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Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known to be involved in the disease pathomechanism. On the other hand, cleft lip/palate (CL/P) usually results from polygenic and environmental factors, with the complex interplay of both leading to this malformation. Pathogenic variants in We conducted targeted next-generation sequencing (NGS) in the proband with SHFM, followed by segregation analysis in the family members. In this study, we report an index patient presenting with isolated SHFM and his brother with CL and facial dysmorphism, as well as their father with isolated hyposmia. Targeted next-generation sequencing revealed a previously reported heterozygous missense pathogenic variant in This study expands the phenotypic spectrum associated with Show less

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

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder caused by impaired insulin secretion from pancreatic β-cells and insulin resistance in target tissues. Genome-wide association studies have identified over 50 genetic variants linked to T2DM, including polymorphisms associated with the disease. This study investigates the impact of the Show less

Dyggve-Melchior-Clausen (DMC) syndrome is an autosomal skeletal dysplasia, caused by mutations in the DYM gene. The features of this condition include developmental delay skeletal deformity, coarse facial features, and skeletal abnormalities. This case report presents a novel mutation association between DMC syndrome and celiac disease, emphasizing unique clinical findings and management strategies. This case report presents the case of an eight-year-old boy from Saudi Arabia, born to consanguineous parents. The patient presented with delayed development, coarse facial features, skeletal deformity, and fused toes. Radiological findings showed hallmark features of DMC syndrome such as a double hump appearance of the spine, short tubular metacarpal bones, and a lacy pattern on the iliac crest. A homozygous pathogenic mutation in the DYM gene was confirmed by whole-exome sequencing. Furthermore, the patient had celiac disease serology positive. To our knowledge, we did not find any case of DMC syndrome and celiac disease. This case expands the clinical spectrum of DMC syndrome by documenting its association with celiac disease, a previously unreported comorbidity. It underscores the importance of comprehensive evaluation, including autoimmune screening, in patients with rare genetic disorders. Further research is needed to explore the potential link between DMC syndrome and autoimmune conditions. Show less

Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, are a group of inherited neurodegenerative disorders that mostly arise in childhood. Each of the NCLs is a genetically distinct disease caused by variants in at least 13 different genes (CLN1-CLN14). NCLs are neurodegenerative, and symptoms can include a combination of childhood dementia, epileptic seizures, motor decline and vision loss, and eventually lead to premature death. There is currently no cure for any subtype of NCL, however, enzyme replacement therapy is available for CLN2 disease, and several treatment strategies are being explored for other NCL subtypes. Early diagnosis and initiation of supportive services (e.g. health, education, social services) are essential to preserve quality of life. Only a few studies have investigated family experiences with NCL, many of which are international in scope. A mixed-method research study was conducted in the UK to understand family experiences in CLN2 and CLN3 disease. It involved an initial literature review, followed by in-depth qualitative interviews. Interview data were analysed using a thematic analysis. Thirteen families (n = 13) participated in the interviews. This represented 16 parents (11 mothers and 5 fathers) of 18 children (10 diagnosed with CLN3 disease and 8 diagnosed with CLN2 disease). Findings were analysed jointly across CLN2 and CLN3 disease. Six overarching themes emerged from the analysis: difficulty in recognising early symptoms; the shock of a diagnosis; the demands of caring for complex and ever-changing needs; a constant battle to access appropriate and timely support services; the extensive impact on the unaffected sibling; and the all-encompassing impact on the family. This study contributes novel UK specific data on family experiences and unmet needs in CLN2 and CLN3 disease. More needs to be done to ensure NCLs are diagnosed early, and timely local support services are made available to protect quality of life for both the affected children and their families. Show less

Neuroinflammation is an inflammatory response occurring within the central nervous system (CNS). The process is marked by the production of pro-inflammatory cytokines, chemokines, small-molecule messengers, and reactive oxygen species. Microglia and astrocytes are primarily involved in this process, while endothelial cells and infiltrating blood cells contribute to neuroinflammation when the blood-brain barrier (BBB) is damaged. Neuroinflammation is increasingly recognized as a pathological hallmark of several neurological diseases, including amyotrophic lateral sclerosis (ALS), and is closely linked to neurodegeneration, another key feature of ALS. In fact, neurodegeneration is a pathological trigger for inflammation, and neuroinflammation, in turn, contributes to motor neuron (MN) degeneration through the induction of synaptic dysfunction, neuronal death, and inhibition of neurogenesis. Importantly, resolution of acute inflammation is crucial for avoiding chronic inflammation and tissue destruction. Inflammatory processes are mediated by soluble factors known as cytokines, which are involved in both promoting and inhibiting inflammation. Cytokines with anti-inflammatory properties may exert protective roles in neuroinflammatory diseases, including ALS. In particular, interleukin (IL)-10, transforming growth factor (TGF)-β, IL-4, IL-13, and IL-9 have been shown to exert an anti-inflammatory role in the CNS. Other recently emerging immune regulatory cytokines in the CNS include IL-35, IL-25, IL-37, and IL-27. This review describes the current understanding of neuroinflammation in ALS and highlights recent advances in the role of anti-inflammatory cytokines within CNS with a particular focus on their potential therapeutic applications in ALS. Furthermore, we discuss current therapeutic strategies aimed at enhancing the anti-inflammatory response to modulate neuroinflammation in this disease. Show less

To identify preoperative clinical predictive factors of postoperative speech changes in Parkinson's disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). Demographic variables, neuroimaging data, and clinical characteristics were retrospectively collected from consecutive PD patients, before, 1 and 10-years after bilateral STN-DBS at the Grenoble University Hospital (France) from 1993 to 2015. Predictors of postoperative speech changes (demographic, clinical and MRI variables) were assessed with univariate and multivariate logistic regression analyses. We considered as "event" a worsening of speech subscore (UPDRS item 18; MDS-UPDRS item 3.1) in the postoperative on-stimulation/off-medication (1-year follow-up) or under chronic treatment (10-years follow-up) conditions compared with the preoperative off-medication condition. 324 PD patients (males: 196; disease duration at surgery: 11.10 [± 4.13] years; age at surgery: 56.25 [± 8.52] years) were included in the analysis. Overall, the speech item of the clinical rating did not change in 138 patients (42.6%), it improved in 113 patients (34.9%) and worsened in 73 patients (22.50%) 1-year after surgery. The preoperative off-medication speech item score and the degree of motor improvement after surgery in the med-off condition predicted the 1-year postoperative speech change. In the long-term subgroup (n=51) the preoperative percentage of daily time spent with fluctuations was associated with long-term speech worsening. Effects of STN-DBS on speech can substantially vary in PD patients. Predictors of short-term speech deterioration appears to be related to preoperative off-medication speech impairment and degree of motor improvement after surgery. Show less

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions marked by extensive epidermal necrolysis and skin sloughing. The study aimed to assess the serum levels of specific proinflammatory interleukins (IL-18, -21, 22, -23, -27, and -31) and their relationship with the severity of SJS/TEN within the Vietnamese population. This descriptive cross-sectional study was conducted from 2018 to 2020. Serum levels of IL-18, -21, -22, -23, -27, and -31 were measured using the fluorescence covalent microbead immunosorbent assay. The study included 61 patients (29 males and 32 females; 21 with SJS and 40 with TEN), with a median age of 51 years (interquartile range: 37-58), and 20 healthy controls. The median lesional area covered 45% of the body surface area (interquartile range: 8-70%). The most frequently identified medications were traditional medicine (19 patients; 31.15%), allopurinol (9 patients; 14.75%), and carbamazepine (8 patients; 13.11%). In the TEN group, the serum level of IL-18 was significantly elevated compared to the healthy control group. A correlation was found between serum levels of IL-18 and IL-27 and the lesional area in SJS/TEN patients, as well as between serum levels of IL-18 and IL-31 and the lesional area in TEN patients. Serum levels of IL-18 were increased in TEN group. Additionally, serum concentrations of IL-18, IL-27, and IL-31 were associated with disease severity as indicated by the lesional area. These interleukins may play an important role in the pathogenesis of SJS/TEN. Show less

The relation between hepatic ChREBP level and insulin sensitivity remains equivocal. Our study, however, provides compelling evidence that hepatic ChREBP depletion can significantly enhance insulin sensitivity in high-fat and sucrose-fed mice. We have identified that transcriptional induction of hepatic PTEN is driven by ChREBP. Mechanistically, two critical stimuli are elicited in the hepatic ChREBP knockdown condition. The PTEN level is reduced for one stimulus, thereby promoting hepatic insulin sensitivity. The second stimulus, where reduced hepatic PTEN leads to the enhanced release of FGF21, spreads systemic insulin sensitivity. These findings identify hepatic ChREBP as a critical modulator of systemic insulin signaling and suggest that ChREBP downregulation may lead to protection against insulin resistance. Building on this, our molecular dynamics simulation analysis has led to the discovery of a small molecule, Quercetin, that sequesters ChREBP in the cytosol. We report that Quercetin treatment can sequester ChREBP in the cytosol and abrogate high-fat and sucrose-fed-mediated ChREBP nuclear translocation, thereby mimicking the insulin-sensitizing abilities of the hepatic ChREBP knockdown condition. These findings have significant therapeutic implications, suggesting that liver-selective downregulation of ChREBP could protect against systemic insulin resistance that frequently develops early in the pathogenesis of NAFLD and T2DM. Show less

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup (KSS) significantly attenuated hepatic steatosis in rats. This study explored the main components of KSS and the mechanisms by which it exerts its protective effects against NAFLD. Twenty-four 6-week-old male Sprague-Dowley (SD) rats were randomly assigned to three treatments: feeding a normal standard diet, a high-fat diet, or a high-fat diet plus gavage KSS. The effects of KSS treatment on hepatic lipid accumulation were assessed using biochemical, histological, and molecular experiments. The amounts of KSS ingredients were measured using biochemical assays. Network pharmacology analyses were performed to identify the hub genes of KSS targets and enriched pathways. CCK-8 assay was used to determine the effect of free fatty acids (FFA), lycopene, and estrogen on HepG2 viability. Quantitative Real-Time polymerase chain reaction (qRT-PCR) and Western blot assays were performed to determine the effect of KSS or lycopene on estrogen signaling and expression of lipid metabolism-related molecules. Statistical analyses were performed using GraphPad Prism and SPSS. KSS alleviated fat deposition in rat liver tissue and affected the expression of hepatic lipid synthesis, catabolism, and oxidative molecules. Lycopene was identified as the ingredient with the highest amount in KSS. Network pharmacology analyses showed that the hub genes were enriched in the estrogen signaling pathway. Cellular experiments showed that lycopene increased the expression of Estrogen Receptor α (ERα), Carnitine palmitoyltransferase 1 A ( KSS ameliorated abnormal lipid metabolism in patients with NAFLD. Lycopene was the major component of KSS, and it affected estrogen signaling and the expression of lipid metabolism molecules. In short, both KSS and LYC could change lipid metabolism by lowering lipid accumulation and raising lipolysis. Show less

Wenchang chicken, renowned for its high-quality meat, is the economic meat breed in Hainan Province, China. This study compared cage-rearing (CR) and free-range (FR) groups in terms of growth performance, slaughter performance, meat quality, IMP (inosine monophosphate) content, AAs, FAs, serum lipid metabolites, and transcriptomic and metabolomic analyses. The CR group showed increased body weight, live weight, and abdominal fat but lower leg muscle percentage and breast muscle redness, suggesting flavor differences. CR chickens had higher IMP, threonine (Thr), and pentadecanoic, oleic, and linoleic acids, while glutamate (Glu) and alpha-linolenic acid were lower compared to FR. Glycine was elevated, but histidine, myristic, and tricosanoic acids were lower in CR leg muscle. Serum analysis revealed higher total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), fatty acid synthase (FAS), thyroid-stimulating hormone (TSH), leptin (LEP), and adiponectin (ADP) in the CR group. Transcriptomic and metabolomic studies identified 252 differentially expressed genes and 34 metabolites linked to metabolic pathways. In summary, CR system can improve production performance, FR system is considered more flavorful. The results can act as a theoretical basis for selecting a suitable rearing method for this unique breed. Show less

Alzheimer's Disease is a chronic progressive neurodegenerative disorder characterized by impaired intellect and cognitive functions. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by initiating the amyloid cascade. Despite significant clinical efforts, most BACE1 inhibitors have failed to yield potent pharmacological effects. Our previous study, identified a group of natural compounds with satisfying pharmacological profiles with high affinity to BACE1, out of which the compound, 'convolidine' emerged as the most promising candidate based on the in-silico parameters such as docking score, interacting residues, binding energy, drug-likeness, ADMET, and biological activity prediction. The present study focused on the inhibitory potential of convolidine against BACE1 using dynamics simulation followed by protein-protein docking and in-vitro validation. Molecular dynamics simulation demonstrated that the BACE1-convolidine complex remained stable throughout the entire 200 ns simulation period. Also, the results of the post-dynamic docking study showed a reduced substrate affinity of BACE1 to its substrate, APP (Amyloid precursor protein), when BACE1 is bound to convolidine, suggesting compounds inhibitory potential. This in-silico assessment was validated in-vitro using a FRET-based BACE1 activity assay, where the result well aligned with the computational predictions. The findings revealed that convolidine could effectively inhibit BACE1, with an IC50 value of 0.49 µM, providing a solid foundation for its development as a promising therapeutic agent for AD management. Show less

Apolipoprotein C3 (APOC3) and angiopoietin-like protein 8 (ANGPTL8) genes are related to lipid metabolism. The relationships between single nucleotide polymorphisms (SNPs) in the APOC3 and ANGPTL8 genes with metabolic dysfunction-associated steatotic liver disease (MASLD) remain controversial. This study aimed to investigate the associations between specific SNPs in the APOC3 and ANGPTL8 genes and MASLD risk, with a particular focus on the mediating role of triglycerides (TG). A total of 440 participants were enrolled and categorised into MASLD and control groups. Genotyping of APOC3 SNPs (rs5128, rs2854116 and rs2854117) and ANGPTL8 SNP (rs2278426) was conducted using polymerase chain reaction-restriction fragment length polymorphism or Sanger sequencing methods. Multivariate logistic regression was employed to estimate the associations between these SNPs and MASLD risk, and mediation analysis was performed to assess the potential mediating effect of TG. We found that APOC3 SNPs were associated with MASLD risk, with increased odds ratios (ORs) indicating a higher risk of MASLD: rs5128 CG + GG genotype (OR = 1.8, 95% CI = 1.1-2.8), rs2854116 TC + CC genotype (OR = 1.9, 95% CI = 1.1-3.1) and rs2854117 CT + TT genotype (OR = 1.9, 95% CI = 1.2-3.2). No association was found between ANGPTL8 rs2278426 and MASLD (p > 0.05). Mediation analysis revealed that TG significantly mediated these relationships, accounting for 80.25% of the effect for rs5128, 64.61% for rs2854116 and 62.59% for rs2854117. In summary, polymorphisms in APOC3 (rs5128, rs2854116 and rs2854117) were associated with MASLD risk, with TG serving as a potential mediating factor. In contrast, ANGPTL8 rs2278426 polymorphism did not show any association with MASLD. Show less

Kidney renal clear cell carcinoma (KIRC), the predominant subtype of renal cell carcinoma, poses significant health risks. The rapid progression and resistance to targeted therapies highlight the need for new tumor markers and therapeutic targets. FADS1, part of the fatty acid desaturase family, regulates fatty acid synthesis and participates in lipid metabolism. However, its role in KIRC is not well-studied. The study utilized bioinformatics analysis through the TCGA database and other platforms to identify FADS1 expression levels in KIRC. Twenty pairs of KIRC clinical tissue samples were used for qPCR verification. Meanwhile, eight pairs of KIRC clinical tissue samples were used for Western blot verification. Conduct statistical evaluation, including Wilcoxon rank sum test and Kaplan-Meier analysis, to explore the correlation between FADS1 expression and clinical pathological features and immune infiltration. In addition, in vitro experiments were conducted to confirm the biological function of FADS1. The findings indicated that FADS1 is highly expressed in KIRC and contributes to tumor development. FADS1's role in lipid metabolism leads to lipid accumulation within tumor cells, which may influence the occurrence and progression of KIRC. TIMER analysis revealed a correlation between FADS1 expression and the infiltration levels of various immune cells, indicating its potential role in modulating immune characteristics. FADS1 could serve as a prognostic biomarker associated with immunity in KIRC, highlighting its potential as a diagnostic and therapeutic target. The study underscores the importance of further research into FADS1's role in lipid metabolism and immune infiltration to develop effective therapeutic strategies. Show less

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline, oxidative stress, neuroinflammation, amyloid-beta (Aβ) accumulation, and tau protein hyperphosphorylation. In this study, we synthesized novel Ramalin derivatives and evaluated their therapeutic potential against AD, focusing on antioxidant, anti-inflammatory, and neuroprotective activities. RA-2OMe, RA-4OMe, RA-2CF3, and RA-4OCF3 showed strong antioxidant effects, while RA-2OMe exhibited potent NO and NLRP3 inhibition (~20%). RA-NAP, RA-PYD, and RA-2Q showed moderate anti-inflammatory activity. BACE-1 inhibition was significant in RA-3CF3, RA-NAP, and RA-PYD, with IC Show less

Myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 rearrangements (MLN- We assigned eligible patients to receive oral pemigatinib 13.5 mg once daily (2 weeks on followed by 1 week off or continuously). End points included complete response rate (primary) and complete cytogenetic response rate. Responses were assessed locally by investigators per protocol-defined criteria and were retrospectively adjudicated by a central review committee using criteria defined by the committee. Of 47 treated patients (safety population), 45 had confirmed In our study, pemigatinib manifested near complete efficacy in chronic-phase patients with MLN- Show less

To clarify the possible mechanism of leptin and α-MSH on the onset of puberty in female offspring rats after prenatal androgen exposure. Sixteen 8-week-old specific pathogen free (SPF) healthy Sprague Dawley (SD) pregnant rats were randomly divided into the testosterone-treated group (TG, female offspring termed PNA group) or the olive oil control group (OOG, female offspring termed VEH group). The female offspring rats of two groups were raised to 21 days (PND21) and weaned. Six female offspring rats at PND21 (VEH:PNA = 3:3) were randomly selected for transcriptome sequencing. Twenty-seven offspring female rats were randomly divided into three groups (VEHI:VEHII:PNA = 9:9:9). VEHI group was observed until the onset of puberty, VEHII and PNA groups were observed until the 8th week. Compared with VEH group, onset of puberty was not observed in PNA group, and hypothalamic Pomc gene expression at PND21 was lower. Compared with the VEHI group, the body weight, abdominal fat, serum testosterone (T), dehydroepiandrosterone (DHEA) and leptin (LEP) levels were upregulated in the PNA group, while serum gonadotropin-releasing hormone (GnRH), mRNA of hypothalamic estrogen receptor α (ERα), α-melanocyte stimulating hormone (α-MSH), melanocortin receptor-4 (MC4R), GnRH and adipose AR, and the protein of androgen receptor (AR) and leptin receptor (LEPR) in the hypothalamic arcuate nucleus (ARC) were decreased. In the PNA group, there were positive correlations between serum DHEA and mRNA of hypothalamic ERα, MC4R and AR, negative correlations between mRNA of adipose AR and serum T and free testosterone (FT). Prenatal androgen exposure delayed the onset of puberty in female offspring, the possible mechanism of which is that prenatal androgen exposure may increase the levels of androgen and LEP, decreases their sensitivity and the expression of AR, LEPR, and MC4R, reducing GnRH secretion. Show less

The incretin receptor agonists semaglutide and tirzepatide have transformed the medical management of obesity. The neural mechanisms by which incretin analogs regulate appetite remain incompletely understood, and dissecting this process is critical for the development of next-generation antiobesity drugs that are more targeted and tolerable. Moreover, the physiologic functions of incretins in appetite regulation and gut-brain communication have remained elusive. Using in vivo fiber photometry, we discovered distinct pharmacologic and physiologic roles for the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We showed that GIP, but not GLP-1, was required for normal nutrient-mediated inhibition of hunger-promoting AgRP neurons. By contrast, both GIP and GLP-1 analogs at pharmacologic doses were sufficient to inhibit AgRP neurons. The magnitude of neural inhibition was proportional to the effect of each incretin on food intake, and dual GIP and GLP-1 receptor agonism more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. Our results have revealed a role for endogenous GIP in gut-brain appetite regulation and indicate that incretin analogs act in part via AgRP neurons to mediate their anorectic effects. Show less

COL4A1, a key component of the basement membrane, has been increasingly implicated in tumor progression, yet its role in colon cancer remains incompletely understood. In this study, we conducted a comprehensive integrative analysis using transcriptomic data from the TCGA-COAD cohort, combined with functional validation in colon cancer cell lines. Gene set enrichment analysis (GSEA) revealed that high COL4A1 expression was associated with oncogenic pathways including epithelial-mesenchymal transition (EMT), KRAS signaling, and inflammatory responses. Immune infiltration analysis indicated that COL4A1 expression negatively correlated with CD8 Show less

Periodontitis (PD) is a chronic inflammatory disease in which oxidative stress plays a crucial role in its progression. Mitophagy eliminates damaged mitochondria and alleviates oxidative stress; however, its specific regulatory mechanisms in PD remain unclear. This study utilized single-cell and bulk RNA sequencing data to identify core genes and investigate their potential roles. We utilized single-cell RNA sequencing data and applied 4 algorithms - area under the curve cell level enrichment, U-statistics-based single-cell signature scoring, single-sample gene set scoring, and AddModuleScore - to assess mitophagy activity and identify candidate genes. Subsequently, based on bulk RNA-seq data, 5 machine learning algorithms, including Least Absolute Shrinkage and Selection Operator Regression, random forest, Boruta, gradient boosting machine, and eXtreme Gradient Boosting, were employed to further screen core genes from the candidate gene set. Finally, immune infiltration analysis, cell communication analysis, and gene interaction network construction were integrated to systematically elucidate the regulatory mechanisms of core genes in the progression of PD. Single-cell RNA sequencing combined with multiple algorithms revealed significantly elevated mitophagy activity in PD tissues, particularly in monocytes/macrophages and endothelial cells. Additionally, we identified 4 core genes: BNIP3L, VPS13C, CTTN, and MAP1LC3B. BNIP3L and CTTN were downregulated in periodontitis, correlating negatively with disease prevalence, immune infiltration, and inflammatory pathways, whereas VPS13C and MAP1LC3B were upregulated, showing positive correlations. CellChat analysis highlighted monocytes/macrophages and endothelial cells with high core gene expression as key mediators of intercellular communication. This study identified BNIP3L, VPS13C, CTTN, and MAP1LC3B as core mitophagy-related genes associated with PD, and highlighted the pivotal roles of monocytes/macrophages and endothelial cells in disease progression. These findings provide new insights into the pathogenesis of PD and offer a theoretical foundation for mitophagy-targeted diagnosis, biomarker identification, and precision therapy. Show less

The WNT signaling pathway is a key driver of colorectal cancer (CRC) initiation and progression, particularly in early-onset CRC (EOCRC) among underserved populations. However, interrogating WNT pathway dysregulation across clinical and genomic dimensions remains technically challenging, limiting both translational insight and personalized intervention strategies. To address this gap, we developed AI-HOPE-WNT, the first conversational artificial intelligence (AI) agent purpose-built to investigate WNT signaling in CRC using natural language-driven, integrative bioinformatics. AI-HOPE-WNT employs a modular architecture combining large language models (LLMs), a natural language-to-code engine, and a backend statistical workflow interfaced with harmonized data from cBioPortal. Unlike general-purpose platforms, AI-HOPE-WNT is uniquely optimized for WNT-specific precision oncology. The tool supports mutation frequency analysis, odds ratio testing, survival modeling, and subgroup stratification by genomic, clinical, and demographic variables. To validate the platform, we recapitulated findings from two previous studies examining WNT pathway alterations in high-risk CRC populations, including mutation prevalence in RNF43 and AXIN2 and survival outcomes associated with WNT pathway status across ethnic and age subgroups. Exploratory queries further assessed treatment response, co-mutation patterns, and population-specific trends. In recapitulation analyses, AI-HOPE-WNT reproduced key trends from prior work, including improved survival in WNT-altered EOCRC and higher RNF43 mutation rates in Hispanic/Latino (H/L) populations compared to non-Hispanic White (NHW) people. Exploratory analyses revealed several novel findings. Among FOLFOX-treated EOCRC patients, APC mutations were associated with significantly different survival outcomes ( AI-HOPE-WNT is the first dedicated AI platform for WNT pathway analysis in CRC. By combining natural language interaction with automated, high-throughput bioinformatics, it democratizes access to pathway-specific precision oncology research. The platform is freely available at: https://github.com/Velazquez-Villarreal-Lab/AI-HOPE-WNT. Show less

When Apolipoprotein B (ApoB) is discordant with either LDL cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C), ApoB is a stronger predictor of atherosclerotic cardiovascular disease (ASCVD). It is unclear whether ApoB also provides better risk stratification when ApoB and LDL particle number (LDL-P) are discordant. Here we examine the relationship between ApoB and LDL-P in the UK Biobank to determine which biomarker provides more accurate risk prediction when ApoB and LDL-P are discordant. The UK Biobank is a prospective observational study of 500,000 adults. Analyses were restricted to 41,099 participants (mean age 57 years, 49.7% female, 95.1% white) with at least 10 years of data following enrollment, three or more recorded ICD codes, plasma lipoprotein and apolipoprotein measurements, and available baseline characteristics. Major adverse cardiovascular events (MACE) and coronary artery disease (CAD) events were plotted against LDL-P and ApoB for all participants. Concordance was defined as the linear regression line with y-intercept forced to zero. Discordant subpopulations were defined as populations 2, 4, 6, 8, 10, 20, and 30% above or below the regression line. The hazard ratio (HR) of cases to controls was determined for the discordant subpopulations and the concordant control group. A HR>1 means that the risk is greater in the discordant group than the reference group, whereas a HR<1 suggests that the cases are less common in the discordant group. Over 10 years of follow-up, 9,663 MACE and 1,754 CAD events occurred. There was no significant increase in HR for CAD events or MACE for the subpopulations with discordant LDL-P vs ApoB. In contrast, among subpopulations with discordant ApoB, the HR for both MACE and CAD events increased as discordance increased and was statistically significant at all percentage discordance cutoffs. At only 2% ApoB discordance, HRs were already elevated for both MACE (HR 1.1, P<0.0001) and CAD (HR 1.1, P<0.0001). Risk increased progressively, reaching HR 1.4 for MACE and HR 2.5 for CAD at 30% discordance. This study suggests that ApoB is a more accurate marker for cardiovascular risk than LDL-P when discordant, as marked by ApoB levels in excess of LDL-P. Notably, risk was already elevated at as little as 2% discordance, suggesting that even modest mismatches between ApoB and LDL-P may be clinically relevant. In keeping with prior data examining discordance between ApoB and LDL-C or non-HDL-C, this data reinforces the utility of ApoB in guiding lipid-lowering strategies and cardiovascular risk assessment. Show less

1,3-dilinoleoyl-2-palmitoylglycerol (LPL) is an important structural lipid in breast milk fat, which plays an important role in the health of infants, and therefore the development of an efficient method for the preparation of such compounds is necessary. In the present study, LPL was efficiently catalytically synthesized by immobilized lipase ANL-MARE as a biocatalyst using tripalmitate and linoleic acid in a solvent-free system, and its digestive properties were investigated. The optimal process conditions for the enzymatic acidolysis of LPL were optimized by response surface test: the molar ratio of PPP:LA was 1:10, the enzyme addition was 13.60%, the reaction temperature was 50℃, and the reaction time was 5 h. At this time, the relative content of LPL in the product was 67.78%, of which the relative content of sn-2 palmitic acid (sn-2 PA) accounted for 71.50%. In vitro gastrointestinal digestion of LPL resulted in the release of 59.69% of its fatty acids. The digested product contained higher levels of free unsaturated fatty acids and palmitic acid monoacylglycerols. In conclusion, the immobilized enzyme ANL-MARE has great potential to catalyze the preparation of LPL, which provides a new strategy and theoretical basis for the efficient preparation of human milk fat substitutes. Show less

Neonatal sepsis (NS) is a major cause of morbidity and mortality in both preterm and term infants; early-onset NS (EONS) occurs in newborns within the first 72 h of life. Cytokines are messengers with low molecular weight that are produced by macrophages and lymphocytes in response to antigenic stimulations or products of inflammation. Different interleukins (IL) have higher values in EONS, when detected from peripheral venous blood. This review aims to analyze if the cytokines determined from the umbilical cord blood (UCB) of newborns may help in the rapid and accurate diagnosis of EONS in newborns originating from pregnancies with maternal-fetal infectious risk. Three databases, namely, PubMed, Scopus, and Web of Science, were searched for original research articles that assessed the relationship between interleukins and EONS. The search results retrieved a number of 18 articles that complied with the inclusion and exclusion criteria. Some studies report that neonates with EONS had higher umbilical plasma levels of cytokines such as IL-1ß, IL-6, IL-8, IL-10, IL-18, and IL-27. However, results are controversial, as many authors failed to establish the cut-off values of cytokines detected from UCB that may predict EONS. The main limitations of the current studies remain the small study samples, the heterogeneous population, and the lack of stratification of the studied population according to gestational age (GA). The cytokines that seem to be more accurate in the early diagnosis of EONS, as reported by the majority of the studies, are IL-6 and IL-8. The level of these cytokines may guide clinicians in the careful administration of antibiotics, thus aiding in the overall reduction of antimicrobial resistance. Show less

Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.). Show less

The cholesteryl ester transfer protein inhibitor obicetrapib decreases levels of atherogenic lipids and raises high-density lipoprotein cholesterol (HDL-C). In this study, we sought to determine the effect of obicetrapib on cardiovascular events. The effects of 10 mg obicetrapib and placebo daily on major adverse cardiovascular event (MACE) rates were investigated in a pooled analysis of 354 patients with heterozygous familial hypercholesterolemia (HeFH) and 2,530 patients with atherosclerotic cardiovascular disease (ASCVD) over 365 days. The association between on-treatment lipids and MACE were also investigated. The cohort (mean age 66 years, 36% female, ASCVD 82%, HeFH 27%, diabetes 35%) had median baseline levels of low-density lipoprotein cholesterol (LDL-C) 92 mg/dL, HDL-C 48 mg/dL, apolipoprotein B (ApoB) 88 mg/dL, non-HDL-C 116 mg/dL, and lipoprotein(a) (Lp(a)) 40.5 nmol/L. Obicetrapib produced greater reductions in LDL-C (-34.0 vs -4.0 mg/dL, -37.8% vs -4.6%), ApoB (-19.0 vs -3.0 mg/dL, -21.7% vs -3.6%), non-HDL-C (-36.0 vs -4.0 mg/dL, -32.4% vs -3.7%), and Lp(a) (-9.8 vs 0 nmol/L, -32.5% vs 0%) and increased HDL-C (+68.0 vs +1.0 mg/dL, +140.0% vs +1.5%). The rate of coronary heart disease death, myocardial infarction, ischemic stroke, or coronary revascularization was lower with obicetrapib (3.9% vs 5.0%; HR: 0.77; 95% CI: 0.54-1.11; P = 0.16), with a risk reduction in the second 6 months (HR: 0.60; 95% CI: 0.37-0.99; P = 0.04). The rate of coronary heart disease death, myocardial infarction, or coronary revascularization was lower with obicetrapib (3.2% vs 4.7%; HR: 0.68; 95% CI: 0.46-1.00; P = 0.048), with a risk reduction in the second 6 months (HR: 0.45; 95% CI: 0.26-0.77; P = 0.003). Achieved levels of LDL-C (P = 0.003), ApoB (P = 0.007), non-HDL-C (P = 0.01), Lp(a) (P = 0.003), and HDL-C (P = 0.0001) were associated with event rates. Obicetrapib treatment associated with a reduction in coronary events, evident beyond 6 months of treatment. Show less

Declining mitochondrial function is an established feature of aging and contributes to most aging-related diseases through its impact on various pathologies such as chronic inflammation, fibrosis and cellular senescence. Our recent work suggests that benign prostatic hyperplasia, which is an aging-related disease frequently associated with inflammation, fibrosis and senescence, is characterized by a decline in mitochondrial function. Here, we utilize glycolytic restriction and pharmacologic inhibition of the mitochondrial electron transfer chain complex I to promote mitochondrial dysfunction and identify the cellular processes impacted by declining mitochondrial function in benign prostate stromal cells. Using this model, we show that mitochondrial dysfunction induced alterations in cell-cell and cell-matrix adhesion, elevated fibronectin expression, resistance to anoikis and stress-induced premature senescence (SIPS). We also showed that ablation of ZC3H4, a transcription termination factor implicated in anoikis-resistance and reduced in BPH relative to normal prostates, phenocopied various phenotypes in the human BHPrS1 prostate stromal cell line that resulted from inhibition of complex I. Furthermore, ZC3H4 ablation resulted in the elevation of mitochondrial superoxide (mtROS) and mitochondrial membrane potential, altered mitochondrial morphology and NAD Show less

Excessive inflammation is a capital cause of scar formation and inflammation microenvironment that result in challenge of axonal regeneration after spinal cord injury (SCI). Macrophages and astrocytes play important roles in the inflammatory response. Tip cells, a critical endothelial sub-population, play pivotal roles in post-injury vascular regeneration. Nevertheless, their characteristics in SCI remain poorly documented. This study based on single cell RNA sequencing (scRNA-seq) and in vitro experiment, investigates the effects of tip cells on astrocytes and macrophages. For astrocytes, tip cells can recruit astrocytes to migrant, contribute to the formation of fence-like structure of astrocytes, finally inhibit the diffusion of inflammation via the Angptl4-Sdc4 ligand-receptor pathway. For macrophages, similarly through the Angptl4-Sdc4 ligand-receptor pathway, tip cells can promote macrophages to polarize more toward the M2 phenotype and inhibit their polarization toward M1 phenotype, thus alleviate the inflammatory response. Tip cells after SCI exhibit conserved ribosomal protein expression, implicating ribosome-dependent signaling in their function. These finding highlight the critical role of tip cells in microenvironment after SCI, offering a potential treatment target for SCI. Show less

This study aimed to compare the safety profile of high-power (HPL) and low-power (LPL) Holmium:YAG lasers in retrograde intrarenal surgery (RIRS), using urinary Kidney Injury Molecule-1 (KIM-1) as an early biomarker for acute kidney injury (AKI). Sixty patients with renal stones (1.5-2.5 cm) were prospectively randomized into HPL and LPL groups. Urinary KIM-1 and KIM-1/creatinine ratios were measured preoperatively and at 4 and 24 h postoperatively. Intraoperative parameters, stone-free rates (SFR), complications, and renal function (eGFR, serum creatinine) were also assessed. Intrarenal temperatures were recorded before and after lithotripsy. Operative time, SFR, complication rates, and renal function parameters were similar between groups (p > 0.05). However, KIM-1 levels were significantly higher in the HPL group at 24 h postoperatively (278.8 ± 239.6 pg/mL vs. 170.3 ± 172.9 pg/mL, p = 0.003), and the KIM-1/creatinine ratio was also elevated (5.5 ± 4.5 vs. 3.1 ± 2.0, p = 0.035). No significant differences were observed in postoperative serum creatinine or eGFR. Intraoperative renal temperatures increased slightly in the HPL group, but the difference was not statistically significant. While high-power laser lithotripsy does not adversely affect global renal function, it is associated with elevated levels of renal injury biomarkers, suggesting greater subclinical renal stress. Show less