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Diffuse midline gliomas with H3 K27-alteration (DMGH3) are lethal and inoperable brain tumors. Although DMGH3s mainly occur in pediatric patients, they have also occurred in adult patients. This study aimed to analyze the clinicopathological significance of targetable genetic alterations in non-pediatric DMGH3. Next-generation sequencing (NGS) was conducted on 18 non-pediatric DMGH3 patients to analyze additional genetic alterations. The median age at diagnosis was 35 years, and the mean follow-up duration was 762 days. Fourteen cases involved the thalamus-hypothalamus (77.8%). Histologic high-grade features (WHO histologic grade ≥ 3) were observed in 11 (61.1%) patients. H3F3A (H3 K27 M) alterations were identified in all 18 patients using immunohistochemistry and NGS. TP53 mutations were found in 11 patients (61.1%), FGFR1 or PIK3CA in 3 (16.7%), ATRX in 6 (33.3%), NF1 in 4 (22.2%), and KRAS or ATM in 1 (5.6%). TP53 mutations were significantly correlated with high-grade histological features and worse overall survival (OS) (P < 0.05). Despite non-pediatric DMGH3 cases exhibiting superior OS compared to pediatric DMGH3 cases, TP53 mutations were associated with poorer OS outcomes. Notably, FGFR1 and PIK3CA mutations, which have been identified as potential targetable genes, were detected. In conclusion, non-pediatric DMGH3s showed predominant tumor localization within the thalamus and improved prognosis compared to those in pediatric cases, with TP53 alterations correlating with high-grade histology and shorter survival. Genetic profiling, particularly identifying targetable mutations like FGFR1 and PIK3CA, could inform personalized treatment strategies and improve patient outcomes. Show less

Tumor suppressors are well known drivers of cancer invasion and metastasis in metastatic castration sensitive prostate cancer (mCSPC). However, oncogenes are also known to be altered in this state, however the frequency and prognosis of these alterations are unclear. Thus, we aimed to study the spectrum of oncogene mutations in mCSPC and study the significance of these alteration on outcomes. Four hundred and seventy-seven patients with mCSPC were included who underwent next generation sequencing. Oncogene alterations were defined as mutations in A total of 477 patients were included with baseline characteristics with 117 patients (24.5%) harbored a mutation within an oncogene. A total of 172 oncogene mutations were found within the population with the most common being Oncogenes are frequency mutated in mCSPC and associated with aggressive features and inferior outcomes. Future work will need to validate these results to better assess its significance in allowing for personalization of care. Show less

Trends in the development of genetic markers for the purposes of genomic and marker-assisted selection primarily focus on identifying causative polymorphisms. Using these polymorphisms as markers enables a more accurate association between genotype and phenotype. Bioinformatic analysis allows calculating the impact of missense polymorphisms on the structural and functional characteristics of proteins, which makes it promising for identifying causative polymorphisms. In this study, a bioinformatic approach is applied to evaluate and differentiate polymorphisms based on their causality in genes that affect the production traits of pigs and cows, which are two important livestock species. The influence of both known causative and candidate missense polymorphisms in the MC4R, NR6A1, PRKAG3, RYR1, and SYNGR2 genes of pigs, as well as the ABCG2, DGAT1, GHR, and MSTN genes of cows, was assessed. The study included an evaluation of the effect of polymorphisms on protein functions, considering the evolutionary and physicochemical characteristics of amino acids at polymorphic sites. Additionally, it examined the impact of polymorphisms on the stability of tertiary protein structures, including changes in folding, binding of protein monomers, and interaction with ligands. The comprehensive bioinformatic analysis used in this study enables the differentiation of polymorphisms into neutral, where both amino acids in the polymorphic site do not significantly affect the structure and function of the protein, and causative, where one of the amino acids significantly impacts the protein's properties. This approach can be employed in future research to screen extensive sets of polymorphisms in animal genomes, identifying the most promising polymorphisms for further investigation in association studies. Show less

In this study, we developed an economical treatment process for highly acidic effluents from steel rolling mills containing toxic heavy metals. Our method involves a pH-dependent approach using mining waste and hydrated lime. The treatment occurs in two steps: First, metal oxides precipitate at pH 3-3.5 using mining waste, followed by lime precipitation at pH 9-9.5. The process, completed in less than 6 h without heavy machinery, reduces sludge formation by extracting high-purity gypsum, a valuable industrial product. Water quality posttreatment matches local groundwater standards. Compared to conventional methods like common effluent treatment plant (CETP) in Jodhpur, India, our approach reduces operational costs by over 58%. In this study, we also characterized the by-product formed, that is, gypsum using various characterization tools and performed a detailed cost analysis. PRACTITIONER POINTS: A quick, efficient, and economical treatment process for extremely acidic (pH ~ 1) wastewater from steel industries. Stepwise treatment strategy without involving heavy machinery or high manpower. Processed water quality closely resembles groundwater with all the major heavy metals been removed. Sludge quantity reduced by regeneration of pure gypsum (96% purity). Reduced the overall operation cost of effluent treatment by 58%. Show less

Obesity is increasingly prevalent worldwide, with genetic factors contributing to its development. The hypothalamic leptin-melanocortin pathway is central to the regulation of appetite and weight; leptin activates the proopiomelanocortin neurons, leading to the production of melanocortin peptides; these in turn act on melanocortin 4 receptors (MC4R) which suppress appetite and increase energy expenditure. MC4R mutations are responsible for syndromic and non-syndromic obesity. These mutations are classified based on their impact on the receptor's life cycle: Show less

Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging. [BMB Reports 2024; 57(9): 417-423]. Show less

Lipid metabolism disorders are frequently noted in atopic dermatitis (AD) patients, prompting the long-term use of lipid-lowering drugs. However, the causal effects of circulating lipids and different lipid-lowering drugs on the risk of AD are not thoroughly understood. Using publicly available genome-wide association studies (GWAS) summary data from two different cohorts, a series of Mendelian randomization (MR) analyses were conducted to explore the causal effects of genetically proxied circulating lipids and lipid-lowering drugs on the risk of AD. Statistically, the random-effects inverse-variance-weighted (IVW) model was used as main analysis and several methods were conducted for sensitivity analysis to test the robustness of our results. Our findings revealed reduced risks of AD related to genetically proxied subtilisin/kexin type 9 (PCSK9) inhibition and lipoprotein lipase (LPL) agonist, while an increased AD risk associated with Niemann-Pick C1-like 1 (NPC1L1) inhibition. Circulating lipids and other drug targets did not show significant associations with AD risk. These results were replicated in the validation cohort; sensitivity analyses confirmed the robustness. This MR study suggests that, independent of circulating lipids, the use of PCSK9 inhibitors and LPL agonists may be associated with a decreased risk of AD, while inhibition of NPC1L1 is implicated in an increased risk. These findings may help optimize personalized selection of lipid-lowering drugs for AD patients and those at risk of AD. Show less

Alzheimer's disease (AD) is marked by cognitive decline, amyloid plaques, neurofibrillary tangles, and cholinergic loss. Due to the limited success of amyloid-targeted therapies, attention has shifted to new non-amyloid targets like phosphodiesterases (PDE). This study investigates the potential of Phytocompounds and derivatives were screened for drug-likeness, toxicity, BBB permeability, and ADME profiles. Molecular docking was conducted with PDE5A, BACE-1, and AChE, followed by molecular dynamics (MD) simulations on the best binding complexes. 8-Prenyldaidzein, a derivative of daidzein, demonstrated favorable drug-likeness and ADME properties. It exhibited strong binding to PDE5A, BACE-1, and AChE, with MD simulations confirming stable protein-ligand interactions. The multi-target potential of 8-Prenyldaidzein, particularly through non-amyloid pathways, offers a promising approach to AD therapy. Its inhibition of PDE5A, BACE-1, and AChE could address multiple aspects of AD pathology. 8-Prenyldaidzein shows strong potential as a multi-target inhibitor for AD treatment. While in-silico findings are promising, further experimental validation is needed to confirm its clinical applicability. Show less

METTL3, an m6A methyltransferase, is integral to the regulation of messenger RNA (mRNA) biogenesis, degradation, and translation through the N6-methyladenosine (m6A) modification. Alterations in m6A homeostasis have been implicated in the development, progression, invasion, and metastasis of certain cancers. The present research aims to examine the consequences of METTL3 knockdown using short hairpin RNA (shRNA) on the proliferation and invasive capabilities of human colorectal and melanoma cancer cell lines. A specific shRNA against METTL3 mRNA was designed and inserted into an expression vector. Highly invasive colorectal cancer cell line SW480 and melanoma cell line A375 were cultured and transfected by METTL3-shRNA and scramble-control vectors and kept under culture condition for 2 weeks. The cells were harvested for analysis of gene expression by quantitative polymerase chain reaction (qPCR), invasion assay using three-dimensional (3D) spheroid assay and cell cycle and apoptosis analyses. In the METTL3-shRNA transfected cells, the expression of METTL3, VIM, SNAI1, SNAI2, ZEB1, CDH1, and TGFB1 genes were downregulated significantly compared with the scramble-control transfected cells. Expression of b-catenin, N-cadherin, vimentin, ZEB1, pro- and active MMP2, OCT4A, SOX2, and MYC proteins were also downregulated following METTL3 knockdown. Transfection by METTL3-shRNA reduced proliferation rate of the cells and increased the apoptotic rate significantly. Both migration and invasion rate of the cancer cells transfected with METTL3-shRNA were significantly decreased. These findings highlight the pro-oncogenic function of METTL3 in colorectal and melanoma cancer cells, indicating that inhibiting METTL3 could be a promising approach for tumor suppression across multiple cancer types; nonetheless, further investigation is essential to confirm these observations. Show less

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor-GLP-1 receptor (GIPR-GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist-GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil-induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity. Show less

The poultry industry is significantly impacted by viral infections, particularly Newcastle Disease Virus (NDV), which leads to substantial economic losses. It is essential to comprehend how the sequence of development affects biological pathways and how early exposure to infections might affect immune responses. This study employed transcriptome analysis to investigate host-pathogen interactions by analyzing gene expression changes in NDV-infected chicken embryos' lungs. RNA-Seq reads were aligned with the chicken reference genome (Galgal7), revealing 594 differentially expressed genes: 264 upregulated and 330 downregulated. The most overexpressed genes, with logFC between 8.15 and 8.75, included C8A, FGG, PIT54, FETUB, APOC3, and FGA. Notably, downregulated genes included BPIFB3 (-4.46 logFC) and TRIM39.1 (-4.26 logFC). The analysis also identified 29 novel transcripts and 20 lncRNAs that were upregulated. Gene Ontology and KEGG pathways' analyses revealed significant alterations in gene expression related to immune function, metabolism, cell cycle, nucleic acid processes, and mitochondrial activity due to NDV infection. Key metabolic genes, such as ALDOB (3.27 logFC), PRPS2 (2.66 logFC), and XDH (2.15 logFC), exhibited altered expression patterns, while DCK2 (-1.99 logFC) and TK1 (-2.11 logFC) were also affected. Several immune-related genes showed significant upregulation in infected lung samples, including ALB (6.15 logFC), TLR4 (1.86 logFC), TLR2 (2.79 logFC), and interleukin receptors, such as IL1R2 (3.15 logFC) and IL22RA2 (1.37 logFC). Conversely, genes such as CXCR4 (-1.49 logFC), CXCL14 (-2.57 logFC), GATA3 (-1.51 logFC), and IL17REL (-2.93 logFC) were downregulated. The higher expression of HSP genes underscores their vital role in immune responses. Comprehension of these genes' interactions is essential for regulating viral replication and immune responses during infections, potentially aiding in the identification of candidate genes for poultry breed improvement amidst NDV challenges. Show less

The most common cause of death in patients with peripheral artery disease (PAD) are major adverse cardiovascular events (MACEs), including myocardial infarction (MI) and stroke. However, data on biomarkers that could be used to help predict MACEs in patients with PAD to guide clinical decision making is limited. Angiogenesis-related proteins have been demonstrated to play an important role in systemic atherosclerosis and may act as prognostic biomarkers for MACEs in patients with PAD. In this study, we evaluated a large panel of angiogenesis-related proteins and identified specific biomarkers associated with MACEs in patients with PAD. We conducted a prognostic study using a prospectively recruited cohort of 406 patients (254 with PAD and 152 without PAD). Plasma concentrations of 22 circulating angiogenesis-related proteins were measured at baseline, and the cohort was followed for 2 years. The primary outcome was 2-year MACEs (composite of MI, stroke, or death). Plasma protein concentrations were compared between PAD patients with and without 2-year MACEs using Mann-Whitney U tests. Differentially expressed proteins were further investigated in terms of their prognostic potential. Specifically, Cox proportional hazards analysis was performed to determine the independent association between differentially expressed proteins and 2-year MACEs, controlling for all baseline demographic and clinical characteristics, including existing coronary artery disease and cerebrovascular disease. Kaplan-Meier analysis was conducted to assess 2-year freedom from MACEs in patients with low vs. high levels of the differentially expressed proteins based on median plasma concentrations. The mean age of the cohort was 68.8 (SD 11.1), and 134 (33%) patients were female. Two-year MACEs occurred in 63 (16%) individuals. The following proteins were significantly elevated in PAD patients with 2-year MACEs compared to those without 2-year MACEs: endostatin (69.15 [SD 58.15] vs. 51.34 [SD 29.07] pg/mL, Among a panel of 22 angiogenesis-related proteins, endostatin, ANGPTL4, and ANGPTL3 were identified to be independently and specifically associated with 2-year MACEs in patients with PAD. Measurement of plasma concentrations of these proteins can support MACE risk stratification in patients with PAD, thereby informing clinical decisions on multidisciplinary referrals to cardiologists, neurologists, and vascular medicine specialists and guiding aggressiveness of medical treatment, thereby improving cardiovascular outcomes in patients with PAD. Show less

Insulin resistance is considered the most important key mechanism in the development of nonalcoholic fatty liver disease (NAFLD). Some studies have reported that hyperinsulinemia decreases the hepatic secretion of apolipoprotein (Apo) B. Chronic hyperinsulinemia in NAFLD may be responsible for the accumulation of triglycerides in hepatocytes. We aimed to investigate whether apolipoproteins are related to histological findings in patients with biopsy-proven NAFLD. We also aimed to evaluate the effects of obesity on apolipoproteins and the pathogenesis of NAFLD. In this cross-sectional study, 91 patients with biopsy-proven NAFLD were included. The control group consisted of 39 healthy subjects who had no history of liver disease or alcohol consumption and were matched for age, gender and smoking. Apoliprotein A1 and Apo B were measured via an immunoturbidimetric method with commercially available OSR6142 Apo A1 and OSR6143 Apo B immunoassay kits on an Olympus AU2700 analyzer. Age, gender, and smoking distribution were similar among nonalcoholic steatohepatitis patients, simple steatosis patients, and controls. The differences in the mean Apo A1 and Apo B levels and the Apo B/A1 ratio among non-alcoholic steatosis, simple steatosis, and control subjects did not reach statistical significance. In addition, patients with obese NAFLD had higher steatosis scores than patients with nonobese NAFLD (p<0.05). Apo A1 and B levels and the B/A1 ratio were not associated with histopathological findings in patients with NAFLD. Fibrosis and ApoB1/A were found to be independent risk factors for metabolic associated fatty liver disease. In addition, obesity increases the grade of hepatic steatosis but does not cause lobular inflammation, ballooning or fibrosis. Show less

Bullous pemphigoid (BP) and prurigo nodularis (PN) are chronic pruritic skin diseases that severely impact patients' quality of life. Despite the widespread attention these two diseases have garnered within the dermatological field, the specific pathogenesis, particularly the molecular mechanisms underlying the pruritus, remains largely unclear. Limited clinical sequencing studies focusing on BP and PN have hindered the identification of pathological mechanisms and the exploration of effective treatment strategies. To address this gap, we collected a total of 23 peripheral blood mononuclear cell samples from BP and PN patients, as well as healthy controls, and performed RNA sequencing analysis. By integrating bioinformatics and machine learning techniques, we aimed to uncover the shared immune regulatory networks and pruritus-related mechanisms between BP and PN. Our study identified 161 differentially expressed genes shared between BP and PN, which were primarily enriched in immune activation and neural pathways, providing crucial molecular insights into the pruritus-related mechanisms of both diseases. Furthermore, using the machine learning algorithms of support vector machines and random forest, we pinpoint 7 crucial genes shared between the BP and PN databases. Among these, IL-27 emerged as a potential pivotal gene, as its mRNA expression levels strongly correlated with clinical parameters including pruritus scores, immunoglobulin E levels, and eosinophil counts. Validation experiments conducted on clinical samples from an additional 22 participants confirmed the upregulation of IL-27 expression in both BP and PN lesions. This study is the first to unveil the shared inflammatory and immune pathways common to BP and PN, highlighting the critical role of IL-27 in the pathogenesis of these conditions. Our findings not only enhance the understanding of the intricate relationship between BP and PN, but also provide a foundation for the development of novel therapeutic strategies targeting these two dermatological conditions. Show less

Major depression is classified into distinct subtypes: simple (SDMD) and major dysmood disorder (MDMD). MDMD patients exhibit elevated atherogenicity and decreased reverse cholesterol transport (RCT). However, comprehensive data regarding lipid metabolism is absent in first episode (FE)-SDMD. In this case-control study, plasma lipid levels, lecithin-cholesterol acyltransferase (LCAT), free cholesterol, apolipoprotein (Apo)A1, ApoB, and ApoE are compared between academic students with first episode SDMD (FE-SDMD) (n = 44) or SDMD (n = 64) and control students (n = 44), after excluding those with metabolic syndrome (MetS). LCAT is decreased, and free cholesterol and ApoE increased in subjects with SDMD and FE-SDMD as compared with controls. There were no significant alterations in high-density lipoprotein cholesterol (HDLc), ApoA1, RCT, ApoB and triglycerides in SDMD. LCAT, free cholesterol and atherogenicity indices are significantly associated with suicidal behaviors and the SDMD phenome. The effects of LCAT on those phenome features is completely mediated by free cholesterol and brooding. SDMD and FE-SDMD patients without signs of subclinical MetS show lowered LCAT and increased free cholesterol as compared with normal controls. There are significant interactions between the SDMD and FE-SDMD diagnosis and subclinical MetS, which result in decreased HDLc and RCT, and an increased ApoB/ApoA ratio. FE-SDMD and SDMD are pre-proatherogenic states, because of decreased LCAT, and increased free cholesterol and ApoE, and their intersections with subclinical MetS. These aberrations may drive atherogenicity, and activation of peripheral and central oxidative, neuro-immune, and degenerative pathways. Individuals with FE-SDMD should be screened and treated for increased atherogenicity risk by measuring free cholesterol and ApoE. Show less

Cutaneous squamous cell carcinoma (CSCC) is a malignant skin tumor characterized by the abnormal proliferation of keratinocytes. Immune cells have a very important role in the development of CSCC. Hence, it was vital to screen the immune cell-related biomarkers for the treatment of CSCC. Gene set variation analysis (GSVA) and immune infiltration analysis were utilised to obtain key immune cells. Weighted gene co-expression network analysis (WGCNA) was conducted to screen key module genes related to immune cell. At the same time, differential analysis was performed to find the differentially expressed genes (DEGs) between CSCC and normal samples. The candidate genes related to immune cell in CSCC patients were certificated by Venn diagram. Protein-protein interaction (PPI) network and receiver operating characteristic (ROC) curves were selected for identifying biomarkers of CSCC. We further performed immunotherapy analysis between two expression subgroups based on single gene. Following by this, the DRUGBANK database was applied to explore the interactions between biomarkers and available therapeutic agents. Finally, the expression of biomarkers was verified through real-time quantitative polymerase chain reaction (RT-qPCR). A total of 4 key immune cells (M0 macrophages, resting dendritic cells, resting mast cells, and activated mast cells) were identified. Furthermore, we obtained 982 key module genes related to immune cell. Meanwhile, 646 differentially expressed genes (DEGs) were identified. Hence, 63 candidate genes related to immune cell were selected by Venn diagram. Then, we identified six biomarkers (SLC27A2, ACOX2, PECR, CRAT, FADS1 and ELOVL5) were screened. High expression group of biomarkers showed relatively high expression of immune checkpoints. Additionally, we found 10 drugs with potential therapeutic value targeting biomarkers. Eventually, the lower expression of biomarkers in tumor group was observed, which was consistent with the result from public databases. Overall, we obtained six immune cell-related biomarkers (SLC27A2, ACOX2, PECR, CRAT, FADS1 and ELOVL5) associated with CSCC, which laid a theoretical foundation for the treatment of CSCC. Show less

The aim of this study is to screen key target genes of osteoarthritis associated with aging and to preliminarily explore the associated immune infiltration cells and potential drugs. Differentially expressed senescence-related genes (DESRGs) selected from Cellular senescence-related genes (SRGs) and differentially expressed genes (DEGs) were analyzed using Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and protein-protein interaction networks. Hub genes in DESRGs were selected based on degree, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. CIBERSORTx and ssGSEA algorithms were then used to assess immune cell infiltration and to analyse the correlation between key DESRGs and immune infiltration. Finally, a miRNA-gene network of diagnostic genes was constructed and targeted drug prediction was performed. Combined with the DEGs and SRGs, we screened 19 DESRGs for further study. Five diagnostic genes were ultimately identified: CDKN1A, VEGFA, MCL1, SNAI1 and MYC. ROC analysis showed that the area under the curve (AUC). Correlation analysis showed that the five hub genes were closely associated with neutrophil, plasmacytoid dendritic cell, activated CD4 T-cell and type 2 T-helper cell infiltration in the development of Osteoarthritis (OA). Finally, we found that drugs such as lithium chloride, acetaminophen, curcumin, celecoxib and resveratrol could be targeted for the treatment of senescence-related OA. The results of this study indicate that CDKN1A, VEGFA, MCL1, SNAI1, and MYC are key biomarkers that can be used to predict and prevent early aging-related OA. Lithium chloride, acetaminophen, curcumin, celecoxib, and resveratrol can be used for personalized treatment of aging-related OA. Show less

Obesity, by any standard, is a global health crisis. Both genetic and dietary contributions to the development and maintenance of obesity were integral factors of our experimental design. As mutations of the melanocortin 4 receptors (MC4R) are the leading monogenetic cause of obesity, MC4R haploinsufficient rats were fed a range of dietary fat (0-12 %) in a longitudinal design. Physiological and motivational assessments were performed using a locomotor task, a 5-choice sucrose preference task, an operant task with fixed and progressive ratios, as well as a distraction operant task. Dendritic spine morphology of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), cells with ample D1 and D2 receptors, was also assessed. The percentage of lipid deposits in the liver of each rat was also analyzed using the Area Fraction Fractionator probe for stereological measurements. MC4R haploinsufficiency resulted in a phenotypic resemblance for adult-onset obesity that was exacerbated by the consumption of a high-fat diet. Results from the operant tasks indicate that motivational deficits due to MC4R haploinsufficiency were apparent prior to the onset of obesity and exacerbated by dietary fat consumption after obesity was well established. Moreover, MSN morphology shifted to longer spines with smaller head diameters for the MC4R+/- animals under the high-fat diet, suggesting a potential mechanism for the dysregulation of motivation to work for food. Increasing our knowledge of the neural circuitry/mechanisms responsible for the rewarding properties of food has significant implications for understanding energy balance and the development of obesity. Show less

Monoamine oxidase (MAO) inhibitors reduce inflammation in a number of in vitro and in vivo models. This finding led to the development of a novel MAO-B selective inhibitor (RG0216) designed to reduce blood-brain barrier penetration. To elucidate RG0216's regulatory role in inflammation-relevant signaling pathways, we employed a transcriptome analytic approach to identify genes that are differentially regulated by RG0216 and then globally identified which inflammation-relevant biological signaling pathways were altered by this drug. Primary human gingival keratinocyte (HGK) cells were treated with RG0216, and RNA was extracted (4 h). RNAseq transcriptome analysis was utilized to identify differentially expressed genes (DEGs), while Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to identify significantly enriched biological pathways. Relevant genes associated with these pathways and RG0216 regulation of Porphyromonnas gingivalis lipopolysaccharide (PgLPS)-induced cytokine/chemokine expression were evaluated using the real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) approach. RG0216 significantly altered the expression of 50 DEGs in HGK cells. Using GO and KEGG analytic approaches, these genes were associated with the biological pathways relevant to mitogen-activated protein kinase (MAPK) and MAPK phosphatases. These phosphatases are part of the 10-member catalytically active dual-specificity phosphatase (DUSP) family. RG0216 induced the expression of DUSP10, reduced the expression of DUSP4 and DUSP6, and decreased IL-6 and IL-8 expression in control and PgLPS-stimulated cultures. In HGK cells, a novel MAO-B inhibitor (RG0216) significantly altered DUSP4, DUSP6, and DUSP10 expression. DUSPs play a regulatory role in MAPK activity and, therefore, can alter cellular inflammatory responses. We found that RG0216 inhibited IL-6 and IL-8 expression. Further studies are planned to examine RG0216's regulatory role in DUSP expression and its impact on the regulation of cytokine/chemokine expression. Show less

Polyunsaturated fatty acids (PUFAs) including omega-3 and omega-6 are obtained from diet and can be measured objectively in plasma or red blood cells (RBCs) membrane biomarkers, representing different dietary exposure windows. Show less

Carotenoids are dietary bioactive compounds with health effects that are biomarkers of fruit and vegetable intake. Here, we examine genetic associations with plasma and skin carotenoid concentrations in two rigorously phenotyped human cohorts (n=317). Analysis of genome-wide SNPs revealed heritability to vary by genetic ancestry (h Show less

Glaucoma is a leading cause of irreversible blindness, often associated with elevated intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction. Diabetes mellitus (DM) is recognized as a significant risk factor for glaucoma; however, the molecular mechanisms through which hyperglycemia affects TM function remain unclear. This study investigated the impact of high glucose on gene expression in human TM (HTM) cells to uncover pathways that contribute to TM dysfunction and glaucoma pathogenesis under diabetic conditions. Primary HTM cells were cultured under normoglycemic (5.5 mM) and hyperglycemic (30 mM) conditions for seven days, followed by mRNA sequencing (mRNA-seq) to identify differentially expressed genes, with quantitative PCR (qPCR) used for confirmatory analysis. STRING network analysis was performed to predict interactions among upregulated and downregulated proteins. mRNA-seq analysis revealed 25 significantly differentially expressed genes in high glucose conditions, including upregulated genes associated with oxidative stress, apoptosis, autophagy, immune response, and fibrosis. Notably, TXNIP was significantly upregulated, indicating increased oxidative stress and apoptosis in TM cells, while downregulation of autophagy-related genes, such as HSPA6 and LAMP3, suggests compromised protein quality control. Immune response genes, including CCL7 and CHI3L1, were upregulated, suggesting an inflammatory response to oxidative stress. Increased expression of fibrosis-related genes, such as SNAI1, FGF7, and KRT19, supports the hypothesis of ECM accumulation in diabetic conditions, potentially elevating IOP. Chronic hyperglycemia in diabetic patients could therefore lead to TM dysfunction, impair aqueous humor outflow, and elevate IOP, thereby increasing glaucoma risk. Targeting oxidative stress and fibrosis pathways offers therapeutic strategies to mitigate glaucoma progression in diabetic populations. Show less

G-protein-coupled receptors (GPCRs) have emerged as critical regulators of bone development and remodeling. In this study, we aimed to identify specific GPCR mutations in osteoporotic patients via next-generation sequencing (NGS). We performed NGS sequencing of six genomic DNA samples taken from osteoporotic patients and two genomic DNA samples from healthy donors. Next, we searched for single-nucleotide polymorphisms (SNPs) in GPCR genes that are associated with osteoporosis. For three osteoporotic patients and one healthy donor, bone biopsies were used to generate patient-specific mesenchymal stem cell (MSC) lines, and their ability to undergo osteodifferentiation was analyzed. We found that MSCs derived from osteoporotic patients have a different response to osteoinductive factors and impaired osteogenic differentiation using qPCR and histochemical staining assays. The NGS analysis revealed specific combinations of SNPs in GPCR genes in these patients, where SNPs in Show less

Extracranial arteriovenous malformations (eAVMs) are complex vascular lesions characterized by anomalous arteriovenous connections, vascular instability, and disruptions in endothelial cell (EC)-to-mural cell (MC) interactions. This study sought to determine whether eAVM-MCs could induce endothelial-to-mesenchymal transition (EndMT), a process known to disrupt vascular integrity, in the eAVM microenvironment. eAVM and paired control tissues were analyzed using RT-PCR for EC ( Show less

The present study examines the role of morphemic units in the initial word recognition stage among beginning readers. We assess whether and to what extent sublexical units, such as morphemes, are used in processing French words and how their use varies with reading proficiency. Two experiments were conducted to investigate the perceptual and morphological effects on the recognition of words presented in central vision, using a variable-viewing-position technique. To explore changes during elementary school years, we tested children from the second and fourth grades, as well as adult readers. The percentage of correct word identification was highest near the center of the word, indicating an optimal viewing position for all three participant groups. Viewing position effects were modulated by age and the properties of the stimuli (length and morphological structure). Experiment 1 demonstrated that lexical decisions are influenced by morphological structure to a decreasing extent as reading skill develops. Experiment 2 revealed that morphological processing in children primarily relies on the orthographic information provided by morphemes (surface morphology), whereas proficient readers process morphological information at a more abstract level, exhibiting a genuine morphological-facilitation effect. Overall, our study strongly indicates that morphemic units play a crucial role in the initial stage of word identification in early reading development. This conclusion aligns with the "word and affix" model, which posits that morphological representations become increasingly independent of orthography as reading ability and word exposure improve. Show less

The prevalence of obesity is increasing worldwide, affecting both children and adults. This obesity epidemic is mostly driven by an increase in energy intake (abundance of highly palatable energy-dense food and drinks) and to a lesser degree a decrease in energy expenditure (sedentary lifestyle). A small proportion of individuals with obesity are affected by genetic forms of obesity, which often relate to mutations in the leptin-melanocortin pathway or are part of syndromes such as the Bardet-Biedl syndrome. These rare forms of obesity have provided valuable insights into the genetic architecture of obesity. Recent advances in understanding the molecular mechanisms that control appetite, hunger, and satiety have led to the development of drugs that can override genetic defects, enabling precision treatment. Leptin deficiency is uniquely treated with recombinant human metreleptin, while those with LEPR, PCSK1, or POMC deficiency can now be treated with the MC4R agonist setmelanotide. This review highlights the most frequent monogenic and syndromic forms of obesity, and the future outlook of precision treatment for these conditions. Show less

Familial hypercholesterolemia (FH) is a genetic disease, usually with onset during childhood, characterized by elevated blood LDL cholesterol levels and potentially associated with severe cardiovascular complications. Concerning mutated genes in FH, such as Show less

Philadelphia chromosome (Ph)-like B-acute lymphoblastic leukemia (B-ALL) is a clinically significant, high-risk genetic subtype of B-ALL cases. There are few data on the incidence, characterization, and treatment outcomes of Ph-like ALL cases from low- and middle-income countries. There is a pressing need to establish a well-organized/cost-effective approach for identifying Ph-like ALL instances. Multiplex reverse transcriptase polymerase chain reaction, nCounter NanoString, and fluorescence in situ hybridization were used to detect and characterize Ph-like ALL cases among recurrent genetic abnormalities (RGA) Of 130 newly diagnosed B-ALL cases, 25% (BCR::ABL1), 4% (ETV6::RUNX1), 5% (TCF3::PBX1), 2% (KM2TA::AFF1), and 65% RGA This study showed the high incidence of Ph-like ALL cases with kinase activating alterations and treatment outcomes from low- and middle-income region. Furthermore, a surrogate cost-effective multiplex panel of 11 overexpressed genes for the prompt detection of Ph-like ALL cases is proposed. Identification of recurrent gene abnormalities (RGA) Show less

Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variant (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort. We show that this methodology successfully determined all known crSVs detected through routine clinical testing. We also identified crSVs, such as an ins(11;10)(q23.3;p12p12) forming a KMT2A::MLLT10 fusion, missed by routine clinical approaches, resulting in the classification of leukemia genetic subtypes for four additional patients. This study demonstrates the diagnostic potential of lrSeq as an assay for SV detection in pediatric leukemia and supports lrSeq as a valuable tool for the accurate detection of crSVs. Show less

Neonatal sepsis is a significant cause of mortality in children under 5 years of age globally, with the highest incidence reported in India. The challenges in diagnosing neonatal sepsis often result in the irrational use of antibiotics. The aim of the study was to determine the diagnostic efficacy of interleukin 27 (IL-27) as a novel biomarker for the early diagnosis of neonatal sepsis. This prospective cohort study was conducted at a tertiary care hospital in North India from May 2019 to April 2020. Eighty neonates suspected of sepsis were enrolled based on the sepsis screen criteria approved by the National Neonatal Forum of India. Blood samples were collected for culture and biomarker analysis, with C-reactive protein (CRP), procalcitonin (PCT), and IL-27 levels measured. The diagnostic performance of IL-27 was compared to that of CRP and PCT. Out of 80 neonates, 56% were male and 44% were female. Blood cultures were positive in 51.2% of cases. The most common pathogens isolated were Gram-negative bacteria (41%), fungi (34%), and Gram-positive bacteria (25%). IL-27 demonstrated a sensitivity of 78.05%, specificity of 61.54%, positive predictive value of 68.09%, and negative predictive value (NPV) of 72.73%. In comparison, PCT showed the highest sensitivity (82.93%), and CRP had the highest specificity (79.49%). IL-27 levels were notably higher in blood culture-positive cases. IL-27 is a promising biomarker for the early diagnosis of neonatal sepsis, showing comparable sensitivity and NPV to PCT, but with lower specificity than CRP. Show less