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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

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

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

The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have numerous benefits, including strong anti-inflammatory and triglyceride-lowering properties. EPA and DHA are primarily obtained by consuming fatty fish; however, they are also endogenously synthesized primarily in the liver from α-linolenic acid (ALA) through a pathway mediated by the delta-6 desaturase (D6D) enzyme. Previous reports in rodents and humans suggest that dietary proteins such as soy and dairy may impact this pathway differently. The primary aim was to investigate the effects of diets containing either soy or milk protein on the expression, abundance, and enzymatic activity of the desaturases and elongases regulating hepatic omega-3 fatty acid biosynthesis. Male C57BL/6N mice (n = 16 per group) were fed a moderate-fat diet for 8 weeks containing either 1% or 3% energy from ALA. Protein content (15% energy) corresponded to either skim milk powder (SMP) or soy protein isolate (SPI). Hepatic fatty acid content was quantified by gas chromatography-flame ionization detection. Gene expression and protein expression were assessed by RT-qPCR and western blotting, respectively. D6D activity was measured in isolated hepatic microsomes. Fat oxidation was examined using a high-resolution respirometer. Hepatic omega-3 fatty acids (ALA, SDA, EPA, DPAn-3) were lower in SPI-fed mice compared to SMP-fed mice. Fads1, Fads2, Elovl2, and Elovl5 expression was higher in SPI-fed mice compared to those fed SMP, while Srebp-1c expression was lower and Cpt1a expression higher in SPI-fed mice. Consistent with the changes seen at the gene expression levels, FADS2 protein abundance was higher in SPI-fed mice, whereas ELOVL5 protein expression was lower in the SPI groups. Little to no differences in microsomal D6D activity and mitochondrial respiration were detected. Our findings suggest that SPI-related reductions in hepatic omega-3 fatty acid content occur independent of changes in desaturase gene expression, protein expression, enzymatic activity, or mitochondrial respiration. Further studies investigating the influence of dietary proteins on ALA metabolism are therefore warranted. Show less

Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (p < 5 × 10 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

This cross-sectional study aims to describe the characteristics of physical activity, sedentary time, sleep quality, and resting EEG among college students with mild depressive symptoms, and further explore pairwise correlations between behavioral patterns, resting EEG, and mild depressive symptoms. This study included 75 college students with mild depressive symptoms (MDS) and 75 college students without depressive symptoms (ND) as research subjects. Physical activity (vigorous physical activity (VPA), moderate physical activity (MPA), and low physical activity (LPA)) and sedentary time（ST） were measured using the International Physical Activity Questionnaire Short Form (IPAQ-SF). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Resting EEG power values were collected from subjects in a quiet, eyes-closed state using an electroencephalography (EEG) device. (1) Characteristic analysis revealed that compared with the ND group, the MDS group exhibited reduced MPA and VPA scores, elevated ST scores, and increased total PSQI scores along with elevated scores across its subdimensions. Their behavioral patterns (Moderate-to-Vigorous Physical Activity (MVPA), Sedentary Behavior (SB), Poor Sleep Quality (PSQ) may have changed, including a decrease in the proportion of MVPA, an increase in the proportion of SB, and an increase in the proportion of PSQ. Analysis of resting EEG revealed increased Alpha2 (α2) band power in the temporal regions (T3 and T5) and increased Beta1 (β1) band power in the frontal region (Fp1) in the MDS group (all p College students with mild depressive symptoms may exhibit altered behavioral patterns and abnormal neural activity in the frontal and temporal regions. Their changed behavioral patterns may correlate with mild depressive symptoms, and recognition models based on certain resting EEG indicators demonstrate preliminary application potential. The association between specific sleep issues and localized EEG activity in this population may provide evidence for further elucidating the mechanistic pathways linking their behavior and brain activity. Future longitudinal studies are recommended to explore causal relationships among these variables. Show less

To explore the cellular behavior of stem cells derived from human exfoliated deciduous teeth (SHED) in response to inorganic pyrophosphate (PP SHED cells were isolated from the dental pulp tissues of human primary exfoliated teeth. Cell proliferation was examined using the MTT assay, colony-forming unit assay, and cell cycle analysis. Cell migration was evaluated using the scratch assay. Osteogenic differentiation was assessed by the expression of osteogenic marker genes and in vitro mineral deposition. Oil Red O staining was employed to determine intracellular lipid accumulation under adipogenic differentiation. For osteoclast differentiation, TRAP staining was used. The global gene expression profile was examined by RNA sequencing analysis. PP PP Show less

Alternative sources of dietary fish oil (FO) are necessary for the growth of the aquaculture industry. This study investigated the potential benefits of black soldier fly larvae oil (BSFLO) as a feed ingredient in the diets of African catfish hybrids ( Show less

Women diagnosed with PCOS exhibit a high prevalence of obstructive sleep apnea (OSA). This study aims to assess risk factors of OSA among patients with PCOS. This retrospective study included 126 patients with PCOS who were categorized into an OSA group (n = 30) and a non-OSA group (n = 96) according to the apnea-hypopnea index (AHI). A control group comprised 72 patients without PCOS who presented during the same period for infertility due to fallopian tube, pelvic, or male factors. Patients with PCOS A multivariate logistic regression model was used to analyze independent risk factors for OSA in the PCOS group. Patients with PCOS had significantly higher AHI values and elevated values for various physical indicators, including body mass index (BMI) and neck, waist, and hip circumferences; prolactin (PRL); fasting plasma glucose (FPG); insulin (FINS); triglycerides (TG); homeostasis model assessment of insulin resistance (HOMA-IR); 2-hour postprandial glucose (2-hPG) and insulin (2-hINS); AHI; and oxygen desaturation index (ODI). Conversely, levels of high-density lipoprotein cholesterol (HDL-C) and lowest oxygen saturation (LSaO OSA in PCOS patients is linked to metabolic indicators. High neck circumference and BMI levels were independent risk factors, highlighting the need for OSA in routine PCOS screening, particularly in the context of metabolic dysregulation. Show less

Traditional approaches to assessing sleep quality in clinical nurses often overlook population heterogeneity and the complex interplay of influencing factors. This study employs Latent Profile Analysis (LPA) and Association Rule Mining (ARM) to identify distinct sleep quality subgroups and uncover key factor combinations, thereby informing targeted intervention strategies. A total of 1,686 nurses from 123 hospitals in Shandong Province were recruited through multistage stratified sampling. LPA was used to classify participants based on seven sleep dimensions from the Pittsburgh Sleep Quality Index (PSQI), while ARM was applied to identify frequent itemsets of sleep disorder triggers. Key influencing factors were further examined using univariate analysis and multivariate logistic regression. Three latent sleep profiles were identified: high (63.11%), moderate (34.10%), and low (2.79%) sleep quality. The low-sleep subgroup was characterized by higher proportions of being unmarried/divorced (42.55%), low monthly income (≤ 3,000 CNY, 42.55%), non-permanent employment (76.60%), and severe psychological distress (44.68%). In contrast, the high-sleep subgroup featured higher rates of being married (85.62%), moderate income (3,001–7,000 CNY, 73.03%), and low psychological distress (51.32%). Key determinants included marital status (OR = 2.153/2.252), income (OR = 9.098), employment type (OR = 1.475), and psychological state (OR = 0.060–0.555). ARM revealed distinct risk combinations: “low income + non-permanent employment” (lift = 3.895) for the low-sleep group; “married + moderate income + non-permanent employment + patient conflict” for the moderate group; and “high income + low psychological distress” buffering night-shift effects in the high-sleep group. By integrating LPA and ARM, this study reveals the multidimensional heterogeneity and interactive mechanisms underlying clinical nurses’ sleep quality. The findings support a stratified intervention framework combining institutional safeguards with precision strategies to enhance sleep health management in nursing populations. Show less

The mammalian microtubule-associated serine/threonine (MAST) kinases are a highly conserved subfamily of AGC kinases that are implicated as therapeutic targets for cancer and diabetes. However, the activity, regulation, and substrates of MAST kinases are poorly understood. We examined the biochemical activity of Mast2, as a representative of the MAST family. The domain of unknown function (DUF1908) is necessary for Mast2 kinase activity in vitro, while the PDZ domain is dispensable. Mast2 kinase activity does not appear to be compatible with the AGC kinase model of T-loop phospho-activation. Instead, it contains a unique insertion that is likely stabilized by ion-pair interactions. The C terminus of the kinase domain contains motifs regulated by mechanistic target of rapamycin (mTOR) in other AGC kinases, and mutation of these conserved residues reduces Mast2 kinase activity. Consistent with mTOR regulation, Mast2 purified from insulin-stimulated cells has increased activity compared to serum-starved cells, and this increase in activity is dependent on mTOR. Finally, stable Show less

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, Show less

Continuous glucose monitoring (CGM) offers a unique opportunity to assess Q6 glucose patterns across the 24-hour day, including nighttime. In individuals with pregnancy hyperglycemia, evidence suggests that optimizing nocturnal glucose levels reduces the risk of large-for-gestational-age births and future metabolic dysfunction. However, the behavioral correlates of nocturnal glucose levels remain poorly understood. Continuous movement devices assess physical activity (PA) and sedentary behavior (SED) across 24-hour days, and to the best of our knowledge, have not been paired with CGM data in individuals with pregnancy hyperglycemia. This secondary analysis of a feasibility trial explored the association of day-time PA and SED with nighttime (i.e., 12-6 AM) interstitial glucose levels in individuals with gestational diabetes mellitus (GDM) or gestational glucose intolerance (GGI). Participants (N = 13; ~31 weeks gestation) wore a Dexcom G6 CGM and ActiGraph Insight Watch for 7 days. Mixed effects models examined associations between daytime moderate-tovigorous physical activity (MVPA), light physical activity (LPA), and sedentary behavior (SED) with nocturnal glucose metrics, including mean glucose, time in range (TIR; 60-99 mg/dL), and area under the curve (AUC). Adjusted models revealed that each 10-minute increase in MVPA was associated with 0.86 mg/dL [95% confidence interval (CI) 0.002, 1.73] higher mean glucose and 313 mg/ dL*min (CI 0.98, 624.55) higher AUC. No associations were observed for total activity, LPA, or SED. These findings illustrate the feasibility and potential of combining CGM with activity monitor data, and the need to further integrate dietary intake data. Improvements in glucose and activity monitoring technology hold great promise for improving scientific and clinical understanding and supporting the development of personalized, data-driven glucose management tools during pregnancy. Show less

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a leading cause of hypertrophic cardiomyopathy (HCM). Although most cMyBP-C mutations produce truncated proteins and cause HCM via haploinsufficiency, the mechanisms by which missense mutations result in disease remain poorly understood. Here, we have evaluated three mutations in immunoglobulin-like domains C1 (P161S, Y237S) and C2 (P371R), predicted to be pathogenic for HCM, assessing their effects on cMyBP-C actin-binding function, protein thermal stability, and residue mobility. Using a fluorescence lifetime-based actin-binding assay, we found that N-terminal mutants P161S, Y237S, and P371R enhanced C0-C2 interactions with actin in both unphosphorylated and phosphorylated states, suggesting that the mutations strengthen actin binding and make the binding resistant to phosphorylation-mediated regulation. Differential scanning calorimetry revealed that mutants exhibit destabilized thermal melting profiles with reduced unfolding temperature, energy, and cooperativity. Molecular dynamics simulations indicated that these mutations induce allosteric effects, increasing fluctuations of unstructured loops in C1 or C2 that contain key actin-binding residues. These alterations in protein stability and residue mobility may promote domains to visit binding-competent conformations more frequently, reduce the energetic cost of complex formation, and/or expose actin-interacting interfaces, thereby enhancing C0-C2 binding and contributing to HCM pathogenesis. Show less

GLP-1 has become a prime target for medical treatment due to its significant therapeutic efficacy. However, the activation mechanisms of class B1 GPCRs, including glucagon-like peptides (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), remain poorly understood. This study focuses on understanding the activation mechanisms of the GLP-1 receptor (GLP-1R) by investigating its conformational changes from activated/inactivated to inactivated/activated states. By analyzing the dynamic conformational changes of the receptor during activation, a closure-open transition in the extracellular domain (ECD) and a movement trend of the transmembrane helices are observed, which indicates a similarity to the activation mechanism of class A GPCRs. Furthermore, the binding characteristics of a dual agonist Tirzepatide (LY3298176) is studied in detail and it is revealed that the conserved residues contribute in a similar fashion toward binding to both GLP-1R and GIPR. Mutations in non-conserved residues in Tirzepatide affect the binding affinity, with C-terminal mutations weakening the binding affinity toward GLP-1R, while N-terminal mutations enhancing the affinity to GIPR, resulting in a biased binding mode. These findings enriched our fundamental understanding of GLP-1R/GIPR activation and provided theoretical guidance for the design and development of future peptide-based agonists and offer insights into the optimization of other dual or multi-target agonists. Show less

A library of 39 amino-benzoxazole derivatives, selected from 57 benzoxazole compounds in the NCI database, was evaluated for their potential as KDR inhibitors using computational docking methods, including CDocker, LibDock, and AutoDock Vina. At a screening concentration of 100 µM, 11 compounds demonstrated over 40% KDR inhibition, with six showing notable activity. The IC50 values of the top six compounds ranged from 6.855 to 50.118 µM, with compound 1 showing the highest inhibitory activity (IC Show less

The cardio-ankle vascular index (CAVI) is a physiological marker that indicates systemic arterial stiffness, and several reports have demonstrated its usefulness as a predictor of cardiovascular disease (CVD). However, there have been no studies examining the clinical significance of CAVI limited to elderly patients with obesity. This prospective study aimed to determine the clinical significance of CAVI as a CVD risk factor in Japanese elderly patients with obesity. This study included a total of 402 Japanese elderly patients with obesity (mean age ± standard deviation: 72 ± 5 years; mean body mass index ± standard deviation: 27.6 ± 2.2 kg/m Group H showed a significantly higher visceral fat area, as measured by abdominal computed tomography, compared to group L. A significant relation with biomarkers, such as homeostasis model assessment of insulin resistance (HOMA-IR); preheparin serum lipoprotein lipase mass (pre-LPL mass) concentration, one of the coronary risk factors; and urinary 8-iso-prostaglandinF2α (U-8-iso-PGF2α) concentration, an indicator of oxidative stress The results of this study indicated that the CAVI increases in the presence of visceral fat accumulation and is significantly associated with key CVD risk factors, such as insulin resistance, low pre-LPL mass, and elevated oxidative stress in Japanese elderly patients with obesity. Furthermore, high CAVI is considered a useful predictor of primary CVD events in such patients. Show less

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Accurate differentiation between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) is critical for informing personalized therapies. Thyroid transcription factor-1 (TTF-1) and p40 are traditionally regarded as mutually exclusive markers of ADC and SCC, respectively. However, a subset of tumors exhibits co-expression of TTF-1 and p40, presenting diagnostic challenges and suggesting underlying biological distinctiveness. This study aimed to characterize the clinicopathological, molecular, and immunohistochemical features of NSCLCs co-expressing TTF-1 and p40, in order to clarify their biological and clinical significance. A retrospective analysis was performed on NSCLC cases diagnosed at the Central Clinical Hospital of the Medical University of Łódź between May 2021 and November 2022. Clinicopathological and survival data were collected. Tumors co-expressing TTF-1 and p40 underwent immunohistochemical evaluation and RNA/DNA-based next-generation sequencing (NGS). Of 94 NSCLC cases analyzed, 18 (19.1%) demonstrated co-expression of TTF-1 and p40. These tumors were significantly more likely to exhibit solid growth patterns compared to control cases (P=0.03), but no significant difference in overall survival (OS) was observed (P=0.46). Among 17 samples subjected to NGS, genetic alterations were identified in 15 (88.2%) cases, with NSCLCs co-expressing TTF-1 and p40 appear to represent a biologically distinct and poorly differentiated subgroup, frequently associated with Show less

The melanocortin-4 receptor is a G protein-coupled receptor and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2, a single transmembrane helix protein known to interact with several different G protein-coupled receptors. However, the consequences of this interaction are not completely understood. Here we report that co-expression of melanocortin-receptor accessory protein 2 has multiple effects on the melanocortin-4 receptor: it enhances G protein-mediated signaling and simultaneously impairs β-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of melanocortin-receptor accessory protein 2 leads to an increased number of monomers of melanocortin-4 receptor by disrupting receptor oligomers. A structural homology model of the active state melanocortin-4 receptor - melanocortin-receptor accessory protein 2 - Gα Show less