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Although studies have suggested a potential link between the nervous system and prostate cancer, the underlying regulatory mechanisms remain unclear. Therefore, it is crucial to identify the genes involved in regulating prostate cancer within the nervous system. We utilized eQTL data from eight neural cell types as exposure factors and GWAS data for prostate cancer as outcome events. Mendelian randomization (MR) analyses were performed to identify causative genes associated with prostate, bladder, and renal cancers in Astrocytes, Endothelial cells, Excitatory neurons, Inhibitory neurons, Microglia, Oligodendrocytes, OPCs/COPs, and Pericytes. Bladder and renal cancers were used as controls. Sensitivity analyses (heterogeneity, pleiotropy, and leave-one-out tests) were conducted to ensure reliability. In astrocytes, seven positive genes were identified as being causally related to prostate cancer: KANSL1, AC005670.2, ARL17B, LRRC37A2, LRRC37A, MAPT, and LINC02210. In. Endothelial cells, Inhibitory neuron and Microglia, three genes (LRRC37A2, ARL17B, and KANSL1) were identified as risk genes that are associated with prostate cancer. Four protective genes were identified in excitatory neurons, including LRRC37A2, ARL17B, KANSL1 and LINC02210. In oligodendrocytes, eight genes were identified, with LRRC37A2, ARL17B, and KANSL1 acting as protective factors, while OR2L13, OR2L3, OR2L5, OR2L2, and OR2M4 were identified as risk factors. Additionally, sensitivity analyses showed no heterogeneity or horizontal pleiotropy in the MR results, confirming their reliability and stability. In addition, no positive genes were found in bladder cancer and renal cancer. Our study highlights the role of the nervous system, particularly astrocytes, in regulating prostate cancer. We identified three genes, with LRRC37A2, ARL17B, and KANSL1 emerging as key protective factors. These findings provide potential targets for prostate cancer diagnosis and treatment. The online version contains supplementary material available at 10.1007/s12672-025-03711-9. Show less

The relationship between plasma lipoprotein(a) [Lp(a)] levels and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. The aim of this study was to examine the combined effects of Lp(a) levels on liver and vascular damage. The study was conducted using the Liver-Bible cohort of individuals with metabolic dysfunction (n = 859, 808 with genomic information) and the Milan Biobank (n = 6963). Genome-wide association studies (GWAS) and polygenic risk scores (PRS) were used to evaluate the inherited factors influencing plasma Lp(a) levels. In the Liver-Bible cohort, genetic variation in the LPA gene was the strongest determinant of Lp(a), followed by liver stiffness measurement (LSM). Additionally, circulating Lp(a) levels, but not genetic predisposition, were inversely related to LSM, suggesting that MASLD severity may affect Lp(a) secretion. Among participants with more severe insulin resistance (n = 250), Lp(a) levels (odds ratio 6.7, 95% CI 1.0-53.0, p = 0.046) and LSM (odds ratio 13.7, 95% CI 1.4-172.2, p = 0.023) were associated with greater prevalence of carotid atherosclerotic plaques, regardless of traditional cardiovascular risk factors. In the Milan Biobank, genetically predicted higher Lp(a) levels tended to increase the risk of liver-related outcomes, whereas genetically predicted MASLD was associated with lower circulating Lp(a) levels. The results of this study suggest that liver damage is more likely the cause of reduced plasma Lp(a) levels rather than a consequence. Assessing plasma Lp(a) levels and the extent of liver damage could improve the prediction of vascular damage. Show less

Chronic lymphocytic leukemia (CLL) is characterized by malignant B lymphocyte accumulation and progressive immune dysfunction. The immune checkpoint molecule TIM-3 and its ligand galectin-9 (Gal-9) contribute to T cell exhaustion, impairing anti-tumour immunity. Interleukin-27 (IL-27) has pleiotropic immunomodulatory properties, but its impact on TIM-3 and Gal-9 expression in CLL remains unclear. Peripheral blood mononuclear cells (PBMCs) from 20 treatment-naive CLL patients were cultured with or without IL-27 (100 ng/mL) for 72 h. Flow cytometry assessed TIM-3 and Gal-9 expression on CD4 IL-27 stimulation significantly increased TIM-3 expression on CD8 IL-27 may enhance immunosuppressive mechanisms in CLL by modulating immune checkpoint expression, potentially contributing to disease progression. These ex vivo findings in PBMCs from CLL patients indicate the IL-27-associated modulation of checkpoint expression under the conditions tested. In the absence of parallel healthy-donor controls, CLL specificity cannot be established in this study. Show less

Alzheimer's disease (AD) remains a major neurodegenerative disorder with limited therapeutic medication. Despite intensive efforts, the clinical development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors has been hindered by off-target effects, poor brain penetration, and toxicity, which is often due to a lack of selectivity over BACE2. In this study, we conducted a comprehensive analysis of over 9,000 reported BACE1 inhibitors to identify key physicochemical properties and interaction fingerprints associated with effective binding. These criteria were used to filter a library of 1.4 million commercially available compounds, prioritizing candidates with better safety and blood-brain barrier (BBB) permeability properties. The top-ranked molecules were evaluated through molecular docking and molecular dynamics (MD) simulations, followed by selectivity assessments against BACE2 and additional off-targets. Among these, two compounds, MCULE-5138978734 and MCULE-2333131051, exhibited strong and stable binding to BACE1 with markedly reduced affinity for BACE2, suggesting improved selectivity. This integrative in silico framework demonstrates a rational strategy for the discovery of selective BACE1 inhibitors and highlights promising lead candidates for further experimental validation in the development of AD therapeutics. Show less

This study evaluates photon-counting CT (PCCT) for the imaging of mouse femurs and investigates how APOE genotype, sex, and humanized nitric oxide synthase (HN) expression influence bone morphology during aging. A custom-built micro-CT system with a photon-counting detector (PCD) was used to acquire dual-energy scans of mouse femur samples. PCCT projections were corrected for tile gain differences, iteratively reconstructed with 20 µm isotropic resolution, and decomposed into calcium and water maps. PCD spatial resolution was benchmarked against an energy-integrating detector (EID) using line profiles through trabecular bone. The contrast-to-noise ratio quantified the effects of iterative reconstruction and material decomposition. Femur features such as mean cortical thickness, mean trabecular spacing (TbSp_mean), and trabecular bone volume fraction (BV/TV) were extracted from calcium maps using BoneJ. The statistical analysis used 57 aged mice representing the APOE22, APOE33, and APOE44 genotypes, including 27 expressing HN. We used generalized linear models (GLMs) to evaluate the main interaction effects of age, sex, genotype, and HN status on femur features and Mann-Whitney U tests for stratified analyses. PCCT outperformed EID-CT in spatial resolution and enabled the effective separation of calcium and water. Female HN mice exhibited reduced BV/TV compared to both male HN and female non-HN mice. While genotype effects were modest, a genotype-by-sex stratified analysis found significant effects of HN status in female APOE22 and APOE44 mice only. Linear regression showed that age significantly decreased cortical thickness and increased TbSp_mean in male mice only. These results demonstrate PCCT's utility for femur analysis and reveal strong effects of sex/HN interaction on trabecular bone health in mice. Show less

Dyslexia, a heterogeneous neurodevelopmental disorder, is characterized by persistent reading and spelling difficulties despite average intellectual potential. Although intellectual functioning in dyslexia is often described as average, emerging evidence suggests meaningful within-group variability. This study examined whether children and adolescents with dyslexia exhibited distinct intellectual profiles based on the Stanford-Binet Intelligence Scales, Fifth Edition (SB5). Data were obtained from a large, diagnostically verified sample of 3458 individuals aged 10-19 years assessed in psychological-pedagogical counseling centers across Poland. We used latent profile analysis (LPA) of all 10 SB5 subtests and compared models that specified 2-6 latent classes. The optimal solution identified two profiles: (a) a small subgroup (5%) with globally reduced intellectual functioning and a profound deficit in verbal working memory (>3 standard deviations below the norm) and (b) the predominant subgroup (95%) with broadly average intellectual functioning and relatively preserved reasoning abilities. Profile membership was associated with socioeconomic status; the low-functioning subgroup was associated with lower parental education and age, as younger participants were more likely to belong to this group. These findings highlight the dimensional nature of intellectual heterogeneity in dyslexia and underscore the diagnostic value of profile-based approaches over global intelligence quotient (IQ) scores. Show less

Alzheimer's disease (AD) is the leading cause of dementia and is often prefaced by mild cognitive impairment (MCI). Detection of AD-related changes via blood-based biomarkers would enable critical therapeutic interventions early in disease progression. Neuronal enriched extracellular vesicle (NEEV) miRNAs regulate peripheral genes as a response to early AD brain changes and hence may have biomarker potential. Plasma NEEVs were captured from plasma samples of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) using an antibody against the neuronal surface marker CD171. miRNAs isolated from NEEVs were sequenced and analyzed using miRDeep2/DEseq2 and QIAGEN RNA-seq portal for differential expression between cognitively impaired (CI) and cognitively unimpaired controls. hsa-miR-122-5p was significantly underrepresented in the CI group in both MAs and NHWs compared to the healthy control. Other population-specific miRNAs (MAs: hsa-miR-26a-5p, hsa-let-7f-5p, and hsa-miR-139-5p, NHWs: hsa-miR-133a-3p, hsa-miR-125b-5p, and hsa-miR-100-5p) identified may have biomarker potential in AD precision medicine. Some of these differentially expressed miRNAs were associated with key AD-related comorbidities such as APOE genotype, age, and metabolic burden and were predicted to target genes within NF-κB -regulated inflammatory pathways. Together, these findings suggest that dysregulated miRNA networks may serve as a mechanistic link between comorbidity burden and AD-related neuroinflammation and neurodegeneration. Show less

Characterized by social communication deficits and the presence of restricted and repetitive behaviors, autism spectrum disorder (ASD) is a significant neurodevelopmental condition. Genetic studies have revealed a strong association between ASD and numerous mutations that alter the function of key proteins, either through activation or inactivation. These alterations are widely hypothesized to affect neuronal morphogenesis; however, a comprehensive understanding of the specific molecular cascades driving these cellular and symptomatic changes remains lacking. In this study, we report for the first time that signaling through the atypical Rho family guanine-nucleotide exchange factor (GEF) Dock7 and ErbB2, an activator acting upstream of Dock7, drives the excessive elongation of neuronal processes observed in association with the ASD- and intellectual disability (ID)-linked semaphorin-5A (Sema5A) Arg676Cys variant (p.Arg676Cys). Knockdown of Dock7 using short hairpin RNA or inhibition of ErbB2 kinase signaling with a specific chemical inhibitor reduced this excessive process elongation in primary cortical neurons. Similar results were obtained in the N1E-115 cell line, a neuronal cell model that undergoes neuronal morphological differentiation. Moreover, inhibition of ErbB2-Dock7 signaling specifically decreased the overactivation of the downstream molecules Rac1 and Cdc42. These findings indicate that the ErbB2-Dock7 signaling axis plays a role in mediating the aberrant neuronal morphology associated with the ASD- and ID-linked Sema5A p.Arg676Cys. Targeting this pathway may therefore offer a potential approach to addressing the molecular and cellular developmental challenges observed in ASD. Show less

Metabolic (dysfunction)-associated steatotic liver disease (MASLD), the hepatic consequence of metabolic syndrome, affects 30% of the global population. Studies in animals and humans investigating the effect of fructose on MASLD present conflicting findings, while in vitro methods often fail to add meaningful evidence due to acute exposures (<72 h) and non-physiological concentrations. This study aimed to determine the effect of fructose on triglyceride (TG) accumulation in HepG2 cells following acute and chronic exposures and assess its effect on the expression of genes related to de novo lipogenesis (DNL). TG concentration was measured after 48 h in response to fructose (20 mM) or glucose (20 mM), with or without a fatty acid mixture (oleic acid/palmitic acid 110 µM/55 µM), in low (5.5 mM)- and high (25.5 mM)-glucose media. To model chronic exposure, cells were maintained in fructose, glucose, or fatty acids for 28 days and the TG concentration was determined every 7 days. The effect of fructose on DNL regulators ( Neither fructose nor glucose, with or without fatty acids, changed the TG levels in cells at 48 h and the media glucose concentration had no effect on this result. Similarly, fructose did not increase TG levels after 28 days. While fructose and glucose did not affect key DNL genes at 6 h, the fatty acid mixture reduced This study shows that fructose did not significantly impact TG synthesis or DNL gene expression in the HepG2 cell model. Future studies should consider using primary human hepatocytes or more complex in vitro models. Show less

Speech impairment is a recognized but unpredictable adverse effect of sub-thalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD). To evaluate the prevalence of speech impairment 1 year after STN-DBS in PD patients and to determine the predictive factors for speech outcome following STN-DBS. Data for 417 patients from the French national PREDISTIM study were collected preoperatively. The combined effect of medical treatment and surgery on speech was compared using specific items from dedicated clinical scales (MDS-UPDRS III.1: primary endpoint) and patient self-assessment questionnaires (items 34 and 35 of the PDQ39: secondary endpoints). For each variable, three patient groups were generated according to speech outcome at 1 year: worsening, stability, and improvement. In the second step analysis, the three groups were compared for demographic and clinical variables at baseline and STN-DBS parameters. There was a significant deterioration in speech of all considered items 1 year after combined STN-DBS and dopaminergic treatment. Four predictive factors for speech deterioration were detected: (i) the absence of preoperative speech impairment (p < 0.001); (ii) severity of motor activity of daily living (MDS-UPDRS II off total score) (p = 0.037); (iii) high-intensity stimulation of the left electrode (i.e., above 3.6 V) (p = 0.046); and (iv) the absence of any change in non-motor experiences of daily life (MDS-UPDRS I total score) (p = 0.048). Speech outcome should be carefully monitored after STN-DBS, especially in PD patients without preoperative speech impairment, with motor difficulties in daily-living activities, and with increased left electrode intensity. ClinicalTrials.gov identifier: NCT02360683. Show less

Suicidal ideation and attempts as well as eating disorders (EDs) are common among Iranian individuals. Additionally, ED symptoms are associated with suicidality. According to the interpersonal-psychological theory of suicide (IPTS), factors such as thwarted belongingness, perceived burdensomeness, and capability for suicide must combine for suicidality to occur. The tenets of IPTS have been supported among individuals with ED symptoms from Western countries. However, no study has yet explored how ED symptoms might co-occur with IPTS factors and potentially relate to suicidal ideation and attempts using latent profile analysis (LPA). Participants (N = 773) were Iranian community members who completed a battery of scales assessing ED symptoms, suicide-related risk factors, as well as suicidal ideation and suicide attempts. The LPA revealed that a six-class solution best fit the data. The classes with the highest levels of IPTS and binge/purge related symptoms also had the highest odds of suicide attempts. Our findings suggest that the measurement of thwarted belongingness, perceived burdensomeness, and capability for suicide is particularly important for individuals with binge/purge type eating disorder symptoms. Overall, IPTS factors should be incorporated into assessments of clients presenting with ED symptoms and suicidality. Show less

Community structures are common features of many real-world networks, and community detection is necessary to understand how these networks are organized. Various approaches have been devised for community detection, with each providing varying degrees of both accuracy and structural understanding. One of them, the Label Propagation Algorithm, is so common because it is simple and computationally cheap. Nevertheless, it does not usually reach great modularity and yields inaccurate community counts and structures in real-world networks. This is mostly due to its naive criteria of selecting the neighbor nodes when it comes to label propagation. To tackle the issue, we developed an adjusted algorithm, which we call Embedding-based Label Propagation (ELP), a hybrid between LPA and node embedding that allows us to combine both local connectivity and global structural data. ELP update step takes into consideration not only the local neighborhood, as in conventional LPA, but also embedding-based similarities to inform more productive neighbor selection. We tested ELP on popular benchmark datasets such as Karate Club, Dolphins, Football, Polbooks, and LFR synthetic networks and compared its results with LPA and other well-established algorithms. The empirical findings show that ELP can always perform better in modularity, NMI and NF1 scores, but it is also scalable to large and complex networks. These results can be used to identify ELP as an effective and powerful method of community-finding in real and artificial-world scenarios. Show less

The formation of self-perpetuating protein aggregates such as amyloids is associated with various diseases and provides a basis for transmissible (infectious or heritable) protein isoforms (prions). Many human proteins involved in the regulation of transcription contain potentially amyloidogenic regions. Here, it is shown that short N-terminal isoforms of the human protein PHC3, a component of the chromatin-modifying complex PRC1 (Polycomb repressive complex 1), can form prion-like aggregates in yeast assays, exhibit amyloid properties in the Show less

Non-suicidal self-injury (NSSI) is a common concern among adolescents. While psychological flexibility (PF) has been established as a key protective factor that prevents NSSI in adolescents, its potential heterogeneity and the mechanisms by which PF influences NSSI remain unclear. The purpose of this study was to explore the heterogeneity of PF among Chinese adolescents and examine whether negative emotions and school interpersonal relationships mediate the associations between PF profiles and NSSI behavior. A convenience sampling method was employed. Participants included 1,562 Chinese adolescents (mean age 13.13 years, SD = 0.99; 54.42% males) from Anhui Province. Latent profile analysis (LPA) was performed to identify the heterogeneity in adolescent PF, and structural equation modeling (SEM) was performed to examine the multiple mediating roles of negative emotions and school interpersonal relationships in the associations between PF profiles and NSSI behavior. The following five distinct PF profiles were identified: the weakly open-highly engaged subgroup (4.42%), the low-PF subgroup (15.43%), the medium-PF subgroup (33.80%), the high-PF subgroup (33.35%), and the extremely high-PF subgroup (13.00%). Both negative emotions and school interpersonal relationships significantly mediated the associations between PF profiles and NSSI behavior. Compared with adolescents in the extremely high PF subgroup, adolescents in the weakly open-highly engaged subgroup, low-PF subgroup, and medium-PF subgroup presented higher levels of negative emotions, poorer school interpersonal relationships, and greater degrees of NSSI behavior. In particular, among the five profile groups, adolescents in the weakly open-highly engaged subgroup exhibited the greatest degree of NSSI behavior. PF profile affected NSSI behavior among adolescents indirectly through negative emotions and school interpersonal relationships, and stronger multiple mediating effects were observed among adolescents with lower levels of PF and openness. Our study highlights the importance of focusing on the heterogeneity of PF among adolescents, the critical role of openness, and the need for tailored interventions to improve PF as well as emotional, interpersonal, and behavioral issues. Show less

A crucial aspect of the association involving inflammation and the development of cancer is the ability of cancer cells to undergo a transition into mesenchymal cells. The process is referred to as epithelial-mesenchymal transition (EMT). Cytokines and chemokines, which are inflammatory agents found in the carcinoma microenvironment, induce epithelial-mesenchymal transition (EMT) changes in malignant cells. Evaluating the role of cytokines in EMT in breast carcinoma and investigating their potential therapeutic implications is the objective of this comprehensive research report. The following search criteria were applied to the Cochrane, Embase, PubMed, and Web of Science databases: "cytokines," "the cytokines," "chemokines," "EMT," "epithelial-mesenchymal transition or transformation," "breast tumor," "breast carcinoma," and "breast cancer." A body of research comprising 54 articles has demonstrated that a number of cytokines, including TNF-α, TGF-β, and IL-6, contribute to the promotion of EMT alterations in breast tumors. The epithelial markers E-cadherin and β-catenin were downregulated as a consequence of morphological changes induced by EMT; conversely, the mesenchymal markers N-cadherin, vimentin, and fibronectin were upregulated. The EMT transforming factors (EMT-TF) TWIST/ZEB/SNAI1/SNAI2 were upregulated. Pharmaceuticals with the capacity to specifically target cytokines or their epithelial-mesenchymal transition (EMT) signalling pathways have the potential to significantly reduce treatment resistance, impede the progression of cancer, and prevent the recurrence of breast cancer. Epithelial-mesenchymal transition (EMT) induced by cytokines is a factor in breast cancer progression and metastasis. Show less

Given the lack of evidence, we cannot definitively determine the relationship between attachment networks and problematic mobile phone use, hindering effective intervention strategies. Therefore, a three-wave longitudinal study was designed to explore the heterogeneity of parent-child attachment networks using latent profile analysis (LPA) and random intercept latent transition analysis (RI-LTA). Participants included 2116 adolescents (ages 14-21; 53.8% girls). Results identified five stable parent-child attachment network profiles, each showing moderate but decreasing stability. Notably, adolescents who were grouped into an attachment network characterized by secure maternal attachment but insecure paternal attachment, similar to those in attachment networks with both insecure maternal and paternal attachment, scored higher levels of problematic mobile phone use than those who were grouped into attachment networks with both secure maternal and paternal attachment. Our findings fill empirical gaps and provide strong evidence supporting attachment-based interventions to reduce problematic mobile phone use. Show less

Electroencephalography (EEG) and magnetoencephalography (MEG), two of the most widely used tools for studying human brain dynamics, are thought to have varying spatial resolutions. Here, we simultaneously recorded EEG and MEG data from 14 participants to directly compare their sensitivities - at both the sensor and source levels - to the auditory Mismatch Negativity (MMN in EEG and MMNm in MEG) elicited by pitch deviants. At the sensor level, we observed that negative components emerged in early (100-190 ms) and late (260-420 ms) latency windows. These responses displayed a fronto-central distribution in EEG and a centro-parietal distribution in MEG. MEG also yielded larger effect sizes than EEG, likely reflecting differences in signal-to-noise ratio between MEG and EEG. At the source level, our findings support the involvement of a fronto-temporal auditory MMN network. Both EEG and MEG identified generators in the superior temporal gyrus, Heschl's gyrus, interior frontal gyrus, and insular regions. Notably, EEG source localization revealed additional generators in the left superior temporal sulcus not detected by MEG, whereas MEG identified late components generators in the right hemisphere that were not observed with EEG. Taken together, these results suggest that EEG and MEG may provide complementary perspectives on auditory processing. However, given the inherent complexity of comparing data acquired with different methodologies and the limited sample size, our conclusions should be regarded as preliminary. Show less

In the last decades, the biological properties of Lp(a) have attracted increasing attention for their possible involvement in a wide range of clinical conditions other than atherosclerotic cardiovascular disease. To date, whether a pathogenic interplay may exist between Lp(a) and cancer remains unclear. Indeed, experimental studies mainly show a protective effect of Lp(a) toward cancer, while results of clinical studies are highly contradictory. Nonetheless, the confirmation of any link between Lp(a) metabolism and cancer may be highly impactful for its translational implications in the current era of a renewed scientific interest in this lipoprotein. Indeed, the increasing availability of laboratory assays for the routine assessment of plasma Lp(a) levels could be proposed as an additional tool for cancer diagnosis and prognostic stratification. In addition, the tumultuous development of anti-Lp(a) therapeutics, if a pro-cancerogenic Lp(a) activity will be confirmed, could have an impact on the natural history of cancer and on its pharmacological management. This review resumes current knowledge on the relationship between Lp(a) and cancer as well as on its possible impact on the oncological field. Show less

Statins are a commonly prescribed cholesterol lowering drug class that can increase the risk of new-onset diabetes (NOD). To investigate the molecular mechanisms underlying this effect, we generated human induced pluripotent stem cells (iPSCs) from individuals identified from electronic health records of Kaiser Permanente of Northern California who were susceptible to developing NOD after statin initiation or controls who maintained stable fasting glucose on statin treatment. RNA-seq analysis of iPSCs incubated with atorvastatin, simvastatin or mock buffer for 24 hours identified the long non-coding RNA Show less

Sarcopenia and frailty are complex geriatric syndromes influenced by a combination of genetic and environmental factors. Recent studies suggest that specific genetic variants, DNA methylation patterns and shortened telomeres are associated with age-related diseases and might contribute to the development of both sarcopenia and frailty. In this study, we investigated the contribution of multi-omics data to sarcopenia, frailty, lean mass index (LMI) and handgrip strength in an elderly Lithuanian population. A total of 204 participants (age 82.2 ± 7.6 years) were included, comprising 122 individuals diagnosed with sarcopenia and/or frailty and 82 healthy, community-dwelling older adults. The results showed that LMI was associated with various health and lifestyle factors. Two genetic variants, CLIC5 rs75652203 and GHITM rs17102732, were found to be significantly associated with handgrip strength at the genome-wide level. Additionally, 12 polymorphisms previously linked to sarcopenia were replicated in relationship to LMI: BOK rs76993203, VAMP5 rs1374370, TMEM18 rs12714414, SFMBT1 rs36033494, BANK1 rs13136118, TET2 rs2647239, FOXO3 rs9384679, L3MBTL3 rs13209574, ZFAT rs13267329, CEP57 rs35793328, PCGF2 rs1985352 and MC4R rs66922415. Furthermore, several genes, many of which are involved in immune system processes, were significantly enriched with differentially methylated sites associated with LMI. Shorter telomeres were also associated with both sarcopenia and frailty. Notably, a significant relationship was observed between telomere length and methylation levels in genes related to lifestyle traits and the risk of developing these conditions. These findings provide new insights into the biological mechanisms underlying sarcopenia and frailty, underscoring the important roles of genetic and epigenetic factors in their pathogenesis among older adults. Show less

We reviewed our institutional database to examine the effect of right ventricular outflow tract (RVOT) stenting on branch pulmonary artery (PA) sizes and their outcomes. RVOT stenting was performed following standard technique. Since 2021, a conscious effort was made to spare the pulmonary valve (PV) whenever feasible. PA annulus and branch PA sizes were serially monitored by echocardiography. Sixty patients, (4.5 [1.75-24] months, weight 6.4 [3.5-9 kg]), were included (Time period:2012-2025). Commonest indications included cyanotic spell (65%) and hypoplastic branch PAs (30%). Pulmonary valve annulus measured 5.1 mm (4.0-7.7); Z score - 3.8 (- 5.1 to - 2.6), and MPA 4.35 mm (3.34-5.7); Z score - 4.9 (- 7.0 to [- 3.1]). At follow-up of 8(25-102) months, branch PAs grew in all, albeit at different paces. RPA z-scores improved from a baseline of - 2.48 (- 5.05 to [- 0.85]) to - 1.55 (- 3.07 to 0.46) and LPA z-scores from - 2.5 (- 4.38 to [- 0.78]) to - 1.08 (- 2.41 to 0.63) in hypoplastic PA group over 1-year period (p value < 0.001). Pulmonary valve was spared in 57% of patients in the cyanotic spell group and 22% of hypoplastic PA group. 29 (48%) patients underwent corrective surgery at 9 (6-14) months from RVOTS. Requirement of transannular patch (TAP) was 38% (11/29) and conduit was 34% (10/29). Valve sparing ICR was feasible in 67% (8/12) when the stent was placed below the valve. In addition to effective palliation, RVOT stenting promotes growth of branch pulmonary arteries even in those with inherently hypoplastic branch PAs. It is possible to effectively palliate selected patients without stenting across the pulmonary valve thereby potentially enabling valve-sparing TOF correction in those with suitable anatomy. Show less

The MAPK/ERK pathway plays a critical role in the regulation of milk production by controlling cellular processes such as proliferation, differentiation and survival, which are essential for lactogenesis and mammary gland function. Bubalus bubalis (Water buffalo), known for its unique physiological and ecological characteristics, serves as an ideal model to explore the evolutionary and molecular roles of MAPK/ERK pathway genes. This study presents the first comprehensive computational analysis of MAPK/ERK genes in B. bubalis, identifying 21 key genes involved in the pathway. Phylogenetic analysis clustered these genes into 13 distinct clades, such as MST1, GRB2, RAS, ETS1, JUN and FOS, and revealed close evolutionary relationships with Bos taurus and Camelus bactrianus. Structural characterization identified 10 conserved motifs, including essential domains like protein kinase, ETS and RAS, reflecting their functional significance. Gene structure analysis revealed substantial variation in exon-intron patterns, while synteny analysis confirmed collinearity with human orthologs, indicating genomic conservation. Physicochemical analysis highlighted a broad range of molecular weights and isoelectric points, with most proteins classified as hydrophilic and thermostable. Gene duplication and selection analyses revealed seven segmentally duplicated gene pairs, with the JUN-ETS1 and DUSP6-MST1 pairs showing evidence of positive selection, suggesting functional divergence. These findings establish a foundational understanding of MAPK/ERK pathway genes in B. bubalis and provide valuable insights into potential targets for genetic improvement, selective breeding and sustainable dairy management strategies aimed at enhancing milk production and quality. Show less

The roles of cancer stem cells and Octamer-binding transcription factor 4 (OCT4) have been implicated in human tumorigenesis and metastasis. However, the role of OCT4 in the metastasis of non-small-cell lung cancer (NSCLC) remains undetermined, especially regarding stem cell-related pathways. Previous research has reported that dual-specificity phosphatase 6 (DUSP6), a mitogen-activated protein kinase (MAPK) phosphatase, is associated with cancer cells that display anti-apoptotic, migratory, and drug-resistance phenotypes. However, the regulation of DUSP6 in NSCLC is unclear. This study focused on the role of OCT4 in NSCLC, particularly its interaction with DUSP6. Here, we show a positive correlation between OCT4 and DUSP6 expression in NSCLC cells. Overexpression of OCT4 increased, whereas knockdown of OCT4 reduced DUSP6 expression. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays revealed that OCT4 transactivated DUSP6 expression by directly binding to the DUSP6 promoter, indicating that DUSP6 is a downstream target of OCT4. Furthermore, knockdown of DUSP6 in OCT4-overexpressing A549 human NSCLC cells decreased cell migration Show less

Bladder cancer (BC) is one of the most prevalent urinary malignant tumors that is intricately regulated by molecular pathways. Multiple studies have demonstrated a clear association between DUSP6 and malignant tumor progression; however, its role and underlying mechanisms in BC remain unclear. Here, we found that DUSP6 exhibits significantly elevated expression in BC tissues compared with normal tissues and is strongly associated with poor overall survival. Transcriptomic analysis revealed a robust correlation between DUSP6 expression and mitophagy, a selective form of autophagy crucial for maintaining mitochondrial integrity. Show less

Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial-mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Show less

Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological function of the DUSP6 gene on white adipocyte adipogenesis in farm animals remains unknown. In this study, we aimed to clarify the effect of DUSP6 on porcine subcutaneous preadipocyte proliferation and differentiation. We first make clear that the patterns of DUSP6 expression is associated with fat contents in porcine fat deposition related tissues. Porcine subcutaneous preadipocytes were isolated and induced to differentiation. Small interfering RNAs were applied to deplete DUSP6. MTT assay, CCK-8 analysis, Oil Red O staining, triglyceride determination and reverse transcription quantitative polymerase chain reaction were applied to study the regulatory role of DUSP6 during adipocyte adipogenesis in pigs. We found that the expression levels of DUSP6 were significantly higher in backfat and longissimus dorsi tissues from fat-type pigs than in those from lean-type pigs. Consistently, the significantly induced expression of DUSP6 was also observed in differentiated adipocytes. In addition, knockdown of DUSP6 greatly inhibited preadipocytes proliferation, through the decreased cell viability and downregulated mRNA expressions of cell proliferation-associated genes, including PCNA, CDK1, CDK2. Furthermore, knockdown of DUSP6 significantly inhibited preadipocytes differentiation, as evidenced by markedly reduced lipid droplet formation, attenuated triglyceride accumulation and downregulated expression levels of adipogenic transcription masters (PPARγ, C/EBPβ, FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder with variable penetrance caused by GnRH deficiency, leading to delayed puberty and infertility. In 50-60% of cases, CHH is associated with non-reproductive abnormalities, most commonly anosmia/hyposmia (Kallmann syndrome, KS). Over 60 genes have been implicated in CHH pathogenesis. We aimed to perform genetic screening in a cohort of 14 patients (10 males, 4 females; mean age 22 ± 7.72 years) with suspected or diagnosed HH/KS. Genetic analysis was conducted using next-generation sequencing (NGS) with a custom panel of 46 candidate genes. Variant interpretation followed ACMG standards and guidelines. Multiple tools were used to predict the structural effects of variants on tertiary protein structure, assessing their pathogenicity. Novel variants were functionally characterized by qRT-PCR on mRNA extracted from peripheral leukocytes. NGS identified nine rare variants and four novel variants in genes previously associated with normosmic isolated HH (nHH) and/or KS ( Show less

Repeated ketamine treatment to maintain a rapid antidepressant effect can lead to side effects over time, highlighting an unmet clinical need for sustaining this drug's antidepressant action from a single administration. Ketamine-induced synaptic potentiation at CA3-CA1 synapses has been proposed to be a key synaptic substrate for antidepressant action. Here, we found that ketamine-induced CA3-CA1 synaptic potentiation could be augmented by transiently increasing extracellular signal-regulated kinase (ERK) activity through pharmacological inhibition of dual-specificity phosphatases 6 (DUSP6). The antidepressant-like behavioral effects of acute ketamine treatment were extended by DUSP6 inhibition for up to 2 months. The selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons abolished these DUSP6 inhibition-mediated synaptic and behavioral effects. These data suggest that ketamine's rapid antidepressant effects can be sustained by selectively targeting downstream intracellular signaling. Show less