to 0.822 (Model II) by adding genetic factors, demonstrating better model performance. This study uncovered the association between FGF-related gene polymorphisms and cerebral infarction among patients with atrial fibrillation undergoing DOAC therapy. Show less

Susceptibility to obesity differs depending on the genetic background and housing temperatures. We have recently reported that CETP expressing female mice are leaner due to increased lipolysis, brown adipose tissue (BAT) activity, and body energy expenditure compared to nontransgenic (NTg) littermates under standard housing temperature (22°C). The aim of this study is to evaluate how CETP expression affects body temperature, composition, and metabolism during cold exposure (4°C) and thermoneutrality (30°C). When submitted to cold, CETP mice maintained rectal temperature, body weight, and food intake similarly to NTg mice along acute or chronic exposure to 4°C. The body oxygen consumption in response to an isoproterenol challenge was 21% higher at 22°C, and 41% higher after 7 days of cold exposure in CETP than in NTg mice. In addition, BAT biopsies from CETP mice showed reduced lipid content and increased basal oxygen consumption rates. Under thermoneutrality (30°C), when BAT activity is inhibited, CETP mice showed higher rectal and tail temperatures, increased food intake, and increased energy expenditure. Lean mass was elevated and fat mass reduced in CETP mice kept at 30°C. In this thermoneutral condition, soleus muscle, but not gastrocnemius or liver of CETP mice, showed increased mitochondrial respiration rates. These data indicate that CETP expression confers a greater capacity of elevating body metabolic rates at both cold exposure, through BAT activity, and at thermoneutrality, through increased muscle metabolism. Thus, the CETP expression levels in females should be considered as a new influence in the contexts of obesity and metabolic disorders propensity. Show less

Recent introduction of new steatotic liver disease categorizations has necessitated updated epidemiologic studies. Specifically, recognition of (1) "MetALD" defined as where metabolic dysfunction-associated steatotic liver disease (MASLD) overlaps with alcohol use and (2) alcohol-related liver disease (ALD) without cardiometabolic risk factors (CMRFs) creates new clinical phenotypes with undefined prevalence. We conducted a cross-sectional multicenter analysis of liver disease associated with alcohol use (ALD and MetALD). We included adults with an International Classification of Diseases (ICD) diagnosis of ALD or both metabolic dysfunction associated liver disease and alcohol use disorder assigned from 1/1/2000-1/1/2024. Among 4057 patients, only 118 (2.9%) did not have any CMRF ("pure ALD"). Compared to patients with CMRF, patients with pure ALD were more commonly female (56% [0 CRMF] vs. 48%, 45%, 38%, and 42% [1, 2, 3, and 4 CMRFs, respectively]; ALD without diagnosed metabolic disease is uncommon and associated with higher rates of cirrhosis, HCC, and all-cause mortality than ALD with concurrent CMRF. Having a BMI measuring 25-30 kg/m Show less

The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate. Using genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness. The genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs. Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995-0.999], P = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996-0.999], P = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively. Our study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue. Show less

Microcystin-LR (MC-LR) is a toxin that causes hepatic steatosis. Our previous study found that exposure to 60 μg/L MC-LR for 9 months resulted in liver lipid accumulation, but the underlying mechanisms remain elusive. Herein, for the first time, fatty acid-targeted metabolome and RNA-seq were combined to probe the effect and mechanism of chronic (12-month) MC-LR treatment on mice lipid metabolism at environmental-related levels (1, 60, and 120 μg/L). It was found that MC-LR dose-dependently raised serum and liver lipid levels. The total cholesterol (TC) levels in the liver were significantly increased following treatment with 1 μg/L MC-LR (equivalent to 0.004 μ/L in human). Treatment with 60 and 120 μg/L MC-LR significantly elevated TC and triglyceride (TG) levels in both serum and liver. Serum fatty acid-targeted metabolome analysis demonstrated that exposure to 1, 60, and 120 μg/L MC-LR caused significant alterations in the fatty acid profile. Chronic 1, 60, and 120 μg/L MC-LR treatment significantly increased serum polyunsaturated fatty acids (PUFAs), including conjugated linoleic acid and eicosapentaenoic acid, which positively correlated with serum or liver TG levels. Chronic exposure to 120 μg/L MC-LR led to a significant decrease in the accumulation of saturated fatty acids, including citramalic acid, pentadecanoic acid, and docosanoic acid, which were negatively correlated with serum or liver lipid levels. These findings suggested that 1 μg/L MC-LR exposure caused mild lipid metabolism disruption, while 60 and 120 μg/L MC-LR treatment resulted in pronounced hepatic steatosis in mice. Transcriptome analysis revealed that chronic environmental MC-LR treatment regulated the expression of genes involved in the phosphatidylinositol 3-kinase (PI3K) complex and fatty acid metabolism. Western blotting and RT-qPCR confirmed that chronic environmental MC-LR exposure activated the PI3K/AKT/mTOR signaling pathway, the downstream of Show less

The aim of this review is to provide an overview of severe hypertriglyceridemia presenting in the form of chylomicronemia that persists despite treatment of secondary causes and the use of conventional lipid-lowering treatment. Persistent chylomicronemia is a rare syndromic disorder that affects carriers of bi-allelic combinations of pathogenic gene variants impairing lipoprotein lipase (LPL) activity, as well as a significant number of individuals who do not meet this genetic criterion. It is associated with a high risk of acute pancreatitis and other morbidities. Effective innovative treatments for severe hypertriglyceridemia are being developed and are becoming available. Patients with persistent chylomicronemia of any cause respond equally to next-generation therapies with LPL-independent mechanisms of action and do not generally respond to conventional LPL-dependent treatments. Not all individuals with persistent chylomicronemia carry a proven pathogenic combination of gene variants that impair LPL activity. Documenting the clinical characteristics of people with persistent chylomicronemia and their response to emerging therapies is essential to correctly establish their risk trajectory and ensure equitable access to personalized treatment. Show less

Lewy body dementia (LBD) is the second common dementia, with unclear mechanisms and limited treatment options. Dyslipidemia has been implicated in LBD, but the role of lipid-lowering drugs remains underexplored. This study aims to investigate the association between lipid traits, drug targets, and LBD risk using Mendelian Randomization (MR) analysis. We performed univariable and multivariable MR analyses to evaluate the causal effects of lipid traits on the risk of LBD. Then, drug-target MR analysis and subtype analysis were conducted to evaluate the effects of lipid-lowering therapies on LBD. In univariable MR, genetically predicted low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) levels were associated with an increased risk of LBD. Mediation analysis suggested a potential interaction between LDL-C and RC in influencing LBD risk. Drug-target MR analysis identified significant associations between genetically proxied inhibition of ANGPTL3, CETP, and HMGCR and LBD risk. This MR analysis provided evidence that elevated LDL-C and RC may increase the risk of LBD. Additionally, targeting ANGPTL3, CETP, and HMGCR may represent potential therapeutic strategies for the prevention or treatment of LBD. Show less

Lipid processing in the retinal pigment epithelium (RPE) is important for maintaining the health and function of the neural retina and the RPE itself. One mode of en mass lipid transport from the RPE is apolipoprotein B-containing lipoproteins (Blps), the assembly of which is regulated by microsomal triglyceride transfer protein (MTP). To gain an initial understanding of how the loss of MTP and, thereby, Blp secretion alters other lipid processing pathways in the RPE, we measured the expression of proteins associated with β-oxidation and lipid droplets in mice lacking MTP expression in the RPE (RPEΔMttp) and age-matched controls. Expression of perilipin 2, a lipid droplet-associated protein, nearly doubled in the RPE of RPEΔMttp, and its localization with neutral lipids also increased. Meanwhile, expression of CPT1A, which mediates the transport of fatty acids into the mitochondria for β-oxidation, was unaffected. These results suggest that the loss of Blp assembly alters intracellular lipid storage patterns. Future studies will examine the effects of the loss of RPE-specific MTP expression and Blp secretion on additional lipid processing pathways. Show less

Genes associated with body mass index (BMI), including FTO rs9939609,MC4R rs17782313, and BDNF rs6265, may influence BMI and regulate energy metabolism. While previous studies have explored health-related behavior changes, few have investigated both biochemical and behavior changes resulting from perceived genetic risk. This study investigated whether recognizing BMI-related genes affects health-related behaviors and alters blood metabolite levels. Normal and overweight adults aged 25-35 years (n = 100) were randomly assigned to an intervention group (n = 65) informed about BMI-related genetic information (FTO rs9939609, MC4R rs17782313, BDNF rs6265) and an uninformed group (n = 35, CON). The intervention group was further divided into Intervention-high risk (IHR, n = 36) and intervention-low risk (ILR, n = 29) subgroups. Dietary intake and physical activity (PA) were assessed using a 3-day dietary record and the IPAQ-short form. Blood metabolites were analyzed through multivariate analyses to identify significant differences among the groups, with measurements taken at baseline, 3 months, and 6 months. The IHR group exhibited increased dietary fat and fast foods intake, along with enhanced vigorous and moderate PA. Six metabolites were selected as biomarkers that were distinguishable among groups, and the relative serum cholesterol levels significantly decreased in the IHR group at 3 months. These results demonstrate that recognizing the BMI-associated genetic risk resulted in a short-term increase in PA but did not improve dietary intake. Increased PA was significantly associated with reduced cholesterol concentration, suggesting the clinical importance of physical activity in the genetically at-risk group. This study was reviewed and approved by the Seoul National University Institutional Review Board (IRB #1901/001-004) and registered on the Clinical Research Information Service (CRIS), KCT0004650 ( https://cris.nih.go.kr/cris/search/detailSearch.do /14091, 2020/01/28). Show less

The mechanism of hepatocarcinogenesis after sustained virological response (SVR) in hepatitis C virus (HCV) patients is unclear. We compared gene profiles of hepatocellular carcinoma (HCC) between HCV-SVR, steatotic liver disease (SLD), and HCV-non-SVR patients. This study analyzed 126 resected HCCs from patients with HCV and SLD, classifying them as HCV-SVR (n = 22), HCV-non-SVR (n = 56), and SLD (n = 48). Deep sequencing of 2910 hotspots in 55 cancer-related genes was conducted to examine mutations and copy number variations in both cancerous and background liver tissues. The HCV-SVR group comprised more patients who consumed alcohol (45.5% vs. 15.7%, p = 0.008), were obese (54.5% vs. 17.9%, p = 0.002), and had dyslipidemia (18.2% vs. 3.6%, p = 0.029) and hyperuricemia (18.2% vs. 3.6%, p = 0.029) than the HCV-non-SVR group. Mutational profiling of the HCV-SVR HCC showed significantly lower alteration rates of AXIN1 (13.6% vs. 42.9%, p = 0.016), ARID2 (9.1% vs. 39.3%, p = 0.013), and TP53 (9.1% vs. 32.1%, p = 0.030) than HCV-non-SVR patients. Compared with HCV-non-SVR-HCC, SLD-HCCs showed significantly lower rates of TERT promoter mutations (62.5% vs. 85.7%, p = 0.004), ARID2 alterations (12.5% vs. 39.3%, p = 0.003), and AXIN1 alterations (12.5% vs. 42.9%, p = 0.002). HCV-SVR/MASH/MASLD/ALD-HCC had significantly lower alteration rates of the Wnt/β-catenin (41.4% vs. 60.7%, p = 0.048) and chromatin remodeling pathways (27.1% vs. 48.2%, p = 0.026) than HCV-non-SVR-HCC. HCV-SVR HCC is linked to alcohol use and metabolic diseases, showing a mutational profile similar to SLD-HCC. Show less

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non-communicable diseases. Here, comparing germ-free (GF) and specific pathogen-free (SPF) mice using spatial transcriptomics, single-cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy-driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain-containing protein (ZBTB20)-Lipoprotein lipase (LPL) (ZBTB20-LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota-host interactions in the crosstalk between commensal gut bacteria and the host. Show less

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been identified, few studies have analyzed individuals of non-European ancestry. We conducted a multi-ancestry genome-wide association study (GWAS) of clinically diagnosed AD and AD-by-proxy using whole genome sequencing data from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), National Institute of Mental Health, UK Biobank (UKB), and All of Us (AoU) consisting of 49,149 cases (12,074 clinically diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants were of non-European ancestry. For clinically diagnosed AD, we identified 14 new loci-five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/AC008738.6), also nominally significant in NIAGADS. In summary, we provide evidence for 16 novel AD loci and advocate for more studies using whole genome sequencing-based GWAS of diverse cohorts. We used whole-genome sequencing data from large and diverse cohorts. We found novel genome-wide association study findings based on whole-genome data. We performed a multiancestry meta-analysis and incorporated results from underrepresented groups. Show less

Childhood obesity (OB) is influenced by complex gene-environmental interaction. While genetics of adult OB have been extensively studied, polygenic childhood OB in non-European populations is still underexplored. Furthermore, in a developing nation such as India, how the environmental component strongly modulated by the socioeconomic status (SES) shapes the genetic susceptibility is crucial to understand. A two-staged genome-wide association study (GWAS; N = 5673) and an independent exome-wide association study (ExWAS; N = 4963) were performed using a generalized linear model assuming additive effect to identify the common and rare genetic variants respectively associated with childhood OB. Rare-variant burden testing was also performed. We used the gene expression profiles and regulatory data from public databases to explain the novel associations. The implications of SES as a potential modifier of genetic susceptibility were evaluated. GWAS identified novel associations in TCF7L2, IMMP2L, IPMK, CDC5L, SNTG1, and MX1, whereas ExWAS uncovered CNTN4, COQ4, TNFRSF10D, FLG-AS1, and BMP3. Both GWAS and ExWAS validated known associations in FTO and MC4R. Furthermore, rare-variant testing highlighted the role of 101 genes. We also observed that SES can modulate the inherent susceptibility to OB. Our study identified genetic variants associated with childhood OB and highlighted the gene-environmental interaction in childhood OB. Show less