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Selenoprotein P (SELENOP) acts as a crucial mediator, distributing selenium from the liver to other tissues within the body. Despite its established role in selenium metabolism, the specific functions of SELENOP in the development of liver cancer remain enigmatic. This study aims to unravel SELENOP's associations in hepatocellular carcinoma (HCC) by scrutinizing its expression in correlation with disease characteristics and investigating links to hormonal and lipid/triglyceride metabolism biomarkers as well as its potential as a prognosticator for overall survival and predictor of hypoxia. SELENOP mRNA expression was analyzed in 372 HCC patients sourced from The Cancer Genome Atlas (TCGA), utilizing statistical methodologies in R programming and machine learning techniques in Python. SELENOP expression significantly varied across HCC grades ( Show less

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking, and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years [standard deviation (SD) = 15.1]. Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE-LE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved. Show less

Congenital myasthenic syndromes (CMSs) are genetic disorders affecting motor function with variable symptoms. RAPSN-related CMS, caused by mutations in the RAPSN gene, leads to muscle weakness. Accurate diagnosis is essential for proper management. This study aims to analyze six Iranian families affected by RAPSN-CMS, focusing on clinical manifestations, genetic variants, treatment response, and outcomes. Clinical assessments, genetic analysis, and whole-exome sequencing were performed on the six families to identify RAPSN gene mutations. The study examined symptoms, disease severity, age of onset, treatment response, and outcomes. Treatment with pyridostigmine and salbutamol was given to assess its effectiveness. Three homozygous known variants in RAPSN gene were identified: c.491G > A in three families, c.264 C > A in two families, and c.-210 A > G in one family. Clinical assessments showed diversity in symptoms and treatment responses. Pyridostigmine and salbutamol treatment improved symptoms and quality of life. This study highlights the significance of molecular diagnosis for RAPSN-related congenital myasthenic syndromes (CMS) in Iran, marking the first comprehensive genetic analysis in the region. The identification of specific pathogenic variants underscores the unique genetic landscape of local patients. Furthermore, our long-term follow-up revealed variable treatment responses, emphasizing the need for personalized care strategies. The clinical variability among patients with identical mutations necessitates a multidisciplinary approach for effective management. By enhancing genetic awareness and refining follow-up methods, we aim to improve diagnosis accuracy and interventions, fostering better outcomes for affected families in the Iranian population. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D. Show less

In humans, 15 genes encode the class B1 family of GPCRs, which are polypeptide hormone receptors characterized by having a large N-terminal extracellular domain (ECD) and receive signals from outside the cell to activate cellular response. For example, the insulinotropic polypeptide (GIP) stimulates the glucose-dependent insulinotropic polypeptide receptor (GIPR), while the glucagon receptor (GCGR) responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen to induce the production of insulin. The glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) elicit a response from glucagon-like peptide receptor types 1 and 2 (GLP1R and GLP2R), respectively. Since these receptors are implicated in the pathogenesis of diabetes, studying their activation is crucial for the development of effective therapies for the condition. With more structural information being revealed by experimental methods such as X-ray crystallography, cryo-EM, and NMR, the activation mechanism of class B1 GPCRs becomes unraveled. The available crystal and cryo-EM structures reveal that class B1 GPCRs follow a two-step model for peptide binding and receptor activation. The regions close to the C-termini of hormones interact with the N-terminal ECD of the receptor while the regions close to the N-terminus of the peptide interact with the TM domain and transmit signals. This review highlights the structural details of class B1 GPCRs and their conformational changes following activation. The roles of MD simulation in characterizing those conformational changes are briefly discussed, providing insights into the potential structural exploration for future ligand designs. Show less

The association between Apolipoprotein A5 (APOA5) genetic polymorphisms and susceptibility to metabolic syndrome (MetS) has been established by many studies, but there have been conflicting results from the literature. We performed a meta-analysis of observational studies to evaluate the association between APOA5 gene polymorphisms and the prevalence of MetS. PubMed, Web of Science, Embase, and Scopus were searched up to April 2024. The random effects model was used to estimate the odds ratios (ORs) and 95% confidence intervals (CI) of the association between APOA5 gene polymorphisms and the prevalence of MetS development. The potential sources of heterogeneity were evaluated by subgroup analyses and sensitivity analyses. A total of 30 studies with 54,986 subjects (25,341 MetS cases and 29,645 healthy controls) were included. The presence of rs662799 and rs651821 polymorphisms is associated with an approximately 1.5-fold higher likelihood of MetS prevalence (OR = 1.42, 95% CI: 1.32, 1.53, p < 0.001; I The present findings suggest that polymorphisms located in the promoter and coding regions of the APOA5 gene are associated with an increased prevalence of MetS in the adult population. Identifying individuals with these genetic variations could lead to early disease detection and the implementation of preventive strategies to reduce the risk of MetS and its related health issues. However, because the sample size was small and there was evidence of significant heterogeneity for some APOA5 gene polymorphisms, these results need to be confirmed by more large-scale and well-designed studies. Show less

Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss of function variants in one of five known canonical genes involved in chylomicron lipolysis and clearance- Show less

The plant cell wall is a dynamic structure that plays an essential role in development, but the mechanism regulating cell wall formation remains poorly understood. We demonstrate that two transcription factors, SlERF.H5 and SlERF.H7, control cell wall formation and tomato fruit firmness in an additive manner. Knockout of SlERF.H5, SlERF.H7, or both genes decreased cell wall thickness, firmness, and cellulose contents in fruits during early development, especially in double-knockout lines. Overexpressing either gene resulted in thicker cell walls and greater fruit firmness with elevated cellulose levels in fruits but severely dwarf plants with lower gibberellin contents. We further identified that SlERF.H5 and SlERF.H7 activate the cellulose biosynthesis gene SlCESA3 but repress the gibberellin biosynthesis gene GA20ox1. Moreover, we identified a conserved LPL motif in these ERFs responsible for their activities as transcriptional activators and repressors, providing insight into how bifunctional transcription factors modulate distinct developmental processes. Show less

Long-term treatment with bisphosphonates is accompanied by an increased risk of medication-related osteonecrosis of the jaw (MRONJ). Currently, no clinically useful biomarkers for the predictive diagnosis of MRONJ are available. To investigate the potential key proteins involved in the pathogenesis of MRONJ, a proteomic LC-MS/MS analysis of saliva was performed. Differentially expressed proteins (DEPs) were analyzed using BiNGO, ClueGO, cytoHubba, MCODE, KEGG, and ReactomeFI software packages using Cytoscape platforms. In total, 1545 DEPs were identified, including 43 up- and 11 down-regulated with a 1.5-fold cut-off value and Show less

Transitions between the fed and fasted state are common in mammals. The liver orchestrates adaptive responses to feeding/fasting by transcriptionally regulating metabolic pathways of energy usage and storage. Transcriptional and enhancer dynamics following cessation of fasting (refeeding) have not been explored. We examined the transcriptional and chromatin events occurring upon refeeding in mice, including kinetic behavior and molecular drivers. We found that the refeeding response is temporally organized with the early response focused on ramping up protein translation while the later stages of refeeding drive a bifurcated lipid synthesis program. While both the cholesterol biosynthesis and lipogenesis pathways were inhibited during fasting, most cholesterol biosynthesis genes returned to their basal levels upon refeeding while most lipogenesis genes markedly overshoot above pre-fasting levels. Gene knockout, enhancer dynamics, and ChIP-seq analyses revealed that lipogenic gene overshoot is dictated by LXRα. These findings from unbiased analyses unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot. Show less

Preeclampsia (PE) is a complex and multifaceted obstetric syndrome characterized by several distinct molecular subtypes. It complicates up to 5% of pregnancies and significantly contributes to maternal and newborn morbidity, thereby diminishing the long-term quality of life for affected women. Due to the widespread dissatisfaction with the effectiveness of existing approaches for assessing PE risk, there is a pressing need for ongoing research to identify newer, more accurate predictors. This study aimed to investigate early changes in the maternal serum proteome and associated signaling pathways. The levels of 125 maternal serum proteins at 11-13 weeks of gestation were quantified using liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) with the BAK-125 kit. Ten serum proteins emerged as potential early markers for PE: Apolipoprotein M (APOM), Complement C1q subcomponent subunit B (C1QB), Lysozyme (LYZ), Prothrombin (F2), Albumin (ALB), Zinc-alpha-2-glycoprotein (AZGP1), Tenascin-X (TNXB), Alpha-1-antitrypsin (SERPINA1), Attractin (ATRN), and Apolipoprotein A-IV (APOA4). Notably, nine of these proteins have previously been associated with PE in prior research, underscoring the consistency and reliability of our findings. These proteins play key roles in critical molecular processes, including complement and coagulation cascades, platelet activation, and insulin-like growth factor pathways. To improve the early prediction of PE, a highly effective Support Vector Machine (SVM) model was developed, analyzing 19 maternal serum proteins from the first trimester. This model achieved an area under the curve (AUC) of 0.91, with 87% sensitivity and 95% specificity, and a hazard ratio (HR) of 13.5 (4.6-40.8) with Show less

Foam cell formation is a hallmark of atherosclerosis, yet the cellular complexity within foam cells in human plaques remains unexplored. Here, we integrate published single-cell RNA-sequencing, spatial transcriptomic, and chromatin accessibility sequencing datasets of human atherosclerotic lesions across eight distinct studies. Through this large-scale integration of patient-derived information, we identified foamy macrophages enriched for genes characteristic of the foamy signature. We further re-clustered the foamy macrophages into five unique subsets with distinct potential functions: (i) pro-foamy macrophages, exhibiting relatively high inflammatory and adhesive properties; (ii) phagocytic foamy macrophages, specialized in efferocytosis; (iii) high-efflux foamy macrophages marked by high Show less

Miro proteins are universally conserved mitochondrial calcium-binding GTPases that regulate a multitude of mitochondrial processes, including transport, clearance, and lipid trafficking. The exact role of Miro in these functions is unclear but involves binding to a variety of client proteins. How this binding is operated at the molecular level and whether and how it is important for mitochondrial health, however, remains unknown. Here, we show that known Miro interactors-namely, CENPF, Trak, and MYO19-all use a similar short motif to bind the same structural element: a highly conserved hydrophobic pocket in the first calcium-binding domain of Miro. Using these Miro-binding motifs, we identified direct interactors de novo, including MTFR1/2/1L, the lipid transporters Mdm34 and VPS13D, and the ubiquitin E3-ligase Parkin. Given the shared binding mechanism of these functionally diverse clients and its conservation across eukaryotes, we propose that Miro is a universal mitochondrial adaptor coordinating mitochondrial health. Show less

Local metabolic demand within cells varies widely and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of MICOS, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery that we term "METEORs". METEORs have a unique composition; MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca Show less

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer and currently lacks effective biomarkers. This research aims to analyze and identify RNA editing profile associated with ccRCC prognosis through bioinformatics and Transcriptome data and clinical information for ccRCC were retrieved from the TCGA database, and RNA editing files were obtained from the Synapse database. Prognostic models were screened, developed, and assessed using consistency index analysis and independent prognostic analysis, etc. Internal validation models were also constructed for further evaluation. Differential genes were investigated using GO, KEGG, and GSEA enrichment analyses. Furthermore, qPCR was performed to determine gene expression in human renal tubular epithelial cells HK-2 and ccRCC cells A-498, 786-O, and Caki-2. An RNA editing-based risk score, that effectively distinguishes between high and low-risk populations, has been identified. It includes CHD3| chr17:7815229, MYO19| chr17:34853704, OIP5-AS1| chr15:41590962, MRI1| chr19:13883962, GBP4| chr1:89649327, APOL1| chr22:36662830, FCF1| chr14:75203040 edited sites or genes and could serve as an independent prognostic factor for ccRCC patients. qPCR results showed significant up-regulation of CHD3, MYO19, MRI1, APOL1, and FCF1 in A-498, 786-O, and Caki-2 cells, while the expression of OIP5-AS1 and GBP4 was significantly down-regulated. RNA editing site-based prognostic models are valuable in differentiating between high and low-risk populations. The seven identified RNA editing sites may be utilized as potential biomarkers for ccRCC. Show less

Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background. The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort. In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform. In univariate analysis, The study indicates that there is an association between Show less

To explore the differential regulation mechanism of heat stress on the egg production performance and egg quality of Jinding ducks, 200 Jinding ducks (360-day-old) in good health and with similar body weights and a normal appetite were selected and randomly divided into a control (normal temperature [NT]) group (20°C-25°C) and a heat stress (HS) group (32°C-36°C), with 4 replicates in each group and 25 ducks in each replicate. The pretrial period was 1 wk, and the formal trial period was 4 wk. At the end of the 4th wk, 12 duck eggs were collected from each replicate to determine egg quality. Pituitary and ovarian tissues of Jinding ducks were collected, transcriptome sequencing was performed to screen differentially expressed miRNAs and mRNAs related to high temperature and heat stress, and a competitive endogenous RNA regulatory network was constructed. The sequencing data were verified by qRT‒PCR method. The following results were obtained: (1) Compared with the NT group, the HS group had a significantly lower laying rate, total egg weight, average egg weight, total feed intake, and feed intake per duck (P < 0.01), an extremely significantly higher feed-to-egg ratio (P < 0.01), and a higher mortality rate. (2) Compared with the NT group, the HS group had an extremely significantly lower egg weight, egg yolk weight, eggshell weight, and eggshell strength (P < 0.01) and an extremely significantly lower yolk ratio and eggshell thickness (P < 0.01, P < 0.05); however, there was no significant difference in the egg shape index, Haugh unit or protein height (P > 0.05). (3) A total of 1,974 and 1,202 genes were identified in the pituitary and ovary, respectively, and there were 5 significantly differentially expressed miRNAs. The differentially expressed genes were involved in the arginine and proline metabolism pathways, ether lipid metabolism pathway, and drug metabolism-cytochrome P450 pathway, which are speculated to be related to the egg production performance of Jingding ducks under high-temperature heat stress. (4) Novel₂₂₁ may target the PRPS1 gene to participate in egg production performance; novel₁₆₈ and novel₂₈₉ may target PIGW; novel₂₈₉ may target Q3MUY2; and novel₂₈₉ and novel₂₀₈ may target PIGN or genes that may be related to high-temperature heat stress. (5) In pituitary tissue, upregulated novel₁₄₁ (center of the network) formed a regulatory network with HSPB1 and HSP30A, and downregulated novel₃₆₆ (center of the network) formed a regulatory network with the JIP1 gene. In ovarian tissue, downregulated novel₂₈₉ (center of the network) formed a regulatory network with the ZSWM7, ABI3, and K1C23 genes, novel₂₂₁ formed a regulatory network with the IGF1, BCL7B, SMC6, APOA4, and FARP2 genes, and upregulated novel₄₀ formed a regulatory network with the HA1FF10 gene. In summary, heat stress affects the production performance and egg quality of Jinding ducks by regulating the secretion of endocrine-related hormones and the release of neurotransmitters as well as the expression of miRNAs and mRNAs in pituitary and ovarian tissues. The miRNA‒mRNA regulatory network provides a theoretical basis for the molecular mechanism that regulates the stress response in pituitary and ovarian tissues, egg quality, and production performance under heat stress. Show less

Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of Show less

Organic afterglow materials have drawn increasing attention for their great potential in practical applications. Until now, most of them just show the lifetimes in milliseconds or seconds, while the realization of long persistent luminescence (LPL) lasting for minutes or even hours is difficult. In 2017, Adachi and Kabe successfully realize the LPL with a duration longer than 1 hour in a purely organic system, which can be even comparable to some excellent inorganic materials. However, partially for the unclear structure-property relationship, organic LPL materials are still rather scarce, especially for the stable ones in air or aqueous solution. In this review, we present the recent progress in organic LPL, mainly focusing on the material design strategy and internal mechanism. It is anticipated that the deep understanding can be beneficial for the further development of organic LPL materials with good stability in air and even aqueous phase. Show less

The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We describe our real-life approach of variant reassessment over time and we assess whether inconclusive variants are decreasing in monogenic obesity. We tested for monogenic obesity (genes: LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R) in 101 children/adolescents (11.7 [7.3-13.7] years, 3.6 [3.3-4.0] z-BMI) in Verona and 183 (11.3 [8.4-12.2] years, 3.2 [2.7-3.9] z-BMI) in Naples from January 2020 to February 2023. In March-July 2024 we reassessed the baseline variants by updated software interpretation and literature renavigation. We initially found 20 VUS, 4 Likely Pathogenic (LP), 5 Likely Benign (LB) and 1 benign variant in 33 individuals. At follow-up, 6 VUS were reclassified as benign/LB, one LP as pathogenic and 3 LB as benign. Overall, 10/30 variants (6/18 in Verona, 3/11 in Naples and a variant found in both centres) were reclassified, leading to a less uncertain report for 13 of 33 variant-carrying patients. Monogenic obesity was diagnosed in 3 probands in Verona and 4 in Naples, carrying variants at MC4R or NTRK2. Our variant reassessment was effective to improve classification certainty for the 39% of patients and suggested that the molecular diagnosis of monogenic obesity is becoming more accurate over time. Show less

Breast cancer (BC) is a global health concern with a growing prevalence. Since BC is a heterogeneous cancer, transcriptome analyzes were carried out on breast tumor tissues relative to their corresponding normal tissues in order to identify gene expression signatures and perform meta-analysis. Five expression profiling by array data sets from breast tumor tissues and non-tumor neighboring tissues were retrieved following a search in the GEO database (GSE70947, GSE70905, GSE10780, GSE29044, and GSE42568). Meta-analysis of gene expression using the Network Analyst tool identified common differentially expressed genes and biological pathways in all data sets. Then, the DEGs were analyzed through PPI network construction, gene ontology, and pathway analysis. The detected hub genes underwent Kaplan-Meier (KM) plotter and UALCAN validation. Finally, Real-time PCR analysis was used on BC patients' samples to determine mRNA levels of cAMP signaling pathway members ATP1A2, FXYD1, and ADCY3. Breast tumor tissues showed 710 differentially expressed genes (DEGs), with 392 overexpressed and 318 underexpressed, compared to normal marginal tissues. On the EnrichR library, GO, and KEGG pathway analyses were performed on the DEGs list. Progesterone-mediated oocyte maturation and the NF-kappa B signaling system were upregulated DEGs' top deregulated signaling pathways. In contrast, pathways related to cancer and the cAMP signaling pathway were the most enriched terms for down-regulated genes. Next, Real-time PCR quantification of cAMP signaling cascade members ATP1A2, FXYD1, and ADCY3 was performed on 50 BC tumoral and non-tumoral tissues for validation. Results of meta-analyzed array data sets revealed DEGs representing BC gene signatures, and cAMP signaling pathway members as effective factors in BC. The results of our real-time PCR expression level determination for ATP1A2, FXYD1, and ADCY3 in breast tumor tissues relative to the normal margins contradicted our bioinformatics investigations, which found increased levels for these genes. Of these, only ATP1A2's expression levels were statistically significant. This study focused on identifying gene expression signatures that provide an invaluable source of evidence for BC-related underlying mechanisms to provide new therapeutic targets and biomarkers. Show less

Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. To identify methylation signatures in ACPs regarding clinical presentation and outcome. Clinical and pathology data were collected from 35 patients with ACP (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multidimensional scaling. Statistical associations between clusters and clinical features were achieved using the Fisher test and global biological process interpretations were aided by Gene Ontology enrichment analyses. Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = .0006), hypomethylated in CpG island, non-CpG Island sites, and globally (P < .001), and associated with greater tumor size (24.1 vs 9.5 cm3, P = .04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell adhesion, cytoskeleton organization, and cytokine binding, and cell type-specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. Two clusters of patients with ACP were consistently revealed by unsupervised machine learning methods, with one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment. Show less

Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, little is known about N15 in Alzheimer's disease (AD). The aim of this study was to investigate the effects of N15 on AD and explore the underlying molecular mechanism. AD mice model was established by lateral ventricular injection with Aβ N15 treatment significantly reduced neurocognitive dysfunction, which also significantly activated the expression of PPARα/γ at an optimal dose of 200 mg/kg. Administration of N15 alleviated the formation of Aβ amyloid in the hippocampus of AD mice, enhanced the BDNF mRNA expression, decreased the mRNA and protein levels of PS1 and BACE1, upregulated ADAM10 mRNA and protein levels. N15 exerts its neuroprotective effects through the activation of PPARα/γ and may be a potential drug for the treatment of AD. Show less

Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway. To elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) administration, and AC16 human cardiomyocyte cell subjected to stimulation with high glucose (HG) and palmitic acid (PA). These models were employed to assess the changes in the senescence phenotype of cardiomyocytes and cardiac function following treatment with SGLT2i. Concurrently, we identified ANGPTL4, a key factor contributing to senescence in DCM, using RNA sequencing (RNA-seq) technology and bioinformatics methods. We further clarified ANGPTL4 role in promoting pathological aging of cardiomyocytes induced by hyperglycemia and hyperlipidemia through knockdown and overexpression of the factor, as well as analyzed the impact of SGLT2i intervention on ANGPTL4 expression. Additionally, we utilized chromatin immunoprecipitation followed by quantitative real-time PCR (ChIP-qPCR) to confirm that FOXO1 is essential for the transcriptional activation of ANGPTL4. The therapeutic intervention with SGLT2i alleviated the senescence phenotype in cardiomyocytes of the DCM mouse model constructed by high-fat feeding combined with STZ, as well as in the AC16 model stimulated by HG and PA, while also improving cardiac function in DCM mice. We observed that the knockdown of ANGPTL4, a key senescence-promoting factor in DCM identified through RNA-seq technology and bioinformatics, mitigated the senescence of cardiomyocytes, whereas overexpression of ANGPTL4 exacerbated it. Moreover, SGLT2i improved the senescence phenotype by suppressing the overexpression of ANGPTL4. In fact, we discovered that SGLT2i exert their effects by regulating the upstream transcription factor FOXO1 of ANGPTL4. Under conditions of hyperglycemia and hyperlipidemia, compared to the control group without FOXO1, the overexpression of FOXO1 in conjunction with SGLT2i intervention significantly reduced both ANGPTL4 mRNA and protein levels. This suggests that the FOXO1-ANGPTL4 axis may be a potential target for the cardioprotective effects of SGLT2i. Collectively, our study demonstrates that SGLT2i ameliorate the pathological aging of cardiomyocytes induced by a high glucose and high fat metabolic milieu by regulating the interaction between FOXO1 and ANGPTL4, thereby suppressing the transcriptional synthesis of the latter, and consequently restoring cardiac function. Show less

Cancer stem cells (CSCs) contribute to metastasis and drug resistance to immunotherapy in lung adenocarcinoma (LUAD), so the stemness evaluation of cancer cells is of great significance. The single-cell RNA sequencing (scRNA-seq) data of the GSE149655 dataset were collected and analyzed. Malignant cells were distinguished by CopyKAT. CytoTRACE score of marker genes in malignant cells was counted by CytoTRACE to construct the stemness score formula. Sample stemness score in TCGA was determined by the formula and divided into high-, medium- and low-stemness score groups. LASSO and COX regression analyses were carried out to screen the key genes related to the prognosis of LUAD from the differentially expressed genes (DEGs) in high- and low-stemness score groups and a risk score model was constructed. Seven types of cells were identified from a total of 4 samples, and 193 marker genes of 3455 malignant cells were identified. There were 1098 DEGs between low- and high-stemness score groups of TCGA, of which CPS1, CENPK, GJB3, and TPSB2 constituted gene signatures. The 4-gene signature could independently evaluate LUAD survival in the training and validation sets and showed an acceptable area under the receiver operator characteristic (ROC) curves (AUCs). This study provides insights into the cellular heterogeneity of LUAD and develops a new cancer stemness evaluation indicator and a 4-gene signature as a potential tool for evaluating the response of LUAD to immune checkpoint blockade (ICB) therapy or antineoplastic therapy. Show less