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Perioperative neurocognitive disorder (PND) is one of the most prevalent neurological complications in elderly surgical patients. Dysregulated lipid metabolism is a hallmark of aging and is strongly associated with cognitive dysfunction. This study aimed to investigate whether ω-6 polyunsaturated fatty acid (PUFA) metabolism contribute to PND and examined whether fatty acid desaturase 1 (FADS1) represents a key regulatory link between fatty acid metabolism and PND in aged mice. An anesthesia/surgery-induced cognitive dysfunction model was established Anesthesia/surgery significantly upregulated hippocampal FADS1 expression (1.91-fold [0.37] vs. 1.00-fold [0.43]; These findings highlight anesthesia/surgery could disrupt ω-6 PUFA metabolism, notably activating the PGD The online version contains supplementary material available at 10.1186/s12974-025-03678-y. Show less

Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in cardiovascular pathophysiology; however, their specific contributions to CHD pathogenesis remain largely unexplored. This study aimed to identify and validate MAM-related biomarkers in CHD through integrated analysis of transcriptomic sequencing data and Mendelian randomization, and to elucidate their underlying mechanisms. We analyzed two gene expression microarray datasets (GSE113079 and GSE42148) and one genome-wide association study (GWAS) dataset (ukb-d-I9_CHD) to identify differentially expressed genes (DEGs) associated with CHD. MAM-related DEGs were filtered using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis, Mendelian randomization, and machine learning algorithms were employed to identify biomarkers with direct causal relationships to CHD. A diagnostic model was constructed to evaluate the clinical utility of the identified biomarkers. Additionally, we validated the two hub genes in peripheral blood samples from CHD patients and normal controls, as well as in aortic tissue samples from a low-density lipoprotein receptor-deficient (LDLR-/-) atherosclerosis mouse model. We identified 4174 DEGs, from which 3326 MAM-related DEGs (DE-MRGs) were further filtered. Mendelian randomization analysis coupled with machine learning identified two biomarkers, DHX36 and GPR68, demonstrating direct causal relationships with CHD. These biomarkers exhibited excellent diagnostic performance with areas under the receiver operating characteristic (ROC) curve exceeding 0.9. A molecular interaction network was constructed to reveal the biological pathways and molecular mechanisms involving these biomarkers. Furthermore, validation using peripheral blood from CHD patients and aortic tissues from the Ldlr-/- atherosclerosis mouse model corroborated these findings. This study provides evidence supporting a mechanistic link between MAM dysfunction and CHD pathogenesis, identifying candidate biomarkers that have the potential to serve as diagnostic tools and therapeutic targets for CHD. While the validated biomarkers offer valuable insights into the molecular pathways underlying disease development, additional studies are needed to confirm their clinical relevance and therapeutic potential in larger, independent cohorts. Show less

To understand the relative contributions of 5' UTR elements to translation output, we performed a comprehensive analysis of upstream open reading frames (uORFs) in the 5' UTRs of the BDNF (brain-derived neurotrophic factor) transcripts. Predicted uORFs were identified in 14 out of 17 BDNF RefSeq transcript isoforms, and we experimentally validated five of these transcripts as being uORF-repressed, suggesting that uORF elements play an important role in shaping the protein output from this locus. We explored several approaches to disrupt BDNF uORF function. Deletion of a 5' UTR exon in BDNF v11 (containing eight predicted uORFs), in order to simulate an exon skipping outcome, resulted in pronounced upregulation in a reporter construct system. This effect was found to be partially uORF-dependent but was also dependent on the disruption of an RNA secondary structure element. However, this transcript variant was found to not be expressed in human brain. Conversely, direct disruption of a single uORF start codon in the widely expressed BDNF v4 transcript variant using an adenine base editing approach resulted in a ∼1.8-fold upregulation of endogenous BDNF protein expression in cell culture. This study characterizes uORF-mediated regulation of the BDNF locus and demonstrates the potential for BDNF protein upregulation via base editing-mediated uORF disruption. Show less

Several studies show that neurosteroids currently play a significant role in autism spectrum disorders (ASD). However, the pathway of neurosteroid synthesis involved in ASD remains unclear. This study aimed to investigate the crosstalk between autism and neurosteroids, focusing on the mechanism of allopregnanolone production. We used the BTBR T+ tf/J (BTBR) mouse, a well-established animal model of ASD that exhibits typical autism-like behaviors along with neuroinflammation. In the hippocampus of BTBR mice, we observed a marked overexpression of pregnenolone and a related reduction in allopregnanolone levels. This neurosteroid imbalance also appears to be associated with an inflammatory pattern and the manifestation of repetitive and asocial behaviors. The combination of low doses of ultramicronized palmitoylethanolamide (PEA-um) and docosahexaenoic acid (DHA) restores allopregnanolone production modulating neurosteroidogenesis. In association with neurosteroid modulation, this restoration reduces repetitive behaviors and improves social interactions in BTBR mice, also modulating the inflammatory profile with a significant reduction in proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. These effects demonstrate an important role of the peroxisome proliferator-activated receptor alpha (PPAR-α), whose expression is particularly reduced in BTBR mice. In addition, the pivotal involvement of PPAR-α was further supported by administering a specific antagonist that abolished the advantageous effects of PEA-um ​+ ​DHA. Overall, our findings demonstrate the potential synergistic effect of the low-dose combination of PEA-um and DHA, confirming their therapeutic effect in ASD and the involvement of neurosteroids in their mechanism of action. Show less

Functional impairment (FI) is a key criterion for diagnosing dementia. However, subtle functional changes may occur during preclinical and prodromal phases but may not be accurately characterized. Furthermore, research linking FI to Alzheimer disease (AD) biofluid biomarkers is limited. Here we examined cross-sectional associations between cerebrospinal fluid (CSF) AD biomarkers and persistent versus transient FI in dementia-free older adults, and the longitudinal association of FI with incident dementia. Data from 1000 participants (age 72.9 ± 7.0; 45.2% female; 62.8% MCI) from the Alzheimer's Disease Neuroimaging Initiative were analyzed. CSF biomarkers included p-tau181, Aβ42, and ptau-181/Aβ42 ratio. Three Functional Activities Questionnaire items of "preparing a hot beverage," "preparing a balanced meal," and "shopping alone" were identified by factor analysis as assessing function rather than cognition directly. Persistent-FI was operationalized as FI present at> two-thirds of pre-dementia visits. Comparator groups included Transient-FI and No-FI. Linear regression modeled the association between FI status and baseline biomarker levels, while Cox regression assessed the association between FI and incident dementia. Models adjusted for age, sex, education, APOE-ε4 status, and MMSE. Compared to No-FI, Persistent-FI was associated with lower Aβ42 (Beta = -8.93; 95% CI: -13.56 to -4.03; p < 0.001), higher p-tau181 (Beta = 10.81; 95% CI: 0.44-22.26; p = 0.041), and ptau181/Aβ42 ratio (Beta = 21.66; 95% CI: 7.02-38.31; p = 0.003). In contrast, Transient-FI showed no significant associations. APOE-ε4 carrier status was more prevalent in the Persistent-FI group compared to No-FI (p = 0.009), but not in Transient-FI (p = 0.931). Compared to No-FI, Persistent-FI had a 6.66-fold greater dementia incidence rate (95% CI: 4.98-8.91, p < 0.001), while Transient-FI had a 1.72-fold greater incidence rate (95% CI: 1.09-2.72, p = 0.021). Findings extend the limited research on the association of FI with CSF AD biomarkers in dementia-free populations. Operationalizing FI-related risk by persistence enhances prognostication, identifying individuals with greater AD pathology and progression risk. This approach could enhance screening, early detection, and risk stratification, informing timely interventions before dementia onset. Show less

Primary cilia, microtubule-based sensory organelles that mediate cell-cell communication, may facilitate signaling in the brain through direct physical contacts (e.g., synapse-like structures). Similarly, specialized glial cells lining the third ventricle (3V) called tanycytes signal through physical interactions and can dynamically alter their morphology in response to external stimuli and physiological changes. Here, we identify robust cilia-tanycyte contacts; we term HUGS ( H ypothalamic, U nifying G lia-cilia S tructures) and discover that these connections are disrupted in a mouse ciliopathy model ( Show less

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive neuronal degeneration, predominantly caused by the accumulation of amyloid-beta (Aβ) and neuroinflammatory processes. Hypoxia, characterized by diminished oxygen levels, intensifies these mechanisms by stimulating hypoxia-inducible factor 1-alpha (HIF-1α), potentially enhancing BACE1 enzyme activity and resulting in increased Aβ synthesis and render neurons especially susceptible to hypoxia, exacerbating disease progression. Existing therapies are constrained by inadequate medication distribution across the blood-brain barrier and associated adverse effects. This study aims to identify potential therapeutic agents targeting HIF-1 We used Results identified several compounds with strong binding affinities and favorable ADMET profiles as potential inhibitors of HIF-1 Show less

Acute kidney injury (AKI) represents a critical complication in patients with acute coronary syndrome (ACS), particularly in patients undergoing percutaneous coronary intervention (PCI). Current tests for detecting early AKI, such as creatinine and cystatin C, have modest sensitivity. This study explores the role of bioinformatics in creating an implementable predictive key gene in cardiorenal pathogenesis and evaluates the diagnostic potential of This is a single-center prospective observational cohort study that enrolled 167 participants: healthy controls ( The online version contains supplementary material available at 10.1186/s12882-026-04926-w. Show less

Monocyte adhesion to vascular endothelial cells is a critical step in the pathogenesis of atherosclerosis. While unconventional myosins are known to participate in various cellular activities, their specific role in monocyte-endothelium adhesion remains unclear.In the present study, we investigated the effects of Myosin IF (Myo1f), a class I unconventional myosin, on atherosclerosis and its underlying mechanisms. A high-cholesterol diet was administered to apolipoprotein E-KO (Apoe Myo1f expression was found to be significantly increased in PBMCs of patients with coronary artery disease. Moreover, Myo1f-deficient mice exhibited a notable reduction in atherosclerotic plaque area and lipid deposition compared to Apoe Our data indicate that Myo1f regulates monocyte adhesion and contributes to the pathogenesis of atherosclerosis by recruiting EPLINα, which stabilizes F-actin. This stabilization enhances MRTFA nuclear translocation, thereby promoting ITGB2 transcription. Show less

Previous Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD), whereas their associations with mild cognitive impairment (MCI) remain unclear. To evaluate the associations between 100 representative AD-associated SNPs and susceptibility to MCI in the Chinese population. We recruited 200 MCI patients and 200 cognitively-healthy controls from the community, matched for age and sex. Associations between SNPs and MCI risk were estimated using lasso regression, adjusted for APOE status, using different genetic models. Fifteen SNPs in nine genes (including CLU, SORL1, PICALM, BDNF, NOS3, MTHFR, TOMM40, BIN1, and PVRL2) were associated with MCI in single-SNP analysis. In the multi-SNP association test, rs1801133 and rs9331888 of CLU were consistently associated with MCI risk in the dominant model. TOMM40 rs2075650 (G) was associated with MCI risk in the dominant model by age and education (OR = 2.41, 95%CI = 1.27-4.59), but disappeared when further adjusted for APOEε4 status. PICALM rs561655 (G) (OR = 0.52, 95%CI = 0.30-0.92) and NOS3 rs1549758 (T) (OR = 0.53, 95%CI = 0.30-0.94) were identified as protective genetic factors of MCI for the first time in dominant model combined with the APOEε4 allele. Moreover, MTHFR rs1801133 (A) and CLU rs9331888 (G) showed more susceptibility to MCI in the additive model. SORL1 rs641120(G) showed a protective effect, whereas BIN1 rs5733839 consistently showed a risk effect for MCI in the overdominant model, regardless of APOEε4 status. This study suggests that some AD-associated SNPs are associated with cognitive decline and may have important implications for future studies. Show less

Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are locally constrained, active receptors in different subcellular locations could produce different downstream effects. This phenomenon may be relevant to the optimal targeting of the glucagon-like peptide-1 receptor (GLP-1R), a type 2 diabetes and obesity target GPCR for which several ligands with varying internalisation tendency have been discovered. To investigate, we compared the signalling localisation effects of two prototypical GLP-1RAs with opposite signal bias and effects on GLP-1R trafficking: exendin-asp3 (ExD3), a full agonist that drives rapid internalisation, and exendin-phe1 (ExF1), which shows much slower internalisation. After using bioorthogonal labelling and fluorescent agonist conjugates to verify the divergent trafficking patterns of ExF1 and ExD3 in β-cell lines and primary pancreatic islets, we used live cell biosensors to monitor signalling at different subcellular locations. This revealed that cAMP/PKA/ERK signalling in β-cells is in fact distributed widely across the cell over short- (<5 min) and medium-term (up to 60 min) stimulation at pharmacological (>10 pM) concentrations, with no major differences in signal localisation that could be linked to internalised versus cell surface-bound GLP-1R. Moreover, washout experiments highlighted that, whilst fast-internalising ExD3 shows much greater accumulation and binding to GLP-1R in endosomes than slow-internalising ExF1, it is a rather inefficient driver of both cAMP production in β-cells and insulin secretion from perfused rat pancreata. These data provide a greater understanding of the cellular effects of biased GLP-1R agonism. Show less

The incidence of obesity has significantly increased worldwide. However, it is still unclear about the genetic susceptibility of obesity. Here we performed the largest European meta-analysis of genome-wide association study, including 98,421 obesity cases and 2,108,019 healthy controls. We identified 322 novel genome-wide significant obesity-associated loci and 23 of 32 known loci. SNP-based heritability analyses revealed that common variants explain 17.19 ± 0.59% of genetic risk for obesity, whereas MiXeR predicted an estimated 1.6 million effective sample sizes explaining 90% of obesity-associated phenotypic variance. Across 345 obesity-associated loci, 2000 likely causal genes are indicated, and 410 causal genes are prioritized. Tissue specificity enrichment analyses demonstrated that obesity-related causal genes mainly expressed in brain putamen basal ganglia, hippocampus, amygdala, substantia nigra, and caudate basal ganglia. The genetic correlation and gene-set analyses showed that apart from obesity-related diseases, some brain diseases and mood (e.g., broad depression, neuroticism, mood swings), inflammatory and allergic diseases diseases (e.g., asthma, spondyloarthritis, Hashimoto thyroiditis), cardiovascular diseases (e.g., hypertension, myocardial infarction, coronary artery disease), and lung disease (e.g., interstitial lung disease, chronic obstructive pulmonary disease, lung cancer) have the positive correlations with obesity. Gene-drug interaction analysis suggested that obesity-associated genes overlapped with targets of current medications for obesity. Finally, we used this meta-analysis to explore some potential targets (e.g., GLP1R, SIGMAR1, MC4R) and drug repurposing (e.g., iloprost, flunarizine, edrophonium chloride) for obesity. We identified 345 genome-wide significant loci, including 322 novel loci for obesity. Based on 345 loci, we provided new biological insights to the etiology of obesity. Of clinical interest, we provided some potential targets and drug repurposing for obesity. Show less

Lower-extremity arterial disease (LEAD) is a manifestation of atherosclerotic cardiovascular disease, affecting 230 million people worldwide with increasing prevalence. Medial arterial calcification (MAC) is common in LEAD patients and contributes to disease-related mortality. However, therapeutic strategies targeting femoral MAC are lacking, and its underlying mechanisms remain unclear. This study aimed to identify molecular drivers of femoral MAC in LEAD. Calcium deposits and pro-calcifying markers were analyzed in human patient samples using von Kossa staining, immunofluorescence, and gene expression analysis. Femorals showed significantly more calcification and pro-calcifying gene expression than carotids. Given MAC abundance in LEAD, we assessed medial calcification in Apoe-/- mice fed a WD for 4/21 weeks. Digital PCR revealed upregulation of Ddr1 and Bmp2 in femoral versus carotid arteries after 21 weeks of WD. DDR1 expression positively correlated with calcification in human femoral samples. In vitro experiments with mouse femoral vs. carotid vascular smooth muscle cells (VSMCs) confirmed a significantly higher prevalence of calcifying proteins (DDR1, BMP2, and RUNX2) in femoral VSMCs. Additionally, calcification analyses in murine and human VSMCs showed that DDR1 inhibition reduced, while DDR1 activation increased, calcium deposition. Transcriptomic analysis revealed elevated NF-κB expression in human femoral arteries, matching data in femoral VSMCs. DDR1 stimulation activated NF-κB, and its inhibition blocked DDR1-induced calcification. This study identifies DDR1 as a key driver of calcification in LEAD, operating through NF-κB activation and the expression of calcifying proteins. Targeting DDR1 may offer a novel therapeutic approach to prevent MAC in LEAD. Show less

Formalin-fixed paraffin-embedded (FFPE) tissue specimens represent precious resources for clinical genomic profiling studies, especially when coupled with comprehensive medical records. Even though next-generation sequencing (NGS) is an effective tool to detect somatic mutations and somatic copy number alterations (sCNA), the biggest challenges in unlocking clinically translatable genomic information from FFPE tissue are low DNA yields and degraded DNA, affected by variable formalin fixation. Another issue is that the proportion of carcinoma and other noncarcinoma cells is variable and can be confounded by intratumoral heterogeneity. To explore these challenges, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from nine primary and metastatic breast cancer and three primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole-genome sequencing (WGS) for copy number landscape profiling (10 samples) and/or a targeted panel for somatic mutation and sCNA analysis (seven samples), subject to cell availability. Seven out of 10 samples (even some with low tumour content or of old age) produced good-quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations. Mutation analysis was performed successfully in 6/7 samples and somatic mutations were detected in all of them. Our workflow enabled the identification of clinically actionable targets, including PIK3CA, ERBB2, FGFR1/2, CDK6, CCNE1, KRAS amplifications and RB, BRCA1/2 losses in patients that would direct therapy. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. Show less

Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by severe hypertriglyceridemia and a risk of recurrent pancreatitis. Patients with biallelic pathogenic variants affecting lipoprotein lipase (LPL)-mediated triglyceride metabolism may remain refractory to conventional lipid-lowering therapies and strict dietary control, leading to recurrent critical illness and progressive multisystem complications. We report a female patient with genetically confirmed FCS and persistent triglyceride levels typically in the 4,000-5,000 mg/dL range despite adherence to diet and lipid-lowering therapy, without clear secondary contributors to severe hypertriglyceridemia. Her course included recurrent intensive care unit (ICU) admissions for hypertriglyceridemia-associated pancreatitis requiring insulin drips, with progression to chronic pancreatitis, pancreatic insufficiency requiring enzyme replacement, insulin-dependent diabetes with continuous glucose monitoring (CGM), chronic pain syndrome with opioid dependence concerns, and psychiatric comorbidity. During a hospitalization approximately 10 months prior to the most recent follow-up, the patient underwent placement of a right chest tunneled central venous catheter and initiated therapeutic plasmapheresis. She was concurrently followed by a triglyceride clinic and continued on olezarsen. At follow-up on February 25, 2025, she reported no hospitalizations since April 2024. A triglyceride value of 4,700 mg/dL was documented shortly before a scheduled plasmapheresis session. This case highlights the complexity of severe FCS when hypertriglyceridemia remains refractory to conventional management and illustrates a care pathway in which chronic outpatient plasmapheresis combined with emerging RNA-based therapy was associated with stabilization and avoidance of recurrent hospitalization. Sustained outpatient success required multidisciplinary coordination, addressing pancreatitis sequelae, glycemic management, chronic pain, psychiatric disease, and central-line monitoring. These observations are hypothesis-generating and highlight the potential role of coordinated outpatient plasmapheresis and emerging RNA-based therapies in the management of severe FCS. To our knowledge, reports describing long-term outpatient stabilization of severe FCS using combined chronic plasmapheresis and apolipoprotein C-III (APOC3)-targeted RNA therapy remain limited, and this case highlights a potential care pathway for patients with refractory disease. Show less

Persistent chylomicronemia is associated with severe hypertriglyceridemia (sHTG) and plasma triglycerides (TG) levels sustainably > 10 mmol/L (880 mg/dL) despite lipid lowering therapies. The main risk of persistent chylomicronemia is acute pancreatitis (AP). During the second and third trimester of pregnancy, TG levels significantly increase, which represents a serious risk of AP in women with preexisting chylomicronemia. New emerging therapies such as plozasiran, a GalNAc-conjugated small interfering RNA (siRNA) against ApoC3, are developed to manage persistent chylomicronemia, but no data are currently available on their safety and efficacy during pregnancy. We report herein the case of a woman with persistent chylomicronemia randomized in the PALISADE study to receive plozasiran 25 mg quarterly, who had an unplanned pregnancy during the clinical trial. The 34-year-old patient received one dose of plozasiran 8 weeks before conception and the experimental treatment was ceased afterwards. The pregnancy went well, TG levels did not rise above 10 mmol/L (880 mg/dL) during the whole pregnancy, even during the last two trimesters where TG levels usually increase two- to four-fold from baseline and she did not experience any AP episode. She delivered a healthy baby at 39 weeks. This case suggests that plozasiran might be safe for the mother and the fetus and could prevent incremental pregnancy-driven TG elevation and occurrence of AP in women with sHTG. This is consistent with the long duration of action and hepatic half-life of plozasiran in clinical studies where TG levels remained sustainably lower than baseline > 9 months after the last injection. Show less

This study used compositional data techniques that address the interdependence of 24-h movement behaviors (sleep, sedentary behavior [SB], light-intensity physical activity [LPA], moderate-to-vigorous intensity physical activity [MVPA]) to examine: (1) how patients undergoing metabolic bariatric surgery (MBS) allocate time among these behaviors before MBS, and (2) whether overall time-use composition and modeled reallocation patterns relate to early weight loss after MBS. Participants wore an accelerometer 24 h/day for 10 days before MBS to measure time in sleep, SB, LPA, and MVPA. Isotemporal substitution models estimated differences in 6-month post-MBS percentage total weight loss (%TWL) associated with reallocations of these pre-surgery movement behaviors. Forty-five participants provided valid data. Pre-MBS time-use composition was associated with %TWL (23.8 ± 5.1%; F = 2.66, p = 0.047). Reallocating 15-60 SB or LPA minutes/day to MVPA was estimated to relate to 0.9-3.5% greater %TWL. Reallocating 15-30 MVPA minutes/day to SB or LPA was estimated to relate to 1.4-5.0% less %TWL (all comparisons p < 0.05). Other reallocations were non-significant. In conclusion, modeled shifts in time from SB or LPA to MVPA and vice versa were associated with estimated increases or decreases in early post-surgical weight loss, respectively. Experimental research is needed to clarify causal relationships and inform interventions to improve MBS outcomes. Show less

Variants of uncertain significance represent the biggest challenge for genomics-based precision oncology. Activated fibroblast growth factor receptors (FGFRs) frequently drive tumorigenesis by different genetic aberrations. However, it remains unknown which of the many point mutations affecting FGFR1, FGFR2, FGFR3 or FGFR4 in cancer are druggable, that is, activating signaling while not mediating FGFR inhibitor resistance. Here we implemented a saturation mutational scanning platform to screen all 11,520 possible point mutations covering the kinase domains of FGFR1-4. Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable FGFR mutations analogous to a strong PS3/BS3 evidence level. The screens also identified loss-of-function mutations and an association of gain-of-function mutations with hydrophobic changes. The functional screens identified 97% of acquired resistance mutations in clinical trials. Our comprehensive catalog of every druggable mutation in the FGFR kinase domains is readily available for clinical decision support. Show less

Apolipoprotein E (APOE) plays a tissue-specific role in diet-induced obesity: brain-expressed APOE promotes obesity, while hepatic APOE appears protective. Physiological plasma APOE levels facilitate clearance of atherogenic lipoproteins; however, supraphysiological levels induce hypertriglyceridemia and impair cholesterol clearance. APOE-induced hypertriglyceridemia has been linked to its carboxyl-terminal region (amino acids 260-270), particularly residues L261, W264, F265, L268, and V269. A bioengineered APOE4 variant, APOE4mut1, where these residues are substituted with alanine, promotes cholesterol clearance without inducing hypertriglyceridemia at any level of expression. This study examined APOE4mut1 effects on adipose tissue metabolism in vivo. Wild-type (C57BL/6) and APOE4 Show less

The fat mass and obesity-associated (FTO) and melanocortin-4 receptor (MC4R) genes have been implicated in the pathophysiology of obesity. However, their regulatory behavior in human gastric tissue and association with postoperative weight loss following metabolic and bariatric surgery (MBS) remain unclear. In this prospective case-control study, gastric tissue from 50 patients with obesity undergoing laparoscopic sleeve gastrectomy and 48 non-obese controls was analyzed for FTO and MC4R mRNA expression using quantitative PCR. Adjusted Inverse propensity score weighting (IPSW-adjusted) and age-/sex-adjusted linear regression were applied. Receiver operating characteristic (ROC) curves were used to evaluate discriminatory thresholds. Correlation with 12-month percent total weight loss (%TWL) was assessed. FTO expression was significantly upregulated (mean fold-change: 4.68, p < 0.001) and MC4R downregulated (mean fold-change: - 0.91, p < 0.001) in patients with obesity. ROC analysis identified thresholds of > 1.515 for FTO (AUC = 1.00) and < 0.525 for MC4R (AUC = 1.00), both with high sensitivity and specificity. No significant correlation was observed between gene expression and %TWL at 12-month follow-up. Gastric expression of FTO and MC4R accurately discriminates between individuals with and without obesity but does not predict postoperative weight loss outcomes after sleeve gastrectomy. These findings indicate diagnostic potential, whereas prognostic value remains unsubstantial. Show less

The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2 Show less

Alzheimer's disease (AD) is a genetically heterogeneous disease, with various genetic variants potentially influencing disease mechanisms differently. Pathway-based polygenic risk scores (p-PRS) can be used to examine how groups of risk genes with similar biological functions impact disease-related endophenotypes such as cognitive decline. potentially aiding in differentiating pre-clinical dementia from normal age-related cognitive decline. Data from 1,737 participants (53.5% female) from the Betula study were analyzed. AD-weighted p-PRS were calculated for five AD-related pathways: immune response, tau, cholesterol, protein-lipid, and amyloid. The p-PRS were tested for associations with all-cause dementia risk ( All-cause dementia risk was significantly predicted by the gw- and immune PRS. Hazard ratios for gw-, immune-, tau-, cholesterol-, and amyloid p-PRS were larger for prediction of AD risk and smaller for VD risk relative to all-cause dementia, while the opposite was seen for the protein-lipid p-PRS. Cognitive decline was stronger associated with the immune p-PRS than the gw-PRS, and this effect was driven by participants that remained non-demented (linear age-effects). Amyloid p-PRS showed accelerated age-effect at the oldest age in both non-demented and subsequently demented. Our results show that AD-weighted p-PRS have differential roles on dementia risk and cognitive decline. Specifically, results suggest a broad role of immune p-PRS in both age-related cognitive decline and dementia risk, while amyloid p-PRS influences AD risk and pre-clinical cognitive decline, and protein-lipid p-PRS does not influence AD risk nor cognitive decline but show a potential role in VD. Results are of value for development of precision medicine based on genetic risk profiling. All-cause dementia and Alzheimer's disease (AD) risk is strongest predicted by apolipoprotein E ( Show less

Primary renal small cell carcinoma (PRSCC) is a rare, poorly differentiated neuroendocrine carcinoma, and its clinicopathological features and the gene mutation spectrum associated with its pathogenesis remain to be elucidated. The present study aimed to characterize the genetic mutation spectrum associated with the pathogenesis of PRSCC, identify novel driver and predisposing genes for the disease, reveal its histopathological features associated with genetic mutations and systematically summarize the clinicopathologic characteristics and prognostic factors of PRSCC patients to provide a theoretical basis for molecularly targeted therapy and prognostic assessment of PRSCC. Whole-exome sequencing (WES) was performed on PRSCC samples to characterize the spectrum of genetic mutations and the results were validated using Sanger sequencing. Immunohistochemistry (IHC) was performed to reveal the histopathological features associated with these mutations. Furthermore, based on the published literature, a population-based study was conducted by searching PubMed and EMBASE databases to systematically summarize the clinicopathologic characteristics and prognostic factors of patients with PRSCC. WES identified 113 somatic single-nucleotide variants, 26 somatic insertions and deletions and mutations in 8 predisposing genes (DST, OR10H3, PTK2B, APOBR, ZNF606, CCN4, ADCK1, and MYH2) and 10 driver genes (KRTAP10-9, HYDIN, ZNF665, KRTAP10-2, GPAM, MUC12, KRT9, CCDC168, DUSP27 and MDC1). Sanger sequencing of germline DNA identified a germline A/G variant in the HYDIN sequence, first reported in PRSCC. Furthermore, IHC analysis indicated that PRSCC was positive for CD56, Syn, insulinoma associated protein 1, CgA and neuron specific enolase. In the population-based study, the majority of patients with PRSCC were elderly (57.92±15.75 years), with a pathological tumor (T) 3/4 stage (68.3%) and presented with lymph node involvement (51.7%) and distant metastasis (51.7%). T stage was an independent prognostic factor for overall survival in patients with PRSCC (P=0.004). Driver mutations in the HYDIN gene may be a key factor in the pathogenesis of PRSCC. HYDIN may serve as a prognostic marker and a target for immunotherapy in the management of PRSCC. However, due to the extreme rarity of PRSCC, the WES analysis in the present study was based solely on individual cases. To ensure the reliability and generalizability of genetic alterations detected by WES, additional PRSCC samples, along with cell and animal experiments, are warranted to confirm the role of these genetic variants (particularly HYDIN) in PRSCC pathogenesis. The functional role of HYDIN mutations in PRSCC pathogenesis requires further validation in future research. Show less

Pregnancy constitutes a critical window of vulnerability during which maternal and environmental exposures may shape fetal development through epigenetic mechanisms. While prenatal maternal anxiety and exposure to green spaces have been independently associated with child neurodevelopment, their potential interactive effects on neonatal epigenetic profiles remain largely unexplored. This study examined the independent and interactive effects of maternal trait anxiety and residential green space exposure during pregnancy on neonatal DNA methylation (DNAm) of the brain-derived neurotrophic factor (BDNF) gene. A sample of 110 mother-infant dyads was enrolled at delivery. Maternal trait anxiety was assessed using the Stait-Trait Anxiety Inventory (STAI-Y) and infants' BDNF DNAm at birth was assessed in 11 CpG sites in buccal cells. Prenatal residential addresses were geocoded and green space availability within 300, 500, and 1000 m buffers was calculated using the CLCplus Backbone 2021 land cover dataset. Hierarchical linear regression models were adjusted for infant sex and prenatal exposure to PM2.5. Results indicated that higher maternal trait anxiety was associated with increased BDNF DNAm at four CpG sites only among infants with lower exposure to green space within a 300 m buffer. This association was not significant at higher levels of greenness, suggesting a neuroprotective effect of natural environments during gestation. Findings provide novel evidence that urban green space may buffer the biological impact of maternal anxiety on neonatal BDNF methylation. This highlights the importance of integrating psychological and environmental-level exposures to elucidate early-life determinants of neurodevelopment. Show less

Plin4 is transcriptionally regulated by peroxisome proliferator-activated receptor gamma and is primarily expressed in white adipose tissue (WAT). We found that expression of Plin4 is elevated in the liver upon prolonged feeding with an obesogenic diet containing saturated fat, fructose, and cholesterol (Western diet). To investigate the functional role of Plin4 in energy metabolism, we generated Plin4 Show less

G protein-coupled receptors (GPCRs) recognize ligands on the cell surface, initiating intracellular signaling pathways that control a variety of biological processes, from neurotransmission and hormone regulation to light detection and smell. As entryways into these pathways, GPCRs are key pharmacological targets, with 30% of FDA-approved drugs targeting them. High-throughput GPCR-based sensors in yeast are proven platforms for the identification of novel GPCR ligands. Most human GPCRs (hGPCRs), however, led to small increases in the signal after activation, hindering the development of high-throughput (HT) assays. To streamline the generation of HT assays for biomedically important hGPCRs, here we analyze five fluorescent reporters in the context of hGPCR-based sensors. Using the serotonin receptor 4 (HTR4)-based sensor as a testbed, we identify YPet, a yellow fluorescent protein previously evolved for improved intracellular fluorescence, as the optimal fluorescent reporter when using flow cytometry, fluorescence-activated cell sorting, or a fluorescent plate reader. YPet increases the dynamic range of hGPCR-based sensors in general, enabling the engineering of HTR4-, MC4R- S1PR2-, HTR1A-, and Mel1A-based sensors with vastly higher increases in signal than previously engineered sensors. YPet even allowed the construction of a functional HTR1D-based sensor, a sensor that had been difficult for the field to construct. Finally, the fast maturation of YPet reduces the time to readout from 4 h to 30 min, unlocking point-of-care diagnostic applications previously inaccessible to hGPCR-based sensors in yeast. Looking ahead, the identification of YPet as the optimal fluorescent reporter for yeast hGPCR-based sensors opens the door to the standardized generation of hGPCR high-throughput assays in this host, and sets the stage for ultrahigh-throughput single-cell experiments toward the identification of new ligands for known GPCRs, GPCR deorphanization, and GPCR engineering to bind designer ligands. Show less

Atherosclerosis, a key pathological basis of cardio-cerebrovascular diseases, is closely associated with aging and endothelial cell senescence. The role of microRNAs (miRNAs) in regulating endothelial cell senescence and atherosclerosis remains incompletely understood. In this study, we discovered that miR-375-3p expression was significantly elevated in the serum of both aged and atherosclerotic mice. Overexpression of miR-375-3p induced endothelial cell senescence, evidenced by increased senescence-associated β-galactosidase (SA-β-gal) staining, upregulation of p15, IL6, and IL8, and inhibited cell colony formation. In vivo inhibition of miR-375-3p in ApoE Show less

Prior evidence indicate that differences in treatment settings between patients with colorectal cancer (CRC) from high-poverty areas (HPA, ≥ 20% residents living under poverty level) and low-poverty areas (LPA) might have contributed to disparities in their health outcomes. We sought to determine whether certain hospitals predominantly provided surgical care for patients with CRC from HPAs and examine associated patient outcomes. We identified patients undergoing surgery for nonmetastatic CRC diagnosed during 1/1/2009-12/31/2019 from SEER-Medicare. We defined poverty-area-serving (PAS) hospitals as hospitals with ≥ 50% patients from HPAs. We compared in-hospital adverse events, 30 day readmission, and long-term mortality between patients from HPAs and LPAs treated at PAS and non-PAS hospitals using logistic and Cox regression. Our cohort included 81,992 patients with CRC (median age = 78 years, 53.8% female, 15.9% in HPAs) treated by 991 hospitals. The 180 (18.2%) PAS hospitals treated 64.2% of patients from HPAs versus 2.6% from LPAs. Compared with patients from LPAs treated at non-PAS hospitals, patients from HPAs treated at PAS hospitals had more frequent in-hospital adverse events (OR[95%CI] = 1.17[1.07-1.29]), 30-day readmission (OR[95%CI] = 1.33[1.20-1.47]), worse all-cause (HR[95%CI] = 1.16[1.10-1.22]), and cancer-specific mortality (HR[95%CI] = 1.23[1.15-1.32]). A group of PAS hospitals treated a significant proportion of patients with CRC from HPAs and few from LPAs and was associated with worse short- and long-term patient outcomes. These findings highlight the presence and negative impact of healthcare segregation by area-level poverty and systemic inequities faced by individuals from HPAs. Multilevel resources are needed to address quality of care and other healthcare-associated needs for individuals from disadvantaged areas. Show less

Neurodevelopmental and neurodegenerative diseases involve critical abnormalities in pathogenesis. Even though there exists copious drugs and treatments, still a need for an effective model for absolute replication of disease pathophysiology and therapeutic drug discovery. This comprehensive systematic review amasses methods and approaches for developing neuronal models for neurological diseases using hPSCs/iPSCs. Abundant culturing methods, growth factors, modulators and toxins were utilised to induce the disease and were appraised. Research articles were traced from Google Scholar, PubMed/NIH, and Science Direct. Publications using hPSCs/iPSCs as differentiated neuronal disease models were screened using PRISMA guidelines, with designed inclusion and exclusion criteria. This protocol highlights the procedures for developing 2D and 3D neuronal models derived from hPSCs/iPSCs. 2D neuronal models include NPCs, NSCs, and neural rosettes, neurons, while 3D methods rely on embryoid bodies, neurospheres, spheroids and organoids due to the enhanced differentiation, survival and maturation of hPSCs/iPSCs. These processes include varied factors for culturing. Growth factors like GDNF, BDNF, cAMP, ascorbic acid, TGF-β, and Dual-SMAD inhibition. Post-analytical techniques like MEA, H&E, TEM, microscopy, immunoassays, and electrophysiology ensures the structural and functional endorsements. These models offer researchers a reliable platform to investigate the disease physiopathology and drug design for neurological disorders. Show less

Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are chronic inflammatory diseases that share immune dysregulation and mitochondrial dysfunction. Understanding the molecular mechanisms linking these diseases to mitochondrial dysfunction is crucial for developing novel diagnostic and therapeutic strategies. Datasets related to IBD and RA were obtained from the Gene Expression Omnibus database. Differentially expressed mitochondrial dysfunction-related genes (MDRGs) were identified using differential expression analysis. Weighted gene co-expression network analysis was performed to identify crosstalk genes (CGs). Logistic regression and support vector machine (SVM) models were constructed using least absolute shrinkage and selection operator regression to identify hub genes. Additionally, the differential expression and diagnostic value of the hub genes were verified using quantitative reverse transcriptase-polymerase chain reaction and validation sets. Finally, immune infiltration analysis was conducted to assess the role of immune cells in IBD and RA. A total of 87 CGs associated with mitochondrial dysfunction were identified between IBD and RA, among which Show less