👤 Jason Cl Tong

Anorexia nervosa (AN) is a debilitating, often lethal, restrictive-type eating disorder without an effective cure. The underlying neural basis of AN has remained elusive without an animal model that has represented all typical AN symptoms. Here we show that aberrant activation of mediobasal hypothalamic (MBH) glutamatergic neurons led to lethal self-starvation, hyperactivity, anhedonia, social phobia, and increased anxiety, all of which represent typical symptoms of AN. These symptoms were selectively exhibited by targeted activation of MBH neurons expressing steroidogenic factor (SF1) and estrogen receptor alpha (ERa). Moreover, the elicited AN symptoms by activation of MBH glutamatergic or SF1/ERa neurons were rescued by removing release of glutamate or brain-derived neurotrophic factor (BDNF) from these neurons. Importantly, BDNF overexpression in SF1/ERa neurons promoted typical AN symptoms, which were suppressed by removing glutamate release. Thus, our findings identify aberrantly enhanced BDNF and consequent augmented glutamate release from SF1/ERa neurons as a neural basis underlying AN. Show less

Intracerebral hemorrhage (ICH) is a destructive cerebrovascular disease, whose secondary injury can trigger severe neuroinflammatory responses. Resolvin D1 (RvD1), as an endogenous specific pro-resolving mediator, has been demonstrated to possess significant anti-inflammatory effects. However, how brain networks relate to RvD1 biosynthesis and the therapeutic potential of RvD1 in post-hemorrhagic repair processes within the brain remain unclear. Serum RvD1 levels were measured at admission and discharge in 40 ICH patients, and their correlation with neurological functional outcomes was analyzed. Combining neuroimaging and Mendelian randomization, we investigated the association between brain network integrity and genetically predicted plasma RvD1 levels. Network pharmacology identified key targets, and an oxyhemoglobin-induced BV2 microglial model validated RvD1's BDNF-dependent anti-inflammatory and anti-apoptotic effects. Serum RvD1 levels decreased from admission to discharge during recovery, with significant correlation between its changes and neurological improvement. Neuroimaging and MR analysis revealed that brain network integrity is significantly associated with genetically predicted plasma RvD1 levels, partially explaining interindividual prognostic variation. Mechanistically, RvD1 modulates microglial metabolism, alleviates oxidative stress, and promotes anti-inflammatory polarization involving the BDNF/AKT signaling network. Genetically predicted plasma RvD1 levels correlate with macro-level brain network integrity while simultaneously promoting micro-level neural repair. This approach overcomes limitations of previous single-pathway or static indicator studies, offering novel biomarkers and intervention strategies with predictive and therapeutic potential for ICH. Show less

Oxidative stress-induced enteric neuropathy is a key driver of slow-transit constipation (STC), primarily through disrupted mitochondrial dynamics and neuronal degeneration. To address this, we developed a bioengineered oral delivery system that supports neuronal recovery and actively enhances mitochondrial membrane fusion. A self-assembling amphiphilic peptide (GFF) was synthesized to encapsulate rhein (RH), a natural anthraquinone with antioxidant, anti-inflammatory, and microbiota-regulating properties. A BDNF-derived tetrapeptide was integrated to further potentiate neurotrophic effects. These components were co-assembled into a therapeutic nanofiber (RFI), which was embedded in a chitosan/sodium alginate hydrogel for sustained oral delivery. In vitro and in vivo studies demonstrated that RFI significantly improved neuronal viability and gastrointestinal motility. Mechanistic investigations revealed that RFI is associated with activation of the AKT signaling pathway and enhancement of mitochondrial membrane fusion, collectively contributing to the restoration of mitochondrial network integrity and neuronal protection. This multifunctional nanoplatform offers a promising therapeutic approach to STC by combining targeted delivery with direct modulation of mitochondrial function. Show less

This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models. In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings. In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion. CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential. Show less

Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current therapies do not always lead to satisfactory treatment outcomes. Enterolactone, a mammalian lignan produced by bacterial transformation from plant lignans, has a preventive effect against cardiovascular disease. However, its effect on atherosclerosis and the underlying mechanism of action remain unclear. To explore the therapeutic effect of ENL on atherosclerosis and elucidate the underlying mechanism. We established a model of atherosclerosis on ApoE-/- C57BL/6 mice by high fat diet. The aortic root was collected and sectioned to assess arterial plaque area, collagen fibrillar proliferation, and lipid content. RT-qPCR was used to determine the inflammatory response in the artery of mice. The serum from mice was isolated to measure lipid levels, and the fecal microbiota was analyzed by 16S rDNA. H In the animals, enterolactone significantly improved lipid metabolism, attenuated ferroptosis occurring in the intima, facilitated the antioxidant mechanisms, and promoted healing of the endothelial lesions, by interacting with Nrf2. Of great importance, enterolactone massively altered the gut microbiota toward a curative outcome by elevating the abundance of beneficial bacteria, such as the SCFA-producing taxa. Additionally, ENL suppresses lipid peroxidation and inflammatory activation in HUVECs by regulating the Keap1/Nrf2/GPX4 pathway, and knocking down Nrf2 attenuates the treatment effect of ENL. Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway. Show less

Dementia with Lewy bodies (DLB) frequently coexists with cerebrovascular injury and Alzheimer's-related pathology, yet accessible in vivo markers of these processes remain limited. The retinal microvasculature shares structural and physiological characteristics with cerebral small vessels and may provide a non-invasive window into neurovascular and neurodegenerative pathology. In this cross-sectional study, 32 individuals with DLB and 31 age-matched cognitively unimpaired controls (CU) underwent swept-source optical coherence tomography angiography (OCTA), brain MRI, and plasma biomarker assessment. Retinal vessel densities of the superficial vascular complex (SVC), deep vascular complex (DVC), and choriocapillaris (CC) were quantified. Plasma amyloid-β, phosphorylated tau-217 (p-tau217), and glial fibrillary acidic protein were measured. Cerebral small vessel disease (SVD) burden and white matter hyperintensity (WMH) volumes were derived from MRI. Associations with cognition and mediation by WMH burden were evaluated using generalized estimating equations and bootstrapped mediation analyses. Compared with CU, individuals with DLB exhibited significantly reduced SVC, DVC, and CC vessel densities (all p < 0.001). Lower retinal vessel densities were associated with higher plasma amyloid burden and elevated p-tau217, as well as greater SVD burden and periventricular WMH volume. APOE ε4 carriers demonstrated more pronounced retinal microvascular impairment, higher WMH burden, and elevated p-tau217 levels than non-carriers. Reduced SVC density was associated with worse global cognition, and this relationship was partially mediated by periventricular WMH volume. Retinal microvascular impairment measured by OCTA is closely linked to Alzheimer's-related plasma biomarkers, SVD, and cognitive decline in DLB. These findings support retinal OCTA as a scalable, non-invasive biomarker reflecting convergent neurodegenerative and vascular pathology in DLB. Show less

Cervical cancer (CC) is the most common gynecological malignancy and is strongly linked to human papillomavirus (HPV) infection. Currently, immune checkpoint blockade therapy has shown limited clinical benefits for CC, highlighting the need to find more effective therapeutic targets. LILRB4, a member of the leukocyte immunoglobulin-like receptor superfamily, is considered a key mediator of cancer immunosuppression. However, its role in the CC immune microenvironment remains unclear. Here, LILRB4 expression was upregulated in CC tissues, and high expression levels were positively associated with advanced disease and immunosuppressive genes in tumors. In an immunocompetent mouse model, LILRB4 expression in CC tumors increased with tumor growth, whereas blocking LILRB4 reduced tumor growth. Flow cytometry analysis revealed that blockade of LILRB4 reduced CD8 Show less

Impaired synaptic plasticity underlies cognitive impairment as a core pathological substrate. While aerobic exercise represents a significant non-pharmacological intervention for enhancing synaptic plasticity, its precise molecular mechanisms remain incompletely defined. This study investigated whether aerobic exercise ameliorates synaptic plasticity and synaptic loss in Apolipoprotein E homozygous knockout (APOE Show less

BackgroundPrevious whole exome and whole genome sequencing (WES/WGS) studies identified genome-wide significant associations for late-onset Alzheimer's disease (AD) with rare variants but highlighted the need for larger samples.ObjectiveIdentify associations of rare coding variants with AD risk in a large-scale, multi-ancestry exome-wide.MethodsWe combined non-overlapping portions of the Alzheimer's Disease Sequencing Project (ADSP) WES (n = 18 717) and WGS (n = 35 014) datasets obtaining a sample (n = 34 202) including participants ages ≥ 60 from four genomic similarity clusters consistent with European ancestry (EA, 9 744 AD cases and 9 095 controls), African American (AA, 1 944 AD cases and 4 215 controls), Caribbean Hispanic (CH 2 344 AD cases and 3 465 controls), and Native American Hispanic (NAH 743 AD cases and 2 652 AD controls) populations. Association of AD with 253,421 bi-allelic variants with minor allele count ≥ 20 in the total sample and each population group was evaluated using GENESIS. Gene-based tests comprising predicted moderate and high-impact variants were performed using SAIGE.ResultsNovel study-wide significant associations (p < 1.97 × 10 Show less

Patients with atherosclerosis suffer from exercise capacity decline and skeletal muscle injury. Soluble guanylate cyclase stimulator vericiguat plays a protective role in the blood vessels and kidneys in addition to treating heart failure, but its effect on skeletal muscles remains unclear. This study aimed to investigated whether vericiguat can improve exercise capacity and mitigate skeletal muscle injury of atherosclerotic ApoE Show less

Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less

The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined. To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models. Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 loss increased the intrinsic firing rate of AgRP neurons and abolished the suppressive effect of α-Klotho on their activity. At the molecular level, FGFR1 knockdown decreased phosphorylation of the transcription factor FOXO1 and elevated AgRP mRNA expression. Our results define a crucial FGFR1 signaling axis in AgRP neurons that coordinately regulates their electrical activity and peptide expression, thereby establishing FGFR1 as an essential regulator of energy homeostasis. Show less

Gynecologic carcinosarcoma is an uncommon but aggressive malignancy that frequently requires systemic therapy but therapeutic options are limited. Development of preclinical models is therefore important for therapeutic advancement. Carcinosarcoma tumor (6 uterine and 1 tubo-ovarian) from 7 surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and/or cell line development. The histologic, immunophenotypic and genetic features were characterized. Based on the observed molecular profiles and targetable molecular alterations, in vivo studies were conducted to evaluate the efficacy of targeted therapy on tumor growth. We established 1 cell line and 6 PDX models which recapitulated the dominant phenotype of the respective parental tumors with preserved mesenchymal differentiation lineage in the sarcomatous component. Genomically, the PDX/cell line models preserved similar complex pattern of copy number alterations and similar mutation landscape when compared to the respective parental tumors. All 7 parental carcinosarcoma tumors and PDX/cell line models harbored pathogenic TP53 mutations. Moreover, we identified recurrent copy number gain/amplification involving several receptor tyrosine kinases (RTK), including amplification and protein over-expression of FGFR1. In vivo drug evaluation using a small molecule inhibitor (AZD4547) of FGFRs showed significant growth inhibition in the carcinosarcoma PDX tumor with the highest FGFR1 amplification and protein expression whereas AZD4547 showed no significant growth effects on carcinosarcoma lacking high level FGFR1 amplification, indicating oncogenic dependency on the amplified RTK pathway. These findings demonstrate the utility of patient-derived tumor models in the identification and the functional validation of potentially targetable molecular alterations in preclinical setting. Show less

Complex PTSD (CPTSD) is often associated with prolonged or repeated trauma exposure and the experience of intimate partner and childhood abuse. CPTSD includes the criteria for PTSD (re-experiencing, avoidance, and sense of threat) in addition to three criteria for self-organization disturbances (affective dysregulation, negative self-concept, and relational disturbance). This study aimed to assess profiles of CPTSD symptoms and their association with psychiatric distress among people with co-occurring Serious Mental Illness (SMI; schizophrenia/schizoaffective, bipolar, and treatment-refractory major depression). Treatment-seeking participants ( A model with three classes best fit the data with the most parsimonious interpretation: 26.7% ( The results demonstrate the heterogeneity in symptom presentation across the PTSD classes and that, despite similar diagnoses, individuals may present with varying symptom patterns. This emphasizes the importance of studying CPTSD in subpopulations of persons with SMI. Show less

BRCA1-deficient epithelial ovarian cancer (EOC) is reported to respond to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis); however, acquired resistance frequently emerges, limiting the long-term clinical efficacy of PARPis. The mechanisms driving acquired PARPi resistance in these patients remain poorly understood. In this study, we performed a systemic screen of epigenetic inhibitors in patient-derived organoids (PDOs) and identified enhancer of zeste homolog 2 (EZH2) as the key driver of PARPi resistance in BRCA1-deficient EOC. We found that in PARPi-resistant cells, intracellular EZH2 translocated from the nucleus to the mitochondria, where it promoted mitochondrial fusion and subsequently prevented PARPi-mediated apoptosis. Mechanistically, we determined that PARPi treatment activated YES1 to phosphorylate EZH2 at the Y728 residue, which promoted the mitochondrial translocation of EZH2 in a TOM20-dependent manner. Using mass spectrometry, we identified MYO19 as a main substrate of EZH2 in mitochondria and found that EZH2 trimethylated MYO19 at the K928 residue to trigger mitochondrial fusion. Moreover, Y728 phosphorylation also increased EZH2 protein stability by hindering TRIM4 binding, thus blocking TRIM4-mediated ubiquitination and subsequent proteasomal degradation. Notably, the efficacy of targeting YES1 or EZH2 to resensitize tumors to PARPis was validated in PDOs, xenograft models and EOC cell lines. Here, our findings reveal a YES1-EZH2-MYO19 post-translational modification cascade, whereby PARPi-induced phosphorylation of EZH2 triggered mitochondrial fusion, and targeting phosphorylated EZH2 rebalanced mitochondrial dynamics and resensitized BRCA1-deficient EOC to PARPis, suggesting a promising therapeutic strategy. Show less

Glucagon-like peptide 1 receptor (GLP-1R) agonists exhibit anti-inflammatory actions, yet the importance of direct immune cell GLP-1R signaling remains uncertain. Although T cells respond to GLP-1, low receptor abundance and suboptimal antisera complicate efforts to characterize immune cell GLP-1R signaling. Here, we evaluate three frequently utilized GLP-1R antibodies, revealing that one of several antibodies, AGR-021, lack ideal specificity for detecting the GLP-1R in mice. Immunostaining with AGR-021 using tissues from two independent GLP-1R knockout mouse lines reveals persistent immunoreactive signals in GLP-1R-null pancreatic islets. Similarly, flow cytometry using AGR-021 reveals no reduction in AGR-021 immunoreactivity in GLP-1R-null splenic T cells. Moreover, western blotting detects AGR-021-immunoreactive proteins from a GLP-1R-negative cell line and fails to detect immunoreactive GLP-1R of the correct size upon overexpression of the receptor. Our findings reveal caveats governing use of multiple widely used GLP-1R antibodies, reemphasizing the importance of rigorous antibody validation for inferring accurate GLP-1R expression. Show less

Dual agonists targeting glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are breakthrough treatments for patients with type 2 diabetes and obesity. Compared to GLP1R agonists, dual agonists show superior efficacy for glucose lowering and weight reduction. However, delineation of dual agonist cell targets remains challenging. Here, we develop and test daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes, and use them to visualize cellular targets. daLUXendins are potent GLP1R/GIPR dual agonists that advantageously show less functional selectivity for mouse GLP1R over mouse GIPR. daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of β cells > α cells = δ cells. Systemic administration of daLUXendin strongly labels GLP1R Show less

Pancreatic alpha cells modulate beta cell function in a paracrine manner through the release of glucagon. However, the detailed molecular architecture underlying alpha-to-beta cell regulation remains poorly characterized. Here, we show that the glucagon-like peptide-1 receptor (GLP1R) is enriched as nanodomains on beta cell membranes that contact alpha cells, in keeping with increased single-molecule transcript expression. At low glucose, beta cells next to alpha cells directly sense micromolar glucagon release by pre-internalizing GLP1R. Pre-internalized GLP1R is associated with earlier beta cell Ca Show less

The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gαs protein and generation of intracellular cAMP. However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G proteins and β-arrestin proteins. Here, the importance of Gαs signaling was tested in mice with conditional, postdevelopmental β cell deletion of Gnas (encoding Gαs) under physiological and pharmacological conditions. Deletion of Gαs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine, and IBMX In the absence of Gαs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gαq signaling. Collectively, these findings validate a central role for cAMP in mediating incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gαs that causes both fasting hyperglycemia and glucose intolerance. Show less

Senescence is significantly associated with cancer promotion. This study aimed to characterize senescent cells at the single-cell level in nasopharyngeal carcinoma (NPC) and elucidate the phenotype of tumorigenic senescent cell clusters. The composition of NPC based on the single-cell sequencing dataset GSE150430 from clinical specimens of 15 treatment-naïve patients and one patient with chronic nasopharyngitis were investigated. Using single-cell transcriptomics, we identified the major types of senescent cells in NPC and determined that senescent epithelial C3 cells and SPP1+ macrophages were associated with tumor progression, and expressed unique arrays of pro-tumor surface proteins and senescence-associated secretory phenotype (SASP) factors. SASP is endowed with inflammatory cytokines and chemokines, which involve in the process of 'inflammatory ageing' and tumor progression. Epithelial cell cluster C3 upregulated epithelial-mesenchymal transition (EMT)-related genes associated with tumor metastasis. SPP1+ macrophages displayed a distinct secretome dominated by pro-inflammatory cytokines such as CCL2, CCL8, and IL-6, and were more enriched in glycolytic pathways compared with other subpopulations of macrophages. In particular, the senescent cell population showed higher and stronger intercellular communication compared with the non-senescent cell population. Furthermore, C3 interacted with SPP1+ macrophages through ANGPTL4-SD2. Our findings reveal the important role of senescent cells in the development of NPC, highlighting potential therapeutic pathways and cancer prevention strategies. Show less

The aim of the present study was to investigate the dietary effects of replacing corn with different proportions of fermented straw on the growth performance and intestinal health of finishing pigs. A total of 275 healthy commercial finishing pigs aged 126 days (average body weight, 82.96 ± 3.07 kg) were randomly allocated into three groups: the control (CTR, basal diet) group, the 5% fermented straw (FJJG5, replacing 5% of the corn) group, and the 10% fermented straw (FJJG10, replacing 10% of the corn) group. There were six replicates in each group and 14-16 pigs per replicate. On day 39 of the experiment, one animal from each replicate was slaughtered for sampling and for further analysis. The results showed that the finishing pigs in the FJJG10 group had a reduced average daily weight gain and an increased feed-to-gain ratio. The FJJG5 group had reduced total cholesterol, high-density lipoprotein, and low-density lipoprotein in their serum, while the FJJG5 and FJJG10 groups had reduced contents of lactate dehydrogenase. In addition, the FJJG5 group exhibited increased T-SOD activity and MDA content in the colon, while the FJJG10 group also showed increased T-AOC activity in their serum and increased contents of MDA in the colon. The FJJG5 group exhibited increased activities of jejunal disaccharidase and lipase, while the FJJG10 group exhibited decreased jejunal crypt depths. Moreover, the FJJG5 group presented an increased relative expression of Show less

Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP×TL interaction term. AD risk was associated with shorter TL (β = -0.18, We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis. Show less

Clubfoot, medically termed congenital talipes equinovarus (CTEV), is a prevalent musculoskeletal birth defect, affecting approximately 0.3% of all live births. This serious congenital anomaly results from structural abnormalities in the foot and lower leg, leading to abnormal positioning of the ankle and foot joints. This review provides a comprehensive overview of the causative factors associated with CTEV and evaluates current therapeutic approaches. Although variations in genes encoding contractile proteins of skeletal myofibers have been proposed as contributors to the etiology of CTEV, no definitive candidate genes have been conclusively linked to increased risk. However, genes such as Show less

Alzheimer's disease (AD), the most common neurodegenerative disease in humans, has been a major medical challenge. Lactoferrin (Ltf) in salivary glands might be identified as a potential detectable biomarker in AD and a therapeutic target for AD. Pharmaceutical studies directly addressing this biomarker, though, are scarce. Using a computational strategy for drug repurposing, we explored the proximal neighborhood of Ltf by exploring its interactome and regulatory constellations. We aimed to focus on the discovery of potential therapeutic agents for AD. Based on extensive analytical evaluation comprising structural congruence scales, profiling disease clusters, pathway enrichment analyses as well as molecular docking, SPR, in vivo studies, and immunofluorescence assays, our research identified three candidate repurposed drugs: Lovastatin, SU-11652, and SB-239063. Taken together, these results highlight strong binding affinities of the drug candidates to Ltf. In vitro studies showed that such compounds decrease β-amyloid (Aβ) production by increasing the fluorescence signal emitted by Ltf in N2a-sw cells, and that they act by modulating the expression of amyloidogenic pathway-associated enzymes (BACE1 and APH1α). In addition, in vivo studies showed a concomitant reduction in the expression levels of amyloidogenic pathway-related enzymes (BACE1 or APH1α). Thus, computational studies have focused on Ltf interactions that may recommend drug repurposing strategies and options for AD. Show less

Dietary guidelines recommend replacing saturated fatty acid with unsaturated fats, particularly polyunsaturated fatty acids. Cohort studies do not suggest a clear benefit of higher intake of polyunsaturated fatty acids but, in contrast, higher circulating linoleic acid (LA) levels-reflective of dietary LA intake, are associated with a reduced risk of type 2 diabetes. However, genetic variants in the fatty acid desaturase 1 gene (FADS1) may influence individual responses to plant-based fats. We explored whether FADS1 variants influence the relationships of LA and α-linolenic acid (ALA) intakes and nut consumption with plasma phospholipid fatty acid profiles and type 2 diabetes risk in a large-scale cohort study and a randomized controlled trial. In the EPIC-InterAct case-cohort (7,498 type 2 diabetes cases, 10,087 subcohort participants), we investigated interactions of dietary and plasma phospholipid fatty acids and nut consumption with FADS1 rs174547 in relation to incident type 2 diabetes using weighted Cox regression. In PREDIMED (492 participants in the Mediterranean Diet + Nuts intervention group, 436 participants in the control group), we compared changes in plasma phospholipid FAs from baseline to year 1. In EPIC-InterAct and PREDIMED, nut consumption was positively associated with LA plasma levels and inversely with arachidonic acid, the latter becoming stronger with increasing number of the minor rs174547 C allele (p interaction EPIC-InterAct: 0.030, PREDIMED: 0.003). Although the inverse association of nut consumption with diabetes seemed stronger in participants with rs174547 CC-genotype (HR: 0.73, 95% CI: 0.54-1.00) compared with CT (0.94, 0.81-1.10) or TT (0.90, 0.78-1.05) in EPIC-InterAct, this interaction was not statistically significant. FADS1 variation modified the effect of nut consumption on circulating FAs. We did not observe clear evidence that it modified the association between nut consumption and type 2 diabetes risk. Show less

Cardiac hypertrophy is an independent risk factor and the primary predictor of heart failure (HF). Mitochondria are crucial for the shift from hypertrophy to heart failure. The expression of fibroblast growth factor 21 (FGF21), a cardioprotective factor, is increased in patients with cardiac hypertrophy but fails to prevent heart failure. Additionally, the molecular mechanism through which FGF21 exerts its beneficial effects on hypertrophic myocardial mitochondria remains unclear. Our study investigated the effect of FGF21 on cardiac hypertrophy, elucidating its mechanism of action through the enhancement of mitophagy-mediated cardioprotection. A transverse aortic constriction (TAC) model and a phenylephrine (PE) model were applied to explore the effect and mechanism of FGF21. P62-mediated mitophagy inducer (PMI) and rapamycin (Rapa) were used to confirm that FGF21-regulated mitophagy under overload pressure conditions. FGF21 knockout markedly exacerbated TAC-induced cardiac function damage, mitochondrial damage, and mitophagy impairment. In vitro, FGF21 knockdown aggravated PE-induced cardiomyocyte hypertrophy and mitophagy dysfunction. FGF21 treatment promoted mitophagy in the TAC and PE models, but this effect was abolished in the absence of PTEN-induced putative kinase 1 (PINK1). The increase in PINK1 expression induced by Rapa can rescue impaired cardiac function and mitophagy impairment in FGF21-deficient TAC mice. Similarly, PMI enhances mitophagy, which inhibits damage to cardiac functions. A further study revealed that the expression of fibroblast growth factor receptor 1 (FGFR1) and FGF21 was opposite in heart failure. Knockdown of FGFR1 inhibited FGF21-mediated mitophagy. FGF21 promotes PINK1-mediated mitophagy to attenuate cardiac hypertrophy, and mismatched FGFR1 expression may hamper the beneficial effect of FGF21 on cardiac hypertrophy. Show less