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In this study, five FADS genes-FADS1a, FADS1b, FADS1c, FADS2, and FADS6-were cloned and characterized in chickens. Their nutritional regulations by diets containing various levels (100, 200, 300, and 400 mg/kg) of curcumin (Curcuma longa) were also determined. We aimed to determine the functions of FADS genes in fatty acid (FA) metabolism in chickens. We identified two critical conserved regions in chicken FADS: DWXXGH and GEXA, likely conferring structural stability to the iron-binding center and modulating the electrostatic potential. The chicken FADS genes are orthologs of vertebrate FADS genes. FADS1a/FADS1b and FADS1c exhibited markedly different tissue-specific transcription. However, FADS1a, FADS1b, and FADS1c responded differently to dietary curcumin, suggesting their functional divergence. Therefore, we propose that FADS1a, FADS1b, and FADS1c were retained in the chicken genome due to neo- or sub-functionalization. Dietary curcumin upregulated four of five chicken FADS genes (except FADS1a), indicating its effect on FA metabolism in chickens. Analyzing the promoter regions of FADS1 genes is essential for identifying their regulatory mechanisms, which may explain their evolutionary fates and functions. Show less

Gout is an acute inflammatory arthritis triggered by monosodium urate (MSU) crystal deposition and activation of innate immune responses. In addition to inflammasome signaling, emerging evidence suggests that metabolic reprogramming of arachidonic acid (AA) pathways amplifies inflammatory responses during gout flares. However, the contribution of upstream fatty acid desaturation processes that regulate endogenous AA availability remains poorly defined. 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PGG) is a naturally occurring polyphenol with reported anti-inflammatory activity, but its effects on MSU-induced fatty acid metabolism and gouty inflammation have not been well established. Publicly available bulk and single-cell transcriptomic datasets from human and mouse gout studies were analyzed to assess dysregulation of AA-associated pathways. MSU-induced inflammatory responses were examined in mouse bone marrow-derived macrophages and in a murine MSU-induced gout model. Macrophages were treated with PGG prior to MSU stimulation, and inflammatory cytokine production, phagocytosis, and expression of fatty acid desaturases were assessed. Lipidomic analysis of macrophages and plasma was performed using gas chromatography-mass spectrometry (GC-MS) to quantify arachidonic acid and related fatty acids. In vivo disease severity, cytokine expression, and anti-inflammatory markers were evaluated following PGG treatment. Analysis of public datasets revealed consistent dysregulation of arachidonic acid-associated inflammatory pathways during gout flares. In macrophages, MSU stimulation increased expression of fatty acid desaturases FADS1 and FADS2 and promoted accumulation of arachidonic acid, concomitant with robust production of pro-inflammatory cytokines. PGG treatment significantly suppressed MSU-induced FADS1, FADS2 and arachidonic acid levels, and attenuated pro-inflammatory cytokine production. PGG also markedly impaired macrophage phagocytosis of MSU crystals. In vivo, PGG treatment significantly reduced clinical disease severity in an MSU-induced gout model, suppressed fatty acid desaturation and arachidonic acid accumulation in plasma, decreased pro-inflammatory cytokine expression, and enhanced anti-inflammatory markers. These findings identify fatty acid desaturation as an important metabolic contributor to gouty inflammation and demonstrate that PGG suppresses MSU-induced inflammation by limiting endogenous arachidonic acid availability, reducing inflammatory amplification, and impairing MSU crystal phagocytosis. Targeting upstream fatty acid metabolism represents a potential therapeutic strategy for modulating acute gout flares beyond conventional anti-inflammatory approaches. Show less

Chronic stress is a risk factor for the development of anxiety, depression, and comorbid systemic conditions. Ayahuasca (AYA) has been used for hundreds of years and it elicits antidepressant and anxiolytic effects. However, it remains unknown whether AYA elicits a behavioral and biochemical protective effect in chronic stress. Therefore, we evaluated the therapeutic potential of AYA in reversing or attenuating the behavioral and biochemical alterations induced by an unpredictable chronic stress (UCS) paradigm in adult zebrafish. Zebrafish underwent an unpredictable chronic stress (UCS) protocol for 14 days or were left undisturbed in their tanks. On the 15th day, AYA was added to the tank at a dose of 0.5 or 1 mL/L for one hour. On day 16, fish underwent the sociability test and the novel tank test. The levels of whole-body cortisol and brain-derived neurotrophic factor (BDNF) were measured via ELISA. AYA restored stress-induced sociability impairments, anxiety-like behavior, and stress-induced hyperlocomotion and increased moving velocity in the novel tank test. Additionally, AYA reversed the stress-induced increase in whole-body cortisol and the stress-induced decrease in whole-brain BDNF. A single exposure of zebrafish to AYA restored the chronic stress-induced impairments in sociability, stress-induced anxiety-like behavior, and biochemical markers of stress and impaired neuroplasticity. These findings support the potential of AYA to reverse stress-induced behavioral and neuroendocrine alterations. Clinical studies are warranted to evaluate the translational relevance of these effects in individuals exposed to chronic stress. Show less

In recent years, the impact of lipoprotein(a) (Lp(a)) on the prognosis of coronary heart disease has been increasingly recognized. Lp(a) is an independent risk factor for cardiovascular disease, and studies have shown that homocysteine (HCY) may influence the association between Lp(a) and the risk of recurrent cardiovascular events. This study investigates the association between Lp(a) levels and recurrent cardiovascular events in patients with varying HCY concentrations. We conducted a 36-month follow-up on 530 patients with coronary heart disease and divided them into low-Lp(a) and high-Lp(a) groups based on Lp(a) levels. The incidence rates of major adverse cardiovascular events (MACE) and acute coronary events (ACE) were compared between the two groups. The association between elevated Lp(a) and cardiovascular risk in different subgroups(based on HCY concentration) was analyzed using Kaplan-Meier curves and Cox proportional hazards models. Elevated Lp(a) remained a significant risk factor for both MACE (HR = 2.07, 95% CI = 1.37-3.12, P = 0.001) and ACE (HR = 2.83, 95% CI = 1.67-4.81, P = 0.001) overall. In subgroup analyses, elevated Lp(a) in patients with moderate-to-high HCY levels constituted a high-risk cohort for MACE and ACE occurrence (HR = 1.87, 95% CI = 1.01-3.46, P = 0.046;HR = 2.85, 95% CI = 1.32-6.18, P = 0.008). Among those with low HCY levels, elevated Lp(a) showed no association with either MACE or ACE (P > 0.05). When HCY is elevated, patients with increased Lp(a) experience amplified risk of recurrent cardiovascular events. This association shifts when HCY is at low levels. Future efforts should emphasize combined assessment of Lp(a) and HCY and explore targeted intervention strategies to reduce residual cardiovascular risk. Show less

Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades. Show less

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)-an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46/216 (21.3%) tumor samples, with 28/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. Show less

This study aimed to systematically elucidate the antihyperlipidemic mechanism of paeoniflorin, and we adopted an integrated multi-omics strategy to screen the key molecular targets and regulatory pathways involved in its action, followed by experimental validation to verify the potential regulatory effects of paeoniflorin on the screened targets and metabolic processes. Rats with high-fat diet-induced hyperlipidemia received paeoniflorin treatment. Liver histopathology was evaluated using hematoxylin-eosin and Oil Red O staining. Serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bile acids, activated partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen were measured using a biochemical analyzer. Integrated multi-omics analyses were performed to investigate paeoniflorin's lipid-lowering mechanism. Critical pathways and targets identified were validated using Western blotting. Paeoniflorin alleviated pathological liver damage in hyperlipidemic rats and improved blood lipid levels, coagulation function, and liver function markers. Multi-omics analyses verified that paeoniflorin downregulated the expression of TREM-1, TLR4, NF-κB, TNF-α, and IL-1β, thereby alleviating hepatic inflammation. Paeoniflorin also upregulated the expression of low-density lipoprotein receptors (LDLR), liver X receptor alpha (LXRα), and ATP-binding cassette subfamily G member 1 (ABCG1), while downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, contributing to balanced cholesterol metabolism. Paeoniflorin normalized glycerophospholipid and branched-chain amino acid metabolism, which correlated with reduced inflammation and improved cholesterol metabolism. Paeoniflorin ameliorates hyperlipidemia through multitarget mechanisms, potentially by suppressing the TREM-1-TLR4-NF-κB signaling pathway to reduce inflammation and by regulating cholesterol metabolism via the PCSK9-LDLR and LXRα-ABCG1 pathways. Show less

To analyze the clinical phenotype characteristics and genetic testing data of idiopathic hypogonadotropic hypogonadism (IHH) female patients, aiming to improve the understanding of genetic etiology and inheritance patterns among female patients. This study recruited twenty-one female patients and their clinical data were collected and analyzed. Based on the olfaction function, the patients were divided into normosmic IHH group and Kallmann syndrome (KS) group. Whole exome sequencing and Sanger sequencing were performed to screen for underlying genetic etiology including genetic variants of known pathogenic genes and PLEXIN pathway genes. Alphafold2 was used for mutant protein structure prediction of Normosmic IHH patients and KS patients had no difference in baseline clinical data. Among the 21 recruited patients, 17 patients and their immediate family members' peripheral blood was collected for sequencing, and four patients were found carrying pathogenic variants involving Female IHH patients have complex genetic etiology and polygenic inheri-tance mode. Both hereditary and sporadic patients may have various degrees of genetic inheritance risk. The missense variant Show less

To explore the associations between accelerometer-measured physical activity patterns and cardiovascular diseases (CVD), CVD-cause mortality, and all-cause mortality in people with osteoarthritis (OA). OA participants from the UK biobank with ≥36 h of accelerometer data, collected over one-week, were analyzed. Moderate to vigorous physical activity (MVPA) patterns were classified as: 'weekend warriors' (≥150 min/week, >50% on 1-2 days), active regular (>150 min/week), or inactive (<150 min/week). Mean min per week of light physical activity (LPA) were categorized into quartiles based on the distribution in the analytical sample. Among 10 210 study participants (mean age 58.1 ± 7.1 years; 64.5% female) followed for a median of 6.9 years, there were 1,538 incident cases of CVD, and 358 deaths, including 90 from CVD. Compared with inactive MVPA, both weekend warrior (adjusted hazard ratio, aHR (95% CIs); 0.73 (0.64-0.82)) and active regular MVPA (0.75 (0.65-0.87)) significantly lowered the risks of incident CVD. Notably, only the weekend warrior group showed significant reductions in CVD-cause mortality (0.55, 0.33-0.92), and all-cause mortality (0.75 (0.59-0.96)). Higher levels of LPA may link to lower CVD, CVD-cause mortality, and all-cause mortality risks in a dose-response manner. Subgroup analysis indicated that more prominent associations were found in individuals with a body mass index >30 or those aged over 60. Engaging in a weekend warrior pattern may confer unique survival benefits for OA patients, especially among older adults and those with obesity. LPA may have dose-dependent protective effects for CVD and mortality risk in OA patients. Show less

The Gram-negative outer membrane (OM) is an asymmetric bilayer that protects cells from environmental stress and antibiotics. This asymmetry, with lipopolysaccharide (LPS) in the outer leaflet and glycerophospholipids (GPLs) in the inner leaflet, requires coordinated synthesis of both lipid classes. The committed step of LPS biosynthesis is catalyzed by LpxC, a prime antibiotic target. Here, we show that lysophospholipids (LPLs), considered byproducts of membrane turnover, act as signaling molecules restoring OM homeostasis when LPS synthesis is limited. In the presence of the LpxC inhibitor PF-5081090 (PF), loss of the LPL recycling system increased growth, suppressed envelope stress responses, improved OM asymmetry, and lowered GPL levels to maintain GPL-to-LPS balance. This recycling system includes the transporter LplT, which moves LPLs across the inner membrane, and the acyltransferase/acyl-ACP synthetase (Aas), which acylates them to regenerate GPLs. These protective effects required the OM phospholipase PldA that degrades mislocalized GPLs into LPLs and free fatty acids. Although previous work showed that PldA-generated fatty acids stabilize LpxC and promote LPS synthesis, our findings reveal a complementary role for LPLs in signaling reduced GPL synthesis when LPS is limiting. Genetic and chemical manipulation of fatty-acid flux altered PF resistance, confirming that decreased GPLs drives protection. The two PldA-derived signals, fatty acids that promote LPS synthesis and LPLs that suppress GPL synthesis, likely operate under different metabolic conditions to interpret membrane stress and restore OM balance. This lipid-feedback mechanism establishes the first signaling function for bacterial LPLs and reveals a new layer of regulation in envelope homeostasis.IMPORTANCEThe multilayered cell envelope of Gram-negative bacteria provides natural resistance to antibiotics. Understanding cell envelope synthesis and regulation is crucial for the identification of new antimicrobial targets and improved drug design. LpxC inhibitors, a new and promising class of antibiotics, impede function of the committed enzyme in lipopolysaccharide synthesis. Here, we characterize a new mechanism of resistance to the LpxC inhibitor PF-5081090, where the accumulation of lysophospholipids signals a reduction in cellular glycerophospholipid levels to repair outer membrane balance. This work proposes a new pathway to restore outer membrane asymmetry, which is a critical aspect of cell envelope integrity, and describes a role for lysophospholipids in bacterial cell signaling when lipopolysaccharide synthesis is disrupted. Show less

Sudden arrhythmic death syndrome (SADS) refers to sudden cardiac death with structurally normal hearts at autopsy, most frequently attributed to inherited arrhythmia syndromes or concealed cardiomyopathies. Postmortem genetic testing may help identify underlying genetic causes. We aimed to investigate the yield of postmortem genetic testing in SADS cases by determining the prevalence of pathogenic or likely pathogenic variants in channelopathy- and cardiomyopathy-associated genes in autopsy-negative SADS victims. This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO (REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251067244). PubMed and Embase were searched on June 4, 2025, for observational studies including individuals aged 1 to 50 years with SADS and negative or nonspecific findings at autopsy. Eligible studies reported postmortem genetic testing for channelopathy and cardiomyopathy genes. Pathogenic or likely pathogenic variant classification followed American College of Medical Genetics and Genomics criteria and ClinGen gene-disease associations. Pooled prevalence was estimated using random-effects models. A total of 45 studies involving 2498 SADS cases were included. Among 1697 SADS victims tested for both channelopathy and cardiomyopathy genes (33 studies), the pooled prevalence of pathogenic or likely pathogenic variants was 11.1% (95% CI, 4.1%-26.6%, Postmortem genetic testing identifies pathogenic or likely pathogenic variants in a significant subset of SADS cases, supporting its utility in postmortem evaluation. Show less

Irritable bowel syndrome (IBS) associated with early-life stress (ELS) commonly manifests as anxiety and visceral hypersensitivity. However, the pathogenic mechanisms underlying these effects are not fully understood. This study aims to investigate the role of brain-derived neurotrophic factor (BDNF) as a key mediator of ELS-induced changes through the brain-gut axis. A Sprague-Dawley male maternal separation (MS) rat model was used to induce anxiety and visceral hypersensitivity associated with ELS. BDNF levels were measured in the limbic system (cingulate gyrus, amygdala, and hippocampus) and serum. The correlation between BDNF levels, anxiety, and visceral hypersensitivity was analyzed. Corticotropin-releasing factor (CRF) expression in the hippocampus and the extent of visceral hyper-sensitivity were assessed in control, MS, and MS+K252a (a BDNF receptor antagonist) groups. MS rats exhibited higher levels of anxiety and visceral hypersensitivity compared to controls. BDNF production in the hippocampus was elevated in MS rats and positively correlated with anxiety (r = -0.78, p < 0.05) and visceral hypersensitivity (r = 0.93, p < 0.01). CRF expression, a key mediator of stress and visceral hypersensitivity, was also increased in the hippocampus of MS rats. Inhibition of BDNF signaling using K252a reduced CRF expression and alleviated visceral hypersensitivity. This study demonstrates that BDNF may mediate ELS-induced anxiety and visceral hypersensitivity through hippocampal TrkB-CRF signaling, providing a mechanistic basis for targeting BDNF in stress-related IBS. Show less

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen metabolism through multiple mechanisms, providing essential nitrogen sources and energy for tumor cells. In-depth exploration of the regulatory mechanisms of tumor nitrogen metabolism not only helps to reveal the molecular basis of tumor development, but also provides a theoretical basis for the development of new tumor therapeutic strategies. In this paper, the relationship between nitrogen metabolism and tumors is systematically elaborated from the characteristics of nitrogen metabolism in normal people, the reprogramming of nitrogen metabolism in tumor patients, the influence of key enzymes on nitrogen metabolism in the tumor microenvironment, as well as the mechanism of tumor nitrogen metabolism regulation, etc., so as to provide references for the related research. Show less

Obesity, a risk factor for atherosclerosis development and progression, is marked by excessive reactive oxygen species (ROS) production. We previously demonstrated that high-glucose (HG) conditions induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the link between elevated mtROS levels in obesity and atherosclerosis progression remains unclear. This study aimed to investigate whether endothelial-specific mtROS suppression by overexpressing manganese superoxide dismutase (MnSOD) could attenuate atherosclerosis progression in high-fat diet (HFD)-induced obese apolipoprotein E-deficient (ApoE KO) mice. Atherosclerotic lesion formation did not differ significantly between normal chow-fed control ApoE KO mice and endothelial cell-specific MnSOD-overexpressing ApoE KO (eMnSOD-Tg/ApoE KO) mice. However, in HFD-fed groups, eMnSOD-Tg/ApoE KO mice exhibited reduced atherosclerotic lesion size, decreased relative ROS levels, and lower Our findings demonstrate that endothelial-specific MnSOD overexpression suppresses obesity-related atherosclerosis in ApoE KO mice. mtROS plays a pivotal role in obesity-associated atherosclerosis, and targeting endothelial mtROS may offer a therapeutic strategy for preventing vascular complications in obesity. Show less

A key methodological challenge for genome-wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work, we have developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus-specific haplotype tree. Here, we develop a genome-wide LOCATER analysis pipeline and apply it to a genome sequencing study of 6795 Finnish individuals with 101 cardiometabolic traits and 18.9 million autosomal variants. We identify 351 significant trait associations at 47 distinct genomic loci and find that LOCATER boosts the single marker test (SMT) association signal at five loci by combining independent signals from distinct alleles. LOCATER successfully recovers known quantitative trait loci not found by SMT, including Show less

Preclinical evidence suggests that maternal fructose (FRU) exposure during pregnancy and lactation can shape offspring emotional development. It remains unclear whether isocaloric perinatal FRU exposure selectively alters distinct components of cocaine reinforcement, motivation, and reinstatement of cocaine-seeking behavior, and whether such effects are associated with mesostriatal receptor adaptations. Male and female Wistar rat offspring from dams fed a standard diet or an isocaloric FRU diet acquired intravenous cocaine self-administration (COC SA) under a stable fixed-ratio schedule of reinforcement across increasing doses (0.25-1.0 mg/kg/infusion), followed by a progressive-ratio (PR) test, extinction, and cue- and cocaine-induced reinstatement. Based on these behavioral findings, synaptosomal melanocortin-4 receptor (MC4R) and dopamine D1/D2 receptors (DRD1/DRD2) were assessed in the nucleus accumbens (NAc) and dorsal striatum (dSTR) of male offspring, in both cocaine-naïve and cocaine-experienced animals. Maternal FRU exposure produced sex-, dose-, and phase-dependent shifts in the session-dependent patterns of cocaine responding, without increasing cumulative cocaine intake. Notably, FRU-exposed males exhibited a lower PR breakpoint, indicating reduced effort-based motivation for cocaine. Extinction learning was preserved in both sexes, although maternal FRU exposure influenced the rate of response decline across sessions. Cue- and cocaine-induced reinstatements were not significantly altered by maternal diet. In cocaine-naïve males, maternal FRU exposure was associated with reduced DRD1 and increased MC4R in both regions, with no change in DRD2. Following COC SA and reinstatement, FRU-exposed males exhibited reduced DRD2 and a lower DRD2/DRD1 ratio in both regions, accompanied by a selective reduction of MC4R in dSTR. Together, these findings indicate that maternal isocaloric FRU exposure selectively shapes the motivational organization of COC SA, most evident under high-effort conditions, without altering reinstatement behavior, and is accompanied by experience-dependent remodeling of mesostriatal dopaminergic and melanocortin receptor profiles in male offspring. Show less

Genetic alterations in FGFR2 drive multiple malignancies, most notably intrahepatic cholangiocarcinoma, where they occur in ∼10-15% of patients. While approved pan-FGFR inhibitors provide clinical benefit, their durability is limited by acquired, often polyclonal, on-target resistance mutations affecting key regions of the FGFR2 kinase domain, including the gatekeeper residue (V565), molecular brake residues (N550, E566, K642), and other key variants. These liabilities motivate the development of next-generation inhibitors. Given FGFR2-associated toxicities and the need for subtype selectivity, FGFR4 inhibition was prioritized as a selectivity determinant, while sparing FGFR1 was considered less critical. Guided by structure-based drug design, a reversible aminopyrimidine screening hit was optimized into a novel covalent inhibitor series active against FGFR2 wild-type and clinically relevant resistance mutations. An advanced lead Show less

TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in the circulatory system extends beyond the heart, as Prdm16 loss in arterial endothelial cells (ECs) impairs arterial reperfusion of ischemic mouse limbs due to endothelial dysfunction, and Zebrafish were used to analyze vascular development, arteriovenous endothelial specification, and the emergence of arteriovenous malformations in the absence or presence of Prdm16 or Notch signaling. Lentiviral-mediated Prdm16 overexpression in human endothelial (progenitor) cells was coupled to qRT-PCR (real-time quantitative polymerase chain reaction), Western blot, and transcriptional profiling to document Prdm16's importance for arterial lineage specification. Coimmunoprecipitation in HEK293 (human embryonic kidney 293) cells was performed to assess physical interaction between Prdm16 and the Notch pathway. Existing mouse and human data sets were reanalyzed to evaluate Prdm16 expression in mammalian arteriovenous malformations. Prdm16 actively promotes arterial EC identity while suppressing venous fate. Like in mice, Prdm16 is expressed by arterial ECs early during vascular development in zebrafish, where it synergistically coordinates arterial development together with canonical notch signaling, as their combined loss in zebrafish leads to arteriovenous malformations. PRDM16's arterializing effect on human ECs is dependent on canonical Notch activity, as it is blunted in the presence of canonical Notch inhibitors and potentiated in the presence of delta-like ligand 4. Mechanistically, Prdm16 does not increase the protein levels of the cleaved intracellular domain of Notch receptors (notch intracellular domain) but rather potentiates the effect of the latter via physical and functional interaction. Prdm16 further finetunes Notch signaling and arterial development by complexing with Hey2 (Hes-related family bHLH TF with YRPW motif 2), the basic helix-loop-helix TF acting downstream of canonical Notch during arterial lineage specification and development. Together, our data demonstrate an intricate interplay between Prdm16 and Notch in ECs and indicate that Prdm16 signaling may constitute a novel therapeutic target for arteriovenous malformations. Show less

Tirzepatide, a dual GLP-1/GIP receptor agonist, is recently approved for the treatment of type 2 diabetes and obesity in adults. Melanocortin-4-receptor (MC4R) deficiency is the most common monogenic cause of obesity and presents with hyperphagia and early onset obesity. While tirzepatide seems to be effective in inducing weight loss in adults with MC4R deficiency, its effects on hyperphagia and weight loss in pediatric patients are unexplored. A 17-year-old girl was admitted to our specialized obesity clinic because of hyperphagia and severe early-onset obesity due to MC4R deficiency. She had an extensive history of lifestyle interventions and psychological support and maintained a high level of physical activity. Despite these efforts, she presented with a BMI of 37 kg/m2 (3.68 SDS) and a substantial psychosocial burden. Vital signs and laboratory evaluations revealed no obesity-related complications. Tirzepatide was initiated at a dose of 2.5 mg weekly and slowly titrated to a maximum dose of 12.5 mg weekly. She initially experienced a substantial reduction in hyperphagia and reported less food noise, a reduction in hunger feelings and prolonged postprandial satiety. However, after 12 weeks hunger scores started to increase again, approaching pre-treatment levels at 28 weeks of follow-up. Metformin was added at 28 weeks in an attempt to better manage of hyperphagia, resulting in a reduction in hyperphagia. Despite these increasing hunger feelings from week 12 to 28, substantial weight loss was achieved, and the patient lost -13.9% of her initial body weight at 28 weeks. After addition of metformin, the patient lost an additional -7% of her weight. Total body weight reduction at week 37 was -20.9%. Tirzepatide was well tolerated, with no adverse effects reported at 41 weeks of follow-up. This case report suggests that tirzepatide is effective in reducing body weight in adolescents with MC4R deficiency. However, the question remains what the effect is on hunger and satiety in the long run and at a higher dose. Cohort studies are needed to assess long-term safety and effectiveness of tirzepatide in the pediatric population and in managing hyperphagia. Show less

Steroid-refractory (SR) disease develops in a substantial fraction of patients with grade II-IV acute graft-versus-host disease (aGvHD) and is associated with poor long-term survival. Improved mechanistic insight is needed to identify reliable predictors of steroid resistance. We retrospectively profiled peripheral blood collected prior to glucocorticoid treatment from allogeneic hematopoietic cell transplantation recipients without aGvHD, with steroid-sensitive aGvHD, and with SR-aGvHD using an integrated multi-omics approach, and validated findings in an independent multicenter cohort. Mass cytometry revealed expansion of activated CD28+ CD8+ effector-memory T (Tem) cells in SR-aGvHD. Absolute counts of these cells at neutrophil engraftment predicted subsequent steroid resistance in the multicenter cohort and performed comparably to established clinical classifiers. This phenotype was associated with a proinflammatory milieu enriched for IL-2, IL-27, and IFN-γ. Single-cell RNA sequencing and functional assays implicated a STAT1-glucocorticoid receptor (GR) regulatory axis in which inflammatory cytokines induce STAT1 phosphorylation and suppress GR expression, consistent with intrinsic glucocorticoid resistance. JAK inhibition rescued cytokine-induced steroid resistance in vitro, while in SR-aGvHD patients, clinical response to ruxolitinib was accompanied by reduced STAT1 activation, restoration of GR expression, and contraction of the expanded CD8+ Tem pool. These findings identify immune dysregulation at SR-aGvHD centered on CD8+ Tem cells with a STAT1-dependent GR deficit and support a mechanistic link to steroid refractoriness. CD28+ CD8+ Tem cell counts may serve as a biomarker of SR-aGvHD and inform development of pre-emptive, pathway-targeted strategies. Show less

The cell-intrinsic capacity of neurons to regenerate axons requires widespread coordination of the transcriptome, activation of multiple kinases, and reorganization of the cytoskeleton. Axonal repair is also influenced by extrinsic activating factors, such as neurotrophins. Here, we found that the neurotrophin BDNF amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i Show less

Cancer-associated fibroblasts (CAFs) drive immunosuppression in hepatocellular carcinoma (HCC). However, their metabolic regulation remains poorly defined. We investigated the role of nicotinamide N-methyltransferase (NNMT) in CAFs. High NNMT expression in CAF tissues was confirmed by western blotting and immunofluorescence staining. Primary CAFs from HCC patients, single-cell RNA-seq (GSE149614), patient-derived organoids (PDOs), and fibroblast-specific NNMT-knockout mice were integrated by metabolomic analyses. NNMT in CAFs binds EZH2 and impedes its nuclear translocation, thereby reducing H3K27me3 enrichment at the promoter of angiopoietin-like 4 (ANGPTL4) to increase ANGPTL4 secretion. Secreted ANGPTL4 engages GLUT1 in HCC cells, activating aerobic glycolysis and increasing histone H3K18la levels. This epigenetic reprogramming transcriptionally upregulates PD-L1 expression, thereby facilitating tumor immune evasion. Additionally, CAF-derived ANGPTL4 promotes angiogenesis in HCC. Therapeutically, targeting the NNMT-ANGPTL4 axis restored CD8 We identified an NNMT-ANGPTL4-driven metabolic-epigenetic cascade in CAFs that induces PD-L1-mediated immune evasion, providing a therapeutic strategy to overcome resistance to immunotherapy in patients with HCC. Show less

Nerve Guidance Conduits (NGCs) are crucial for reducing trauma during nerve repair, directing axonal growth, and preventing scar tissue formation. In this study, tubular functional NGCs were developed based on vertically aligned electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers (vNGC). They were functionalized by conjugating them with bioactive mimetic peptides: a laminin-derived peptide (LD-BP) to promote vascularization, and nerve growth factor (NGF-BP) and brain-derived neurotrophic factor (BDNF-BP) mimetic peptides to support neural differentiation. The vascular differentiation of HUVECs in response to LD-BP, and the neuronal differentiation of PC12 cells in response to NGF-BP and BDNF-BP, were assessed. The results demonstrated that this approach enabled the fabrication of tubular vNGCs with various diameters, and that vertically aligned PLGA nanofibers significantly improved their structural integrity. Furthermore, BP-conjugated vNGCs outperformed non-conjugated control groups in promoting both vascular and neural differentiation. Importantly, peptide conjugation did not induce cytotoxicity or significantly alter the biodegradability of the vNGCs, supporting their suitability for biomedical applications. Finally, bifunctional vNGCs (BiF-vNGCs), conjugated with LD-BP, NGF-BP, and BDNF-BP, were tested in a rat model of sciatic nerve injury. The BiF-vNGCs showed superior performance compared to unmodified vNGC, Control and s-Control groups, effectively promoting vascularization and neural regeneration in vivo, offering a viable alternative to conventional nerve regeneration methods. Show less

Metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), dyslipidaemia, and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly recognised as chronic inflammatory conditions driven in part by innate immune dysregulation. Among the metabolic factors implicated in this process, branched-chain amino acids (BCAAs) have emerged as key regulators linking nutrient sensing to immune cell function. Circulating BCAA concentrations are consistently elevated in these metabolic diseases. However, experimental and clinical studies also show that BCAA supplementation can improve metabolic and immune outcomes in specific contexts, revealing a paradoxical relationship between BCAA metabolism and inflammation. This narrative review examines how dysregulated BCAA metabolism and accumulation of branched-chain keto acids (BCKAs) shape the functional programming of innate immune cells across these conditions, including monocytes/macrophages, granulocytes, dendritic cells, and natural killer cells. Evidence indicates that the immunometabolic effects of BCAAs depend not solely on circulating concentrations but on the efficiency of their intracellular catabolism. When BCAA oxidation is preserved, these amino acids support mitochondrial metabolism and immune competence. Conversely, impaired catabolism leads to the accumulation of branched chain ketoacids, which activate inflammatory pathways and contribute to metabolic dysfunction. Resolving this paradox requires the need of targeting catabolic flux restoration rather than simple BCAA restriction or supplementation, and requires stratifying patients by enzymatic capacity, BCAA/BCKA ratios, and disease stage. Pharmacological modulators, including BCKDK inhibitors and BCAT1-targeted agents, show promise in simultaneously addressing metabolic and immune dysregulation. Show less

The purposes of this study were to identify different psychological capital subtypes among college students through latent profile analysis (LPA) and to explore the associations of psychological capital subtypes, internet usage duration and physical exercise frequency with on both depression and anxiety. Cross-sectional study design was implemented. A cross-sectional survey was conducted using the "Questionnaire Star" platform. The questionnaires of Psychological Capital Scale, PHQ-9, and GAD-7 were administered to 1089 college students from a university in Zhengzhou, China. Latent profile analysis was applied to identify latent subtypes of psychological capital. Multivariate regression analysis was performed to investigate the associations of psychological capital subtypes with both depression and anxiety. Three psychological capital latent profiles were identified: low self-efficacy (11.7%), moderate (57.8%), and high psychological capital (30.5%) in Chinese college students. High psychological capital group showed significantly higher scores of self-efficacy, resilience, hope, and optimism than other two groups (P < 0.001). Internet usage time and physical exercise frequency exhibited positive associations with psychological capital subtypes. Compared with the low self-efficacy group, the moderate and high latent groups had significantly lower scores of both depression and anxiety. Older students had higher scores of both depression and anxiety than younger. Three latent profiles, low self-efficacy, moderate, and high psychological capital, were identified in Chinese college students. Self-efficacy is the key dimension distinguishing between the different subtypes. Adequate internet use and physical exercise frequency improved psychological capital profile. High psychological capital levels effectively reduced the scores of both depression and anxiety. Show less

The Apolipoprotein E ε4 (APOE ε4) allele and white matter hyperintensities (WMH) have been implicated in the pathogenesis of Alzheimer's disease (AD). To investigate the dual roles of WMH in statistically moderating and mediating the relationship of APOE ε4 with AD and related phenotypes, as well as the potential biological correlates. Data were derived from 34,783 non-demented participants in the UK Biobank (UKB; mean age = 55 years; follow-up = 4.3 years) and 863 in the Alzheimer's disease Neuroimaging Initiative (ADNI; mean age = 71.9 years; follow-up = 3.8 years). Multivariable models evaluated associations of APOE ε4 status, WMH, and their interaction with cognition, neurodegeneration, core pathologies, and AD risk. Mediation analyses were performed to quantify the extent to which WMH statistically explained ε4-outcome associations. Cerebrospinal fluid proteomic and bioinformatic analyses were used to explore biological clues in a subsample of ADNI (n = 708). APOE ε4 carriers exhibited larger WMH volumes (p < 0.001, UKB) and faster WMH change rates (p = 0.019, ADNI). In UKB, WMH statistically mediated a small proportion of associations between APOE ε4 and poorer numeric memory performance, smaller hippocampal volume, increased incident AD and all-cause dementia (ACD). In ADNI, WMH showed statistical mediation signals in the associations of APOE ε4 with faster rates of cognitive decline, amyloid-β (Aβ) deposition, and neurodegeneration. Notably, WMH interacted with APOE ε4 to exacerbate cognitive decline, hippocampal atrophy, and Aβ deposition. Proteomic analyses suggested that neuroinflammatory and axonal injury pathways may be associated with the observed mediating and moderating patterns. WMH mediated and enhanced the associations of APOE ε4 with AD-related phenotypes. These findings warrant further studies to clarify the underlying mechanisms and clinical implications. Show less

A vital question in neuroscience is whether and how efficiently cellular models may be differentiated into functional neuronal cells in culture. Despite the frequent use of the human neuroblastoma cell line SH-SY5Y, differentiation protocols vary extensively, with the most common being differentiation via the addition of retinoic acid and brain-derived neurotrophic factor. However, due to the lack of a reliable evaluation method, their adequacy as synaptic models remains unclear. Here, we investigate whether SH-SY5Y cells constitute a functional model for synaptic studies by phenotypically and ultrastructurally analyzing synaptogenesis in SH-SY5Y cells subjected to different differentiation protocols. Electron microscopy (EM) techniques, including conventional EM, cryo-EM, and cryo-electron tomography, were systematically applied to characterize synaptogenesis in SH-SY5Y cells. Further characterization was performed using immunostaining and functional assays, such as live exocytosis assays and whole-cell patch-clamp electrophysiology. Despite exhibiting some presynaptic-like features, differentiated SH-SY5Y cells do not form morphologically or functionally complete synapses under the conditions tested. Immunostaining results were consistent with previous findings, showing synaptic markers. However, functional investigations did not detect synaptic activity. High-throughput EM analyses revealed an absence of synaptic structures in these cells. Additionally, an alternative differentiation approach incorporating additional neurotrophic factors promoted the formation of presynaptic-like compartments containing synaptic vesicle-like vesicles (SVLVs). In contrast to typical synaptic vesicles, these SVLVs exhibited a pleomorphic size distribution and lacked connectors. These findings underscore the need for cautious interpretation of results derived from SH-SY5Y cells when investigating molecular synaptic architecture or function, as well as neurodegenerative diseases. Show less

Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology. Show less

While VPS13C is a recessively inherited Parkinson's disease (PD) gene, its potential dominant effects in idiopathic Rapid-eye movement (REM) sleep behavior disorder (iRBD) remain unexplored. The relation between its monogenic form and the onset of PD suggested that subtype specificity may need to be considered. We examined the presence of likely pathogenic VPS13C variants in 150 iRBD and 180 α-synucleinopathy patients (iRBD-first and movement disorder-first). VPS13C variants were significantly enriched in iRBD patients, and ten iRBD risk variants have been identified. iRBD risk VPS13C variant carriers demonstrated more severe RBD symptoms and greater autonomic dysfunction, correlating with REM sleep EEG and autonomic network activity abnormalities. Notably, enrichment was specific to the iRBD-first α-synucleinopathy subtype, and iRBD risk VPS13C variant carriers showed accelerated progression to overt α-synucleinopathy. These results suggest that VPS13C not only contributes to iRBD susceptibility but also serves as a marker for the iRBD-first α-synucleinopathy and faster disease conversion. Show less

The role of parenting styles during early adolescence has always been a subject of significant concern. However, previous studies have predominantly treated parenting styles as a static construct, leading to a limited understanding of their dynamic patterns. This study employed a longitudinal person-centered perspective to examine the stability of and transitions in parenting style profiles during this critical period, as well as their associations with adolescents' internalizing and externalizing problem behaviors. Data were obtained in November 2023 (T1) and November 2024 (T2) from 893 Chinese students (53.5% female; M The analysis identified three distinct parenting profiles: harsh, supportive, and low-involved. Each profile demonstrated a high degree of stability over time, although some meaningful transitions were observed. Adolescents who consistently experienced supportive parenting or transitions toward the supportive profile generally reported lower levels of internalizing and externalizing problems. Conversely, those exposed to stable harsh parenting or a shift toward the harsh profile showed higher levels of these problems. Furthermore, internalizing problems appeared to be more susceptible to changes in parenting profiles than externalizing problems. The findings underscore the potential for positive shifts in parenting styles to serve as protective factors against problem behaviors in early adolescence, offering valuable implications for prevention and intervention strategies. Show less