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BACE-1 is a prime therapeutic target for treatment of Alzheimer disease as it cleaves the β-site of APP leading to formation of amyloid plaques. A dataset of 229 benzo-fused heterocyclic compounds reported as BACE-1 inhibitors was utilized to develop various QSAR models (regression and classification) utilizing Monte Carlo algorithm. The dataset was randomly split into different sets for generation of models. The IIC and CCC were calculated to increase the predictive ability of generated models. Among various models, split-1 of Model-1 demonstrated the highest robustness and predictive accuracy for pIC Show less

Selective serotonin reuptake inhibitors (SSRIs), widely used antidepressants, have been associated with metabolic adverse effects, including weight gain and disrupted lipid metabolism. This study investigates the potential adipogenic and lipogenic effects of two commonly prescribed SSRIs, citalopram (CIT) and sertraline (SER), using the murine 3T3-L1 preadipocyte cell line. Key markers, such as adiponectin secretion, G3PDH activity, and the expression of critical transcription factors (PPARγ, CEBPα, SREBP1) and lipogenic enzymes (FASN, LPL), were evaluated. Furthermore, assessment of intracellular lipid accumulation via Oil Red O staining was used as a measure for enhanced adipogenesis. The results show that CIT significantly increased adiponectin secretion and G3PDH activity, with comparable potency to the positive control, rosiglitazone. Both SSRIs upregulated the transcription of key adipogenic genes but displayed discrepancies in protein expression. Despite these molecular changes, neither CIT nor SER promoted lipid accumulation, indicating disruption of adipogenic and lipogenic processes without direct stimulation of fat storage. These findings underscore the complexity of SSRI-induced metabolic effects and the need for further studies to evaluate their long-term impact. Show less

Severe gastrointestinal (GI) symptoms occur in people with CLN3 disease, a neurodegenerative disorder. If left untreated these GI symptoms compromise life quality and may contribute to death. We hypothesized GI symptoms in CLN3 disease are at least partially due to neurodegeneration in the enteric nervous system (ENS), the master regulator of bowel function. We examined the integrity of the ENS in human CLN3 autopsy small bowel and colon, and in CLN3 deficient ( Human CLN3 bowel displayed a profound loss of enteric neurons and their neurites, with pathological effects upon enteric glia. Our findings demonstrate that CLN3 deficiency profoundly damages enteric neurons and glia in both murine and human CLN3 disease, contributing to GI dysfunction. This study provides preclinical evidence that systemic gene therapy may effectively treat multiple aspects of bowel pathology, expanding the therapeutic landscape beyond the CNS.What you need to know. Significant gastrointestinal (GI) symptoms are evident in many pediatric neurological conditions. We hypothesized that, in addition to central nervous system (CNS) effects, defects in the enteric nervous system (ENS) may underlie these GI symptoms in some neurodegenerative diseases. Revealing such defects would open up new opportunities for treating these life-limiting and debilitating symptoms. The enteric nervous system is significantly impacted in human CLN3 disease, a feature that is recapitulated in CLN3 mice. Progressive enteric neurodegeneration in these mice follows a similar time course to neuron loss in the brain, resulting in severe bowel distention.Nevertheless, bowel distention and the majority of the pathology within the enteric nervous system can be mitigated via neonatal gene therapy. Our human data will need to be replicated in larger numbers of CLN3 cases, and methods will need to be developed to treat the human bowel, avoiding the risk of liver tumors. These results reveal that a neurodegenerative disease previously thought to primarily affect the CNS, damages the bowel's enteric nervous system and that ENS degeneration can be prevented in mice by gene therapy. These data provide a new perspective on this pediatric disorder and may have relevance to other pediatric neurologic diseases. The progressive loss of neurons in CLN3 disease is not confined to the brain but also occurs in the bowel enteric nervous system, contributing directly to GI dysfunction.Neurodegeneration in the enteric nervous system can be prevented by treating the bowel with gene therapy. Show less

The biological functions and role in human diseases of lipoprotein (a) discovered more than 60 years ago are still not fully understood. The high homology of apo(a) with plasminogen initially leads us to think of Lp(a) as a player in the coagulation system as pro-thrombotic factor. Over the years, a solid body of evidence from biology, epidemiology and from genetics and mendelian randomization has contributed to identify Lp(a) as a causal factor of atherosclerotic coronary heart disease, aortic calcific valve stenosis and ischaemic stroke. The active involvement of Lp(a) in atherogenesis and aortic calcific valve stenosis has been demonstrated by experimental data regarding the role of oxidized phospholipids, which are the cargo of Lp(a) and the presence of a Lp(a) receptor in valve interstitial cells. In secondary prevention, patients optimally treated for low density lipoprotein cholesterol (LDL-C) but with high Lp(a) levels show a residual cardiovascular risk. To date the LDL-C affecting drugs have a marginal effect on Lp(a). Statins produce a modest increase, monoclonal PCSK9i and Inclisiran a modest decrease not sufficient to reduce significantly the risk associated to Lp(a). Only lipoprotein apheresis and obicetrapib, a CETP novel inhibitor, reduce respectively by 75% and 40% Lp(a) levels. To obtain a lifetime risk reduction of 50% similar to that achieved by reducing LDL-C of about 40 mg/dl, Lp(a) should be reduced of about 100 mg/dl. The ongoing trials on drugs such as ASO, SiRnas, assembly inhibitors and maybe in the future the gene editing could obtain these results. Show less

Diabetic foot ulcer (DFU), a serious complication of diabetes, is a life-threatening disease that often leads to lower limb amputation and a shortened lifespan. Interleukin-27 (IL-27) is a member of the IL-12 family and has the potential to exert dual effects on the immune response. The role of IL-27 in diabetic skin wound healing is unknown. The aim of this study was to investigate whether there is abnormal expression of IL-27 in diabetic skin and whether supplementation with IL-27 can promote diabetic wound healing by modulating macrophage polarization. We established a streptozotocin (STZ)-induced diabetic mouse model and constructed diabetic wounds. We assessed protein expression by western blotting (WB) and immunohistochemical (IHC) staining. We also performed hematoxylin-eosin (H&E) staining and Masson's trichrome staining. In the presence of lipopolysaccharide (LPS) and high glucose (HG), we treated the mononuclear macrophage line RAW264.7 and bone marrow-derived macrophages (BMDMs) with IL-27. To assess macrophage polarization, we examined the expression of inducible nitric oxide synthase (iNOS), IL-1β and arginase-1 (Arg-1). To understand the underlying mechanisms, we used macrophage IL-27ra knockout mice to knockout macrophage IL-27 receptors. Our in vivo experiments revealed that the expression of IL-27 in the skin of diabetic mice was significantly decreased and that supplementation with IL-27 promoted diabetic wound healing. In vitro, compared with the LPS group, supplementation with IL-27 alleviated the suppression of multiple cellular functions, such as iNOS and IL-1β expression, cell migration, and phagocytosis, in macrophages after HG exposure. Mechanistically, we found that IL-27 expression was decreased and that the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation was inhibited in diabetic skin, leading to an inability of wound macrophages to polarize to an M1 phenotype effectively, which in turn blocked M1-to-M2 polarization of wound macrophages and ultimately delayed wound healing. The present study revealed that supplementation with IL-27 promoted M1-to-M2 polarization of wound macrophages and diabetic wound healing through the IL-27-IL-27Rα-p-STAT3 axis. These findings suggest that IL-27 may be a potential therapeutic target for DFU. Show less

The mechanistic target of rapamycin (mTOR) pathway plays a critical role in cell growth and metabolic homeostasis. The ribosomal protein S6 kinases S6K1 and S6K2 are the major effectors of the mTOR pathway key to translation efficiency, but the underlying regulatory mechanisms remain largely unclear. In this study, we searched for mTOR regulators and found that the splicing factor SRRM2 modulates the levels of S6K1 and S6K2, thereby activating the mTOR-S6K pathway. Interestingly, SRRM2 facilitates the expression of S6K2 by modulating alternative splicing, and enhances the stability of the S6K1 protein by regulating the E3 ubiquitin ligase WWP2. Moreover, SRRM2 is highly expressed in colorectal cancer (CRC) tissues and is associated with a poor prognosis. SRRM2 promotes CRC growth in vitro and in vivo. Combined, these data reveal an oncogenic role of SRRM2 in CRC through activating the mTOR-S6K pathway by two different approaches, further suggesting SRRM2 as a potential therapeutic target for CRC. Show less

Growing evidence suggests that lipid metabolism may play a crucial role in mood disorder pathophysiology, and the correlation between blood lipids and mood disorder remains further clarified. This prospective, population-based cohort study utilized data from the UK Biobank. The study included 268,098 and 292,121 participants who had never been diagnosed with depression or bipolar disorder and who had complete data at both the baseline and follow-up points. A principal component analysis (PCA) was conducted on seven blood lipids, and the first three principal components (PCs) were derived. Cox regression analysis was employed to examine the correlation between the risk of mood disorders and the PCs. Multiplicative interaction and sensitivity analyses were also conducted. The relationship between blood lipids and neurological biomarkers was explored using Spearman's analysis. PC1, primarily reflecting levels of Apolipoprotein B (ApoB), cholesterol, and low-density lipoprotein cholesterol (LDL-C), showed a protective effect against depression, with HRs of 0.98 (95 % CI: 0.96,1.00) in the fully adjusted Cox regression model. In contrast, PC2, characterized by opposite loadings for triglycerides and high-density lipoprotein cholesterol (HDLC), was positively associated with the risk of depression and bipolar disorder.(HR = 1.03,95 % CI: 1.01,1.06; HR = 1.11, 95 % CI: 1.01,1.23). Increased PC2 level was related to a significant increase in bipolar disorder risk among participants with high genetic risk (genetic risk score > 90 %, HR = 1.22, 95 % CI: 1.02,1.46). Complicated correlations between blood lipids and serum neuroproteins were detected. These findings suggest complex associations between blood lipid profiles and the risk of depression and bipolar disorder. Show less

Many traditional treatments include honey owing to its magnificent health beneficiary effects. Recent studies have demonstrated the potent anti-diabetic activity of honey. However, its actual mechanism of action remains elusive. Moreover, being rich in sugar (75%-80%), its role in maintaining glucose homeostasis remains questionable. Although the polyphenol content of honey aids its hypoglycaemic activity, the small quantity of bioactive compounds in honey (0.5%-1.0%) may not be solely responsible for this. In the current study, an attempt was made to understand the role of Indian lychee honey (LyH) in regulating blood glucose levels under diabetic conditions. This study investigated whether LyH, although rich in sugars, can be used as an alternative to regulate glucose and lipid homeostasis under insulin-resistant conditions by regulating the ChREBP/Glut4 signalling pathway. This study was first performed Show less

Previous studies found relationship between fluoride exposure and lipid metabolism. In present study, a cross-sectional study was conducted. Urinary fluoride concentrations and lipid metabolism indicators were tested. Single nucleotide polymorphisms of ATP2B1 were sequenced. The median of urinary fluoride was 1.32 mg/L. Urinary fluoride was positively associated with the decrease in serum ApoA1 (OR = 1.48 [95% CI, 1.27-1.72]), inversely with ApoB elevation (OR = 0.69 [95% CI, 0.59-0.80]). Rs12817819 with carriers of T allele was associated with the decrease in serum ApoA1 (OR = 0.46 [95% CI, 0.26-0.81]), but inversely in rs17249754 with carriers for A allele (OR = 1.48 [95% CI, 1.07-2.06]) and rs7136259 with carriers for T allele (OR = 1.70 [95% CI, 1.22-2.37]). There was an interaction between urinary fluoride which was lower than 0.9 mg/L and rs7136259 for carriers of T allele (OR = 2.67 [95% CI, 1.34-5.31]) in serum ApoA1 decrease. It indicated fluoride exposure might be associated with the alteration of serum ApoA1 and ApoB in adults. Show less

Central obesity poses a significant health threat. Lutein-rich fruits and vegetables may help manage obesity. Limited evidence suggests that lutein exerts health effects by inhibiting advanced glycation end products (AGEs), but data on its effects in centrally obese individuals are sparse. Thus, we aimed to investigate the effects of lutein supplementation in subjects with central obesity. A double-blind, randomized controlled trial was conducted involving patients with central obesity. Anthropometric indices, dietary intake, metabolic parameters, carotenoid and AGEs levels were compared between those receiving a 32-week intervention of 10 mg d Show less

Hypertriglyceridemia (HTG), which arises from defects in triglyceride-rich lipoprotein (TRL) metabolism, is associated with increased morbidity and mortality from pancreatitis and atherosclerotic cardiovascular disease. Traditional therapies, including fibrates and omega-3 fatty acids, have shown limited efficacy in controlling triglyceride (TG) levels and cardiovascular risk. This review explores the role of emerging therapies that target TG and TRL metabolism via novel biochemical pathways. Apolipoprotein C-III inhibitors appear most effective for patients with variants of severe HTG, particularly multifactorial and familial chylomicronemia syndromes, by enhancing TRL metabolism through both lipoprotein lipase-dependent and independent mechanisms. Angiopoeitin-like proteins 3 and 4 inhibitors appear most useful for mixed hyperlipidemia, with favorable effects across the entire spectrum of apoB-containing atherogenic lipoproteins. For patients with HTG and concomitant complications of insulin resistance, including metabolic associated steatotic liver disease and type 2 diabetes mellitus, fibroblast growth factor-21 analogs may provide significant benefit. HTG is a diverse condition. Apolipoprotein C-III inhibitors, angiopoeitin-like proteins 3 and 4 inhibitors, and fibroblast growth factor-21 analogs represent significant advancements in the treatment of HTG, offering new hope for effectively managing this condition across its full spectrum of disease. Show less

Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing. Show less

Estrogen is synthesized throughout various tissues in the body, and its production is regulated by the rate-limiting enzyme aromatase (encoded by the Cyp19a1 gene). Notably, aromatase is also expressed in central nervous system cells, allowing for localized estrogen synthesis in regions such as the hypothalamus. Estrogens produced within these neurons are referred to as neuroestrogens. In this study, we investigated the role of neuroestrogens in the regulation of appetite through modulation of hypothalamic pathways in OVX, ArKO, and aromatase-restored mice. Estrogen suppresses appetite by influencing the expression of appetite-regulating peptides, including POMC and NPY, via MC4R. We explored the direct effects of neuroestrogens, independent from ovarian estrogen, on appetite suppression and the underlying molecular mechanisms. We monitored body weight and food intake and evaluated the expression of Cyp19a1, Mc4r, and other appetite-related genes. Our findings indicate that OVX and ArKO mice exhibited increased body weight and food consumption, which correlated with altered expression of Mc4r and Cyp19a1. Conversely, restoration of Cyp19a1 expression in a neuron specific manner significantly decreased food intake and increased Mc4r expression in the hypothalamus. Furthermore, neuroestrogens enhanced leptin responsiveness. Our results imply that neuroestrogens likely contribute to appetite regulation and may be relevant for body weight reduction. Show less

We aimed to investigate the potential associations between serum apolipoprotein levels in early pregnancy and the risk of gestational diabetes mellitus (GDM) and adverse pregnancy outcomes. This was an observational study of the population-based Odense Child Cohort. Pregnant women were followed from inclusion until childbirth. Apolipoprotein levels, including 12 apolipoproteins (ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoH, ApoJ, and ApoM) were measured by targeted proteomics using liquid chromatography mass spectrometry on late first trimester serum samples stored in a biobank. GDM was defined by WHO 2013 diagnostic criteria. A total of 991 pregnant women were included, of which 415 (41.9%) were diagnosed with GDM. GDM was associated with increasing ApoB (adjusted odds ratio [OR]: 1.26, P = .002) and ApoD levels (adjusted OR: 0.84, P = .021). ApoB levels in early pregnancy correlated significantly and positively with insulin resistance (r = 0.22, P < .001) and beta-cell function in third trimester (r = 0.20, P < .001), whereas early pregnancy ApoD levels were inversely correlated with insulin resistance (r = -0.14, P < .001) and beta-cell function (r = -0.12, P < .001). Finally, high levels of ApoD was significantly associated with lower risk of large-for-gestational-age infants (adjusted OR: 0.78, P = .041). High levels of ApoB and low levels of ApoD in early pregnancy were independently associated with an increased risk of GDM, insulin resistance, and large-for-gestational-age infants (low ApoD only), suggesting potential roles for future management of pregnancy outcomes. 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

The Golgi apparatus (GA) serves as the center of protein and lipid synthesis and modification within cells, playing a crucial role in regulating diverse cellular processes as a signaling hub. Dysregulation of GA function can give rise to a range of pathological conditions, including tumors. Notably, mutations in Golgi-associated genes (GARGs) are frequently observed in various tumors, and these mutations have been implicated in promoting tumor metastasis. However, the precise relationship between GARGs and glioma, a type of brain tumor, remains poorly understood. Therefore, the objective of this investigation was to assess the prognostic significance of GARGs in glioma and evaluate their impact on the immune microenvironment. The expression of GARGs was obtained from the TCGA and CGGA databases, encompassing a total of 1564 glioma samples (598 from TCGA and 966 from CGGA). Subsequently, a risk prediction model was constructed using LASSO regression and Cox analysis, and its efficacy was assessed. Additionally, qRT-PCR was employed to validate the expression of GARGs in relation to glioma prognosis. Furthermore, the association between GARGs and immunity, mutation, and drug resistance was investigated. A selection of GARGs (SPRY1, CHST6, B4GALNT1, CTSL, ADCY3, GNL1, KIF20A, CHP1, RPS6, CLEC18C) were selected through differential expression analysis and Cox analysis, which were subsequently incorporated into the risk model. This model demonstrated favorable predictive efficiency, as evidenced by the area under the curve (AUC) values of 0.877, 0.943, and 0.900 for 1, 3, and 5-year predictions, respectively. Furthermore, the risk model exhibited a significant association with the tumor immune microenvironment and mutation status, as well as a diminished sensitivity to chemotherapy drugs. qRT-PCR analysis confirmed the up-regulation or down-regulation of the aforementioned genes in glioma. The utilization of GARGs in our constructed model exhibits a high level of accuracy in prognosticating glioma and offers promising avenues for the development of therapeutic interventions targeting glioma. Show less

Lipoprotein subclasses and high-density lipoprotein (HDL) functions are associated with atherosclerotic cardiovascular disease (ASCVD), but researches on them in patients with nephrotic syndrome (NS) are limited. The aims of this study were (1) to analyze the changes in quantity and quality of lipoprotein in patients with idiopathic nephrotic syndrome (INS) and patients in remission from NS, and (2) to evaluate the lipid-related atherosclerotic risk in these patients. 51 patients with idiopathic nephrotic syndrome (NS group), 72 NS patients with complete remission (NS remission group), and 80 healthy controls (control group) were recruited. The levels of conventional lipids, lipoprotein subclasses, including VLDL, IDL (C, B, A), LDL (LDL1-7), HDL (large, intermediate, small) and HDL cholesterol efflux capacity (CEC), were measured and compared across the three groups. Conventional lipid parameters [TG, TC, LDL-C, apo-B and Lp(a)] and lipoprotein subclasses (VLDL, IDL-C, IDL-B, LDL-2 and sdLDL) were higher in NS group when compared to NS remission group and control group (P < 0.05). CEC in NS group was significantly lower than that in control group [21.0 (18.3-27.2) % vs 25.7 (23.3-28.9) %] (P < 0.001) and improved to 22.8 (20.6-23.7) % in NS remission group with the disease recovery. Proatherogenic changes in conventional lipid parameters, lipoprotein subclasses and HDL-CEC were observed in patients with NS, suggesting that more rigorous lipid regulation strategies may help reduce cardiovascular disease risk in patients with NS. Show less

While the plasma phylloquinone (PK) concentration is inversely correlated with cardiovascular risk, the involvement of PK in regulating endothelial function has not been directly investigated. Therefore, in this study we assessed the effects of short-term treatment with PK-deficient diets (5-10 weeks) on endothelial function in normolipidemic 14-week-old male C57BL/6JCmd mice and age-matched dyslipidaemic male E3L.CETP mice. Our results show that in normolipidemic mice dietary PK deficiency was associated with a marked reduction of PK levels in the plasma and liver (liquid chromatography-mass spectrometry measurements) and with impaired endothelium-dependent vasodilation assessed in vivo by magnetic resonance imaging (MRI). Dietary PK deficiency-induced endothelial dysfunction was fully reversed by PK supplementation. In dyslipidaemic E3L.CETP mice, dietary PK deficiency exacerbated preexisting endothelial dysfunction. Furthermore, dietary PK deficiency decreased menaquinone-4 (MK-4) levels in the aorta but did not affect blood coagulation (calibrated automated thrombography), microbiota composition (culturing and next-generation sequencing), and gut menaquinone production. In conclusion, our study demonstrated for the first time that sufficient dietary PK intake supports endothelial function in normolipidemic and dyslipidaemic mice indicating nutritional significance of dietary PK in the maintenance of endothelial function in humans. Show less

Mutations in the Leucine-rich repeat kinase 2 ( We investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of In this extensive discovery cohort, we identified several elevated serum immune regulatory factors associated with This study highlights distinct immune profiles associated with LRRK2 mutations and PD in the periphery and CNS. Serum levels of SDF-1alpha and TNF-RII were elevated in LRRK2 mutation carriers, while CSF immune markers were reduced. In PD, irrespective of LRRK2 status, reduced CSF inflammatory analytes and weak serum signals were observed. These results provide insight into immune dysregulation linked to LRRK2 mutations. If replicable in independent datasets, they offer potential avenues for biomarker and therapeutic exploration. Show less

Triple negative breast cancer (TNBC) is the most aggressive subtype and disproportionately affects African American women. The development of breast cancer is highly associated with interactions between tumor cells and the extracellular matrix (ECM), and recent research suggests that cellular components of the ECM vary between racial groups. This pilot study aimed to evaluate gene expression in TNBC samples from patients who identified as African American and Caucasian using traditional statistical methods and emerging Machine Learning (ML) approaches. ML enables the analysis of complex datasets and the extraction of useful information from small datasets. We selected four regions of interest from tumor biopsy samples and used laser microdissection to extract tissue for gene expression characterization via RT-qPCR. Both parametric and non-parametric statistical analyses identified genes differentially expressed between the two ethnic groups. Out of 40 genes analyzed, 4 were differentially expressed in the edge of tumor (ET) region and 8 in the ECM adjacent to the tumor (ECMT) region. In addition to statistical approach, ML was used to generate decision trees (DT) for a broader analysis of gene expression and ethnicity. Our DT models achieved 83.33 % accuracy and identified the most significant genes, including Show less

We report eight children with de novo pathogenic DNA variants in chromatin-related genes: MORC2, CHD7, KANSL1, KMT2D, ZMYND11, HIST1HIE, EP300, and KMT2B. All children experienced infection or vaccine-provoked neuroregression or abrupt-onset neuropsychiatric syndromes. Most had delayed development (n = 6) before the first regression, and four had immune deficiency or autoimmunity (n = 4). At a mean age of 4 years 2 months (range 1-8 years), symptoms included infection-provoked autistic/language regression (n = 6), cognitive decline (n = 3), gait deterioration (n = 3), or abrupt-onset anxiety, obsessive-compulsive disorder, and/or tics (n = 5). Three children had ongoing infection-provoked deteriorations. Six children benefited from intravenous immunoglobulin (n = 3) or antibiotics (n = 4). Ribonucleic acid expression of the eight chromatin genes was similar in neuronal, glial, and peripheral leukocytes, unlike non-chromatin neurodevelopmental genes, which have predominantly neuronal expression. These cases demonstrate the role of chromatin dysregulation in autistic regression and abrupt-onset neuropsychiatric syndromes, potentially related to brain and immune gene dysregulation. Show less

The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis and mechanisms of this medicine are still unclear. Isoliensinine (IL) is a major alkaloid derived from lotus embryos. Our previous research has demonstrated that IL can exert strong anti-inflammatory and neuroprotective effects in vitro. To reveal the underlying therapeutic effect and mechanism of IL on Alzheimer's disease (AD)-like mice induced by AlCl The AD-like mice were modeled by intragastric injection (i.g.) of AlCl IL (1, 3, and 10 mg/kg) treatment effectively ameliorated cognitive impairment in AD-like model mice. IL inhibited the decrease of brain index and body weight in AD-like mice and alleviated neuronal damage in the cortex and hippocampus (DG, CA1, and CA3). IL decreased the levels of Ca IL has a significant therapeutic effect on pathological alterations and cognitive impairment in AlCl Show less

The viability of cells and the integrity of the genome depend on the detection and repair of damaged DNA through intricate mechanisms. Cancer treatment employs chemotherapy or radiation therapy to eliminate neoplastic cells by causing substantial damage to their DNA. In many cases, improved DNA repair mechanisms lead to resistance to these medicines; therefore, it is essential to expand efforts to develop drugs that can sensitise cells to these treatments by inhibiting the DNA repair process. Multiple studies have demonstrated a correlation between the overexpression of Apurinic/Apyrimidinic Endonuclease (APE1), the primary mammalian enzyme responsible for excising apurinic or apyrimidinic sites in DNA, and the resistance of cells to cancer therapies; in contrast, APE1 downregulation increases cellular susceptibility to DNA-damaging agents. Thus, the effectiveness of existing therapies can be improved by promoting the targeted sensitization of cancer cells while protecting healthy cells. The current study aims to employ explainable artificial intelligence (XAI) to enhance the accuracy and reliability of machine learning models for the prediction of APE1 inhibitors. Various ML-based regression models are employed to predict the pIC50 value of different medicines. Bayesian optimization and the Permutation Feature Importance (PFI) approach are employed to determine the best hyperparameters of machine learning models and to discover the most significant features for recognizing drug candidates that target APE1 enzymes, respectively. To acquire comprehensive elucidations for the predictive models in our research, two XAI methodologies, namely SHAP and LIME, are used. The SHAP analysis reveals that the features 'C1SP2' and 'ASP-2' are essential in influencing the model's predictions. The SHAP values demonstrate variability for features such as 'maxHBint2' and 'GATS1s,' signifying that their impact is dependent on specific instances within the dataset. The LIME study corroborates these findings, demonstrating that 'C1SP2' and 'ASP-2' are the most significant positive contributors, whereas features like 'SHCHnX,' 'nHdCH2,' and 'GATS1s' result in a decrease in the predicted values. Due to the limited sample size of the APE1 dataset, direct training on this dataset posed challenges in model generalization and reliability. To overcome this limitation, the BACE-1 dataset is leveraged for model training, enabling the ML models to learn from a more extensive and diverse chemical space. Among the tested algorithms, XGBoost demonstrated superior predictive performance, achieving R Show less

Vascular calcification (VC) significantly increases the incidence and mortality of many diseases. The causal relationships of dyslipidaemia and lipid-lowering drug use with VC severity remain unclear. This study explores the genetic causal associations of different circulating lipids and lipid-lowering drug targets with coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC). We obtained single-nucleotide polymorphisms (SNPs) and expression quantitative trait loci (eQTLs) associated with seven circulating lipids and 13 lipid-lowering drug targets from publicly available genome-wide association studies and eQTL databases. Causal associations were investigated by univariable, multivariable, drug-target, and summary data-based Mendelian randomization (MR) analyses. Potential mediation effects of metabolic risk factors were evaluated. MR analysis revealed that genetic proxies for low-density lipoprotein cholesterol (LDL-C), triglycerides (TC) and Lipoprotein (a) (Lp(a)) were causally associated with CAC severity, and apolipoprotein B (apoB) level was causally associated with AAC severity. A significant association was detected between hepatic Lipoprotein(A) (LPA) gene expression and CAC severity. Colocalisation analysis supported the hypothesis that the association between LPA expression and CAC quantity is driven by different causal variant sites within the ±1 Mb flanking region of LPA. Serum calcium and phosphorus had causal associations with CAC severity. Inhibitors targeting LPA might represent CAC drug candidates. Moreover, T2DM, hypercalcemia, and hyperphosphatemia are positively causally associated with CAC severity, while chronic kidney disease and estimated glomerular filtration rate are not. Show less

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less

Dominant follicular development and atresia are governed by the proliferation of granulosa cells (GCs), a process influenced by the delicate balance between apoptosis and autophagy. Oxidative stress, a pivotal catalyst of GCs apoptosis, modulates gene expression through epigenetic mechanisms, including chromatin remodeling. Nevertheless, the regulatory mechanisms underpinning GCs functionality in relation to prolificacy remain inadequately elucidated. In this study, we discovered that the chromatin accessibility of nuclear receptor subfamily 1 group D member 1 (NR1D1) was markedly enhanced in dominant follicular GCs from low-prolificacy sheep, as evidenced by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), which correlated with elevated NR1D1 transcript levels. Remarkably, NR1D1 emerged as a novel regulator of follicular development, exhibiting heightened expression in dominant follicles. The overexpression of NR1D1 induced cell cycle arrest, autophagy activation, and mitochondrial dysfunction via the AMPK pathway, while its knockdown fostered GCs survival and functionality. Furthermore, NR1D1 inhibits the transcription of HSD17B12, thereby contributing to oxidative stress (ROS)-induced apoptosis, as demonstrated by CUT&Tag-qPCR and dual luciferase assays. The downregulation of HSD17B12 partially alleviated the effects of NR1D1 knockdown on GCs functionality. These findings indicate that NR1D1 orchestrates GCs proliferation and apoptosis through the suppression of HSD17B12 and the activation of the AMPK pathway, establishing NR1D1 as a novel transcription factor implicated in follicular development and ovarian function, with significant implications for prolificacy. Show less

This study integrated the the effects of dietary Lys/Met ratio in a low protein diet on the meat quality in Tibetan sheep. A total of 90 weaned Tibetan sheep, 2 months old with initial weight of 15.37 ± 0.92 kg were randomly divided into 3 treatments, which were supplemented with Lys/Met ratio at 3 (LP-H), 2 (LP-M), and 1 (LP-L) in the basal diet (10 % crude protein), respectively. After slaughter (150 days of age), the growth performances and meat quality of longissimus dorsi muscle were evaluated. The LP-L group showed significantly higher final body weight compared to the LP-M group (P < 0.05). Serum albumin and total protein levels were significantly higher in the LP-L group than in the LP-H group (P < 0.05). Furthermore, meat from the LP-L group had significantly higher protein, calcium, and vitamin E content compared to the LP-M group (P < 0.05). Transcriptomic analysis revealed 3,479 differentially expressed genes enriched in pathways related to muscle growth, energy metabolism, and signaling transduction. Metabolomic analysis identified 771 differential metabolites, significantly enriched in ABC transporters, beta-alanine metabolism, and taste transduction pathways. Integrated analysis highlighted the upregulation of the ABCD4 gene and L-valine metabolite in the LP-L group, contributing to improved phenotypic traits. These findings provide molecular insights into the regulatory mechanisms underlying the effects of dietary Lys/Met ratios on Tibetan sheep meat quality and offer a basis for developing nutritional strategies to enhance premium meat production. Show less

This study aimed to investigate serum inflammatory factor levels of polycystic ovary syndrome (PCOS) in female patients with bipolar disorder (BD) to explore the related inflammatory molecular mechanisms preliminarily. The study recruited 72 female drug-naïve patients with BD and 98 female healthy controls (HCs). Demographic information, menstrual cycles, sex hormone levels, and ovarian ultrasound data were collected from them. Additionally, their serum inflammatory factor levels and the proteomics of peripheral blood mononuclear cells were analyzed. The levels of interleukin (IL)-8 and IL-13 were significantly higher in patients with BD than in HCs (p < 0.05), and the IL-8 level was higher in BD patients with PCOS than in those without (adjusted p = 0.07). Bioinformatics analysis revealed that downregulated genes with significant differences between the two groups were all involved in immune-inflammatory-related pathways, and the expression of downregulated genes BTN3A2, MAP2K5, JCHAIN-B, and DMAP1 showed substantial differences and consistent trends between the two groups. IL-8-related chronic inflammatory response is closely associated with PCOS in BD patients, and genes such as BTN3A2 may mediate this chronic inflammatory response by negatively regulating the abnormal differentiation of T helper 17 cells, serving as one of the mechanisms underlying its pathogenesis. Show less

Diabetic retinopathy (DR) is the leading manifestation of diabetic microangiopathy. However, effective biomarkers and therapies are lacking. Circular RNAs (circRNAs) have been implicated in various diseases including DR. However, the role of circRNAs in DR remains elusive. In the present study, circNXN was upregulated in high glucose (HG)-treated human retinal microvascular endothelial cells (hRMECs). circNXN knockdown inhibited the proliferation, migration, and angiogenesis of hRMECs and promoted apoptosis. In addition, circNXN acted as a sponge for miR-338-3p to facilitate the FGFR1 (fibroblast growth factor receptor 1) expression. Furthermore, rescue assays revealed that the reduced promoting effect on hRMECs induced by the knockdown of circNXN could be reversed by a miR-338-3p inhibitor in HG-treated hRMECs. Additionally, in a DR rat model, circNXN downregulation ameliorated retinal vasculature changes. Our findings reveal a new therapeutic strategy for DR that may provide a new approach to clinical DR therapy. Show less

White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored. We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals. Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (N Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease. Show less