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Psychological maltreatment (PM) is a multidimensional construct that includes both cognitive and emotional aspects of maltreatment. It has devastating effects on individuals, which differ from one person to another. Utilizing latent profile analysis (LPA) facilitates exploring interactions among latent subgroups. However, few studies have investigated this construct using a person-centered approach. Therefore, in the present study, we conceptualized a multidimensional construct and utilized LPA that includes PM, emotional problems (i.e., depression, anxiety, negative self-concept, somatization, and hostility), and emotion dysregulation as profile indicators. Furthermore, the cognitive aspect of the sub-classes was predicted through cognitive flexibility. Data were gathered from 523 adolescents aged 14- 17 ( The findings indicate that five distinct latent profiles have emerged: Profile 1 “ Research based on mixture modeling approaches offers a supplementary perspective to the existing literature on psychopathology. The findings may help practitioners identify victims of psychological maltreatment through cognitive flexibility and significantly enhance the development of intervention strategies based on their profile types. Show less

Apolipoprotein E (ApoE) mediates the bidirectional transport of lipids between cells. In the brain, this includes the transfer of lipids from neurons to glia. ApoE4, a major risk factor for Alzheimer's disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) confer resistance to disease, yet little is known regarding how these variants affect lipid trafficking. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by extracting oxidized unsaturated lipids through the ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids, leading to endolysosomal dysfunction. By reducing the oxidized lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity caused by excitotoxicity. Our findings reveal how ApoE2 and ApoE3Ch help protect neurons from neurodegeneration. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder underlying most cardiovascular events sialic acid (SIA), a terminal metabolite of glycolipid catabolism, modulates vascular injury, but its role in endothelial dysfunction remains unclear. To investigate whether N-acetylneuraminic acid (Neu5Ac) accelerates AS development. ApoE Show less

AXIN1 (axis inhibition protein 1), as a rate-limiting component of canonical Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin signaling pathway, may influence midbrain dopaminergic neurons. A recent genome-wide association study identified AXIN1 as a candidate gene for Parkinson's disease (PD). Our study aimed to investigate the potential relevance of AXIN1 single nucleotide polymorphisms (rs13337493 and rs9921222) in the risk, clinical characteristics, and pathology of PD. Data were collected from the Northern Han Chinese and Parkinson's Progression Markers Initiative (PPMI) cohorts. Associations between AXIN1 variants, PD-related biomarkers, and clinical manifestations were analyzed. Both loci were identified as risk factors in the Northern Han Chinese population, and the A allele of rs13337493 [odds ratio (OR) 1.320, 95% confidence interval (CI) 1.052, 1.653, P Our findings support a gatekeeper role for AXIN1; its polymorphisms contribute to increased PD susceptibility and accelerated motor progression, yet may also trigger a compensatory presynaptic response, as evidenced by elevated CSF DOPA levels, to counteract neurodegeneration. Future studies should include larger sample sizes, more diverse ethnic populations, and protein-level investigations. Show less

Executive function (EF) deficits are a core cognitive feature of autism spectrum disorder (ASD) and are closely associated with social responsiveness. Previous research has primarily focused on children with ASD, whereas how specific executive components relate to social functioning in adults remains less clear. This study examined whether patterns of association between EF and social responsiveness differ between children and adults with and without ASD. Data were obtained from the Autism Brain Imaging Data Exchange II (ABIDE II), including 423 participants aged 8-23 years (ASD = 184; controls = 239). EF was evaluated using the Behavior Rating Inventory of Executive Function (BRIEF/BRIEF-A), and social responsiveness was assessed with the Social Responsiveness Scale (SRS). Covariates of age, sex, and full-scale IQ (FIQ) were controlled using entropy balancing in children and multiple regression in adults. Hierarchical regression, moderated mediation analysis, and latent profile analysis (LPA) were conducted to examine the moderation, mediation, and heterogeneity effects, respectively. Across both child and adult samples, individuals with ASD exhibited significantly higher T-scores than controls on nearly all BRIEF and SRS subdomains after covariate adjustment (all adjusted p < 0.01), indicating widespread EF and social responsiveness impairments. Moderation analyses revealed no significant age group × EF interaction, indicating that the association between EF and social responsiveness was consistent across development. Mediation analysis revealed age-specific pathways, with EF broadly mediating social responsiveness in adults but showing more selective mediation in children. LPA identified four distinct subtypes, which were independent of age, sex, and FIQ. EF-social responsiveness associations were evident across development, but the functional contribution of specific executive components became more differentiated with age. Working memory showed greater relative prominence in adulthood. Latent profile analysis revealed heterogeneity in how executive difficulties align with social challenges, supporting developmentally informed assessment and clinical interpretation rather than direct treatment recommendations. Show less

Microglia-mediated neuroinflammation, considered one of the most plausible pathogenic hypotheses underlying Alzheimer’s disease (AD), plays a pivotal role in the initiation and progression of this devastating condition. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated promising neuroprotective effects in both preclinical and clinical studies. Previously, we developed an orally-administered GLP-1RA peptide called OHP2, which is capable of crossing the blood-brain barrier for the treatment of AD. OHP2 has been shown to effectively reduce brain inflammation in AD mouse models. In this study, we discovered that OHP2 treatment induced IL-27 secretion from astrocytes and modulated microglial reprogramming from the neurotoxic M1 phenotype to the neuroprotective M2 phenotype through glycolysis/cGAS lactylation clock/mTOR pathway, thereby alleviating excessive neuroinflammation. These findings provide a rationale for further pharmacological investigations into OHP2 and suggest that IL-27 may hold significant implications for AD therapy as a metabolic regulator. [Image: see text] The online version contains supplementary material available at 10.1186/s12974-025-03683-1. Show less

Lipidomic analysis enables the detailed characterization of platelet concentrates from donors of different ages, offering valuable insights into the role of lipid mediators in aging and transfusion-related adverse reactions (AR). In this study, we analyzed lipidomic profiles from a cohort of single-donor apheresis platelet concentrates, classified into three age groups: 20-44, 45-59, and 60-70 years. Total levels of LPC, LPA, S1P, and eicosanoids did not exhibit significant age-related changes. However, LPA 18:1, LPC 18:1, and S1P levels decreased with advancing age. When examining the relationship between different age groups and their association with AR, we found that LPA, LPC, and eicosanoids are associated with AR in an age-dependent manner. Based on these findings, we investigated the effect of age-related levels of LPA, LPC, and S1P on platelet and endothelial cell biology. These lipid mediators were found to modulate platelet activation, as demonstrated by increased expression of P-selectin, phosphatidylserine, platelet aggregation, as well as endothelial activation, marked by elevated expression of ICAM-1, VCAM-1, and CD40. Our findings present a comprehensive lipidomic profile of single-donor apheresis platelet concentrates across various age groups, highlighting several lipid mediators that may be implicated in aging and AR. Show less

Genetic variations, including rs17782313 (C/T) in the MC4R gene, are associated with lipid levels. Gene-diet interactions contribute to disease development. This study aimed to investigate the effects of interactions between total energy intake, protein intake, and MC4R rs17782313 on lipid parameters in Saudi adults. In a cross-sectional study of 268 Saudi adults (aged 20-55 years), dietary data were assessed using a 136-item validated semiquantitative food frequency questionnaire, and MC4R (rs17782313) was genotyped using real-time polymerase chain reaction. Total energy and protein calorie intake interacted with the MC4R rs17782313 polymorphism to influence total cholesterol (TC) (p Low total energy and protein intake is associated with low lipid levels among all genotypes at rs17782313 in Saudi adults. Further validation in larger cohorts is warranted to confirm these findings and explore their clinical implications. Show less

This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents completed questionnaires assessing their levels of depression and self-esteem, while their fathers and mothers correspondingly reported on their own co-parenting behaviors using the Parental Co-parenting Scale in this cross-sectional study. Dates were analyzed using LPA, RSA, and mediation consecutively. The results show that: (1) We identified three distinct co-parenting profiles: positive parental co-parenting, negative parental co-parenting, and mixed parental co-parenting. (2) In cases of congruent parental co-parenting, high positive parental co-parenting was associated with lower adolescent depression, whereas high negative parental co-parenting was linked to higher depression, and the difference manifests in different forms among boys and girls. Girls showed nonlinear changes in depression while boys exhibited linear trends. (3) In cases of incongruence in parental co-parenting, mothers' co-parenting exerted a stronger influence on boys' depression, while girls were not affected by mothers' and fathers' discrepancies. (4) Self-esteem mediated the relationship between parental co-parenting (in)congruence and depression across both genders. This study provides evidence for the mechanism through which parental coparenting influences adolescent depression and offers a basis for future interventions targeting adolescent depression. Show less

Few HIV-specific epitopes restricted by non-classical HLA-E have been described, and even less is known about the functional profile of responding CD8+ T cells (CD8s). This study evaluates the functional characteristics of CD8s targeting the Gag epitope KF11 (KAFSPEVIPMF) restricted by either HLA-E (E-CD8s) or HLA-B57 (B57-CD8s). CD8s from 8 people with HIV (PWH) were cocultured with KF11 peptide presented by cell lines expressing HLA-B*57:01, HLA-E*01:01, or HLA-E*01:03. CD8 responses were analyzed using single-cell RNA and TCR sequencing. Supernatants were also assessed for soluble protein profiling. HLA-I multimers were developed to identify CD8s restricted by HLA-B57 and/or HLA-E ex vivo. B57-CD8s secreted higher levels of cytotoxic cytokines such as IFN-γ, whereas E-CD8s produced more chemotactic cytokines, including RANTES, CXCL10 (IP-10), and IL-27, findings that were corroborated through single-cell RNA sequencing. TCR clonotypes stimulated by KF11 were cross-restricted by HLA-B*57 and HLA-E*01:03 as demonstrated by in vitro T cell reporter assays and ex vivo multimer screening. Ex vivo CD8s were singly restricted by HLA-B57 and HLA-E, with dual restriction only observed in PWH with lower viral load. These findings demonstrate that certain HIV-specific CD8s in PWH exhibit dual restriction by HLA-B*57 and HLA-E*01:03, leading to functionally distinct immune responses depending on the restricting allele(s). Show less

The engagement and burnout profiles of preschool teachers are closely linked to young children's developmental outcomes. This study investigated engagement and burnout profiles among 529 Chinese preschool teachers in relation to their emotional states, varying experiences, and professional backgrounds. The sample predominantly consisted of early-career educators, with 47.8% aged between 21 and 30 years and 33.1% having 0-5 years of work experience. Using a quantitative cross-sectional design and latent profile analysis (LPA), this study identified four distinct profiles: slightly exhausted (48.58%), moderately burned out (18.53%), engaged (25.90%), and highly burned out (6.99%). Positive emotional states, such as enjoyment, were associated with higher work engagement, while anxiety was associated with a higher probability of belonging to burnout profiles. In contrast, perceived career success and negative emotions like anger did not significantly predict work engagement and burnout profiles. Teachers with extensive teaching experience and pre-service early childhood education (ECE) training were more likely to maintain high work engagement. This study highlights the critical role of emotional states and professional ECE training in promoting preschool teachers' work engagement and sustainable practice, particularly among early-career teachers. Show less

Obesity is a well-established risk factor for asthma pathogenesis. However, the underlying mechanisms remain incompletely understood, and effective therapeutic interventions are currently lacking, making asthma management in obese individuals particularly challenging. Asthma is characterized by chronic airway inflammation, eosinophilic infiltration, and airway hyperresponsiveness (AHR). In this study, we investigated the novel role of fibroblast growth factor 21 (FGF21), a stress-inducible hepatokine with pleiotropic metabolic regulatory functions, in obesity-associated AHR using a diet-induced obesity mouse model (n = 10). Serum samples were collected from obese and lean asthma patients, along with relevant clinical indicators, including body mass index (BMI), forced expiratory volume in 1 second (FEV1%), and the FEV1/forced vital capacity (FVC) ratio, to facilitate the investigation. Moreover, diet-induced obese mice with innate AHR (male, n = 10) were employed to clarify the effects of FGF21 and FGF21-neutralizing antibody on obesity induced AHR. In vitro, LAD2 human mast cells and P815 murine mast cells activated by compound 48/80 were used to elucidate the underlying mechanisms. Our findings demonstrate that serum FGF21 levels exhibit reportedly elevated in participants with obesity and are associated with impaired pulmonary function. In diet-induced obese (DIO) mice, FGF21 levels were increased in both serum and bronchoalveolar lavage fluid (BALF). In vivo investigations demonstrate that administration of recombinant FGF21 exacerbated AHR in DIO mice, whereas FGF21-neutralizing antibody treatment ameliorated obesity-induced AHR and suppressed mast cell infiltration. Mechanistically, FGF21 was found to potentiate mast cell activation through cholesterol biosynthesis modulation. Crucially, pharmacological inhibition of FGFR1 abrogated FGF21-induced mast cell hyperactivity and cholesterol synthesis, indicating FGFR1-dependent signaling in this process. These findings may represent the FGF21/FGFR1 axis as a potential therapeutic target for obesity-related AHR and asthma. Show less

Hydrophobic membrane proteins are widely believed to require lipid bilayers for proper folding, collapsing or aggregating in aqueous environments. Using lactose permease (LacY) as a model membrane protein, we show instead that folding Show less

This study integrates the "Stress and Coping" theory with the "Ordinary Magic" model to propose a sequential "challenge appraisal -resource gain -cognitive resilience" framework. The framework aims to elucidate the psychological adaptation processes contributing to athletes' cognitive resilience in high-temperature environments. The study specifically explores the mediating role of challenge appraisal in the relationship between psychological resources and cognitive resilience, as well as the moderating effect of team support on this relationship. Data were collected from 240 professional athletes via a questionnaire-based survey, capturing multidimensional psychological and contextual variables. The analysis utilized structural equation modeling (SEM), latent profile analysis (LPA), and moderated effect testing to assess the proposed mediation, heterogeneity, and moderation pathways. Findings reveal that cognitive resilience in high-temperature environments is a dynamic process influenced by cognitive reappraisal and resource coupling. The study demonstrates that challenge appraisal mediates the relationship between psychological resources and cognitive resilience, with team support acting as a moderating factor. These results provide empirical support for targeted psychological interventions and the development of team-support systems in sports involving thermal stress. Additionally, the findings offer a theoretical advancement in sports psychology by transitioning from a static trait-oriented approach to a more dynamic "individual-context" interaction paradigm. This shift highlights the complex nature of psychological adaptation mechanisms in extreme environments. Show less

Endometriosis is a heterogeneous chronic inflammatory disorder associated with substantial diagnostic delay and limited therapeutic options, highlighting the need of robust non-invasive biomarkers and actionable molecular targets to complement existing low-sensitivity tests. To identify conserved pathogenic mechanisms with translational potential, here, we uniformly reprocessed three independent the Gene Expression Omnibus (GEO) microarray cohorts (GSE7305, GSE25628, and GSE11691) and applied a strict, directionally consistent intersection strategy to identify conserved transcriptional signals. We identified 262 consensus differentially expressed genes enriched for immunity/inflammation, cell adhesion and migration, and angiogenesis, consistent with key biological hallmarks of lesion establishment and persistence. Protein-protein interaction topology prioritized 11 highly connected hub genes ( 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

Brain aging is characterized by memory loss and cognitive impairment. With the growth of the population and advances in medical care, the size of the aging population is increasing. Therefore, the discovery of anti-aging drugs has become a popular topic in recent years. Fibroblast growth factor 21 (FGF21) has been reported to inhibit oxidative stress, reduce inflammation, and delay senescence. The present study was designed to investigate the effects of recombinant human FGF21 (rhFGF21) on senescence in the brain in a mouse model of D-galactose (D-gal)-induced aging. The behavioral tests revealed that rhFGF21 improved D-gal-induced learning and memory impairment in mice. RhFGF21 improved the morphology of cortical and hippocampal neurons and increased the expression of PSD95 in the model mice. RhFGF21 reduced the number of microglia and astrocytes in the cortex and hippocampus, increased the activities of the antioxidant enzymes (GSH-PX, CAT, and SOD), and inhibited the expression of p-NFκB and p53 proteins, as well as the mRNA expression of the inflammatory cytokines (IL-1β, IL-6, TNFα, and iNOS). SIRT1 regulates senescence and inflammation, and FGF21 participates in physiological and pathological processes by binding to the FGFR1. Therefore, we measured SIRT1 and activated FGFR1 (p-FGFR1) levels. RhFGF21 administration increased the expression of cortical and hippocampal SIRT1 and p-FGFR1 in D-gal-induced aging mice. These data suggested that rhFGF21 alleviated learning and memory impairment in a mouse model of D-gal-induced aging by increasing antioxidant enzyme activity, inhibiting inflammation, and senescence-related gene expression via modulating FGFR1 and SIRT1. Show less

This study aims to identify distinct mindfulness profiles among young and middle-aged lymphoma patients and to examine the mediating role of psychological resilience in the relationship between these mindfulness profiles and social function deficits. From November 2024 to June 2025, a total of 324 young and middle-aged lymphoma patients were recruited using convenience sampling from a tertiary cancer hospital in Urumqi, Xinjiang, China. Participants completed the Mindful Attention Awareness Scale, the 10-item Connor-Davidson Resilience Scale, and the Social Dysfunction Screening Scale. We used latent profile analysis (LPA) to identify distinct mindfulness profiles and tested the mediating role of psychological resilience with the Bootstrap method. Latent profile analysis identified three distinct mindfulness profiles among the patients: a low mindfulness type (29.3%), a moderate mindfulness type (40.1%), and a high mindfulness type (30.6%). Furthermore, psychological resilience partially mediated the relationship between these mindfulness profiles and social function deficits. Young and middle-aged lymphoma patients exhibit heterogeneous mindfulness profiles. Higher mindfulness can enhance psychological resilience, which in turn alleviates social function deficits. Therefore, healthcare providers should develop personalized interventions targeting psychological resilience based on patients' specific mindfulness profiles to improve their social function. Show less

Testicular adult granulosa cell tumors (AGCTs) are rare and show several clinical, pathological, and molecular differences with their ovarian counterparts. FOXL2 p.Cys134Trp, the ubiquitous molecular driver of ovarian AGCTs, is infrequent (~ 7%) in testicular AGCTs. Recently, FGFR1 hotspot mutations were reported as a potentially "alternative molecular driver" in FOXL2-wild type (WT) ovarian AGCTs. A systematic assessment of FGFR1 status has not been performed in testicular AGCTs. Recently, our group analyzed a series of twenty testicular AGCTs using two NGS panels that lacked coverage of FGFR1. Among twelve cases analyzed successfully, none harbored pathogenic FOXL2 variants. In this study, we reassessed the tumors from our prior series with an NGS panel that covers FGFR1. Among the 14 tumors (70%) that were sequenced successfully, none harbored pathogenic FGFR1 variants. Considering the AGCTs assessed in this study and those previously reported in the literature, none of the 24 tumors analyzed to date have shown pathogenic FGFR1 variants. The present study reinforces the concept that testicular sex cord-stromal tumors classified as AGCTs are different from ovarian counterparts. Show less

Previous research on breast cancer patients has primarily examined singular behavioral indicators, often overlooking the coexistence and interaction between physical activity and sedentary behavior-particularly screen-based sedentary time. This study aims to identify the latent activity pattern categories among breast cancer patients during chemotherapy intervals and explore their associated factors to inform targeted behavioral interventions. A cross-sectional survey was conducted with 292 breast cancer patients undergoing chemotherapy intervals at four general hospitals in Foshan, Guangdong Province. Latent Profile Analysis (LPA) was applied as a person-centered analytic approach to identify distinct activity pattern profiles. Data were collected using a general information questionnaire, the Adult Sedentary Behavior Questionnaire (ASBQ), the Chinese version of the International Physical Activity Questionnaire (IPAQ-SC), the Exercise Self-Efficacy Scale (ESES), the Perceived Social Support Scale (PSSS), and the Hospital Anxiety and Depression Scale (HADS). The activity patterns of breast cancer patients were categorized into three groups: Moderate Activity-Dominant Group (37.33%), Screen-Sedentary High-Risk Group (8.22%), and Activity-Sedentary Coexistence Group (54.45%). Logistic regression analysis showed that, compared to the Moderate Activity-Dominant Group, patients with low exercise self-efficacy and higher anxiety and depression levels were more likely to be classified into the Screen-Sedentary High-Risk Group and Activity-Sedentary Coexistence Group. Higher education levels and being on medical leave were associated with a higher probability of belonging to the Activity-Sedentary Coexistence Group (all Activity patterns in breast cancer patients show significant heterogeneity. Healthcare providers should pay attention to the individual physical activity characteristics of patients and offer personalized physical activity guidance. Tailored interventions that meet the needs of breast cancer patients should be developed to improve health outcomes. Show less

Apolipoprotein E (ApoE) is a key regulator of lipid metabolism that binds to lipid nanoparticle (LNP) surfaces to mediate cellular interactions. However, the ApoE-LNP behavior is highly dependent on the LNP composition, and the underlying mechanisms remain unclear. Here, we show that subtle alterations in LNP surface lipids profoundly reshape the ApoE-LNP structure and intracellular trafficking. Using cryogenic electron microscopy and live-cell imaging, we demonstrate that replacing 10 mol % 1,2-distearoyl- Show less

Cosmetic dermatology has largely focused on topical applications targeting the stratum corneum. However, emerging evidence suggests that visible aging is a systemic readout of internal "organ clocks" and molecular dysregulation across the epidermis and dermis. This review proposes an "inside-out strategy" that seeks to re-conceptualize aesthetic vitality as a measurable indicator of systemic physiological resilience. The author describes theoretically proposed organ-skin axes, including the role of molecular signaling of kidney-derived klotho (KL1 fragment) via FGFR1-α-klotho complexes and muscle-derived irisin through the AMPK/PGC-1-α pathway in modulating skin homeostasis. Drawing on recent breakthroughs in non-human primate models (2023-2025), this synthesis explores the potential of systemic interventions-including nicotinamide adenine dinucleotide (NAD+) precursors (sirtuin 1 SIRT1 activators), senolytics (targeting BCL-2/p16), and glucagon-like peptide-1 (GLP-1) receptor agonists-as candidates to potentially synchronize these internal clocks. Furthermore, the review identifies direct regenerative interventions, such as retinoids (RAR/RXR signaling), chemical peels (HIF-1-α induction), exosomes (miR-21/29 delivery), and poly-L-lactic acid PLLA (mechanotransduction via YAP/TAZ), positioning them as potential physical and chemical epigenetic modulators that may support the restoration of cellular transcriptional fidelity. This article proposes a new paradigm for regenerative aesthetics that focuses on restoring the youthful phenotype by optimizing systemic molecular crosstalk and epigenetic transcriptional fidelity. Show less

Muscle satellite cells (SCs), essential for skeletal muscle regeneration, decline in number and function with age, contributing to sarcopenia. A fully defined viscoelastic hydrogel that preserves SC-myofiber interactions and supports tunable densities of fibronectin-derived RGD ligands was used to investigate age-related defects in extracellular matrix sensing by SCs. Elevating RGD density increased the number of activating and proliferating SCs on myofibers from young mice, whereas SCs from aged mice were unresponsive. Loss of FGF receptor 1 signaling in SCs from aged mice abrogated the coordinated Syndecan-4 and Integrin-β1 matrix response observed in SCs from young mice. Activating Integrin-β1 promoted asymmetric division and self-renewal in SCs from young mice whereas combined FGFR1 and Integrin-β1 signaling drove symmetric expansion. In SCs from aged mice, FGFR1 dysfunction disrupted this balance, impairing asymmetric division, but constitutive FGFR1 activation restored receptor co-localization, self-renewal, and fibronectin responsiveness. Therefore, FGFR1 integrates matrix and growth factor signals, suggesting that targeting the FGFR1-Integrin-β1 axis may enhance SC regenerative potential in aging organisms. 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

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

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

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

Transfer between limbs in younger adults is typically asymmetrical, with greater changes observed in one limb following practice with the other limb, depending on the controlling hemisphere (Pan & van Gemmert). This asymmetry is linked to lateralized hemispheric control of movement (Sainburg), irrespective of high (HPA) or low (LPA) levels of physical activity (McGregor et al.). Acute exercise affects motor skill transfer (Neva et al.). The purpose of this study was to examine the effects of reported chronic physical activity level on bilateral transfer in young adults. Fifty young right-handed participants (18-30) were grouped by physical activity level and randomly assigned a training limb. Individuals performed a 30° visual rotation drawing task. Pretest established baseline performance of each limb, followed by 40 practice trials on the assigned limb. Post-tests mirrored pretests assessing changes. HPA improved movement time (MT), normalized jerk (NJ), trajectory length (TL), and initial direction error (IDE) in the dominant limb following non-dominant practice ( Show less