👤 Sumaithangi Thattai Arun Kumar

The tumor microenvironment (TME) is a highly dynamic network shaped by immune, vascular, and stromal interactions, further modulated by extracellular factors. The high tumor heterogeneity complicates treatment due to evolving resistance. Biodynamic imaging (BDI), a 3D coherence-gated holography technique, quantifies intracellular motion to assess phenotypic responses to therapy. We applied BDI to prostate cancer (PCa) treated with IL-27-based combinations to evaluate the dynamic responses of immunotherapy. This study is the first to integrate BDI with RNA-seq to correlate physiological changes with gene expression. Using a subcutaneous PCa model, tumors were treated ex vivo with chemotherapy and immunomodulatory agents. BDI enabled capturing motion frequency shifts (0.01-12.5 Hz), while RNA-seq revealed the molecular changes in the tumors. IL-27 showed potential to modulate the immunologically "cold" TME and enhance therapeutic efficacy. This integrative approach offers a novel platform for evaluating combination strategies in PCa and may inform more effective treatment decisions. Show less

Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2α expression in resistant tumor cells through inducing c-Myc. cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2α loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2α, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2α effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer. Show less

Glaucoma is a leading cause of irreversible blindness, normally associated with dysfunction and degeneration of the trabecular meshwork (TM) as the primary cause. Trabecular meshwork stem cells (TMSCs) have emerged as promising candidates for TM regeneration toward glaucoma therapies, yet their molecular characteristics remain poorly defined. In this study, we performed a comprehensive transcriptomic comparison of human TMSCs and human TM cells (TMCs) using RNA sequencing and microarray analyses, followed by qPCR validation. A total of 465 differentially expressed genes were identified, with 254 upregulated in TMSCs and 211 in TMCs. A functional enrichment analysis revealed that TMSCs are associated with development, immune signaling, and extracellular matrix remodeling pathways, while TMCs are enriched in structural, contractile, and adhesion-related functions. A network topology analysis identified Show less

Background & objectives Central TB division facilitated development of a line probe assay (LPA) artificial intelligence (AI) tool. The tool was developed, trained, and validated for performance by collecting more than 18,000 LPA strips across culture and drug susceptibility Testing (C&DST) laboratories. The Indian Council of Medical Research (ICMR)-National Institute for Research in Tuberculosis (NIRT) evaluated the LPAAI tool independently. The objective was to establish and verify an AI-driven system for automatically interpreting LPA strips, which are employed in tuberculosis drug resistance screening, to improve accuracy, consistency, and scalability across diverse laboratory settings. Methods The AI system integrates faster regions convolutional neural network (FR-CNN) for strip detection, detection transformer (DETR) for band localisation, and a hierarchical neural network (HNN) for classification of bands, loci, and drug labels. Independent validation was conducted by ICMR-NIRT using 2810 first-line (FL)-LPA and 241 reflex second-line (SL-LPA) across ten intermediate reference laboratories (IRLs). Results AI comparative models demonstrated an accuracy range of 92-100 per cent, with sensitivity between 80-100 per cent and specificity from 86-100 per cent for the tub, rpoB, katG, InhA, gyrA/gyrB,rrs, and eisgenes. The overall F1 score varies from 0.81 to 1.00, indicating perfect precision and recall. Interpretation & conclusions This AI system offers a novel, modular architecture capable of expert-level interpretation of LPA strips. The AI tool performs at par with expert readers and offers a reliable, scalable solution for LPA interpretation.AI tool adoption can reduce interpretation time, enhance result uniformity, and improve treatment delivery across India's TB programme, supporting national goals for TB elimination. Show less

Multidrug-resistant tuberculosis continues to be a major threat to mankind and is a major social and economic burden to society. Line probe assay (LPA) is a method for detecting Mycobacterium tuberculosis (MTb) in combination with resistance to rifampicin and isoniazid by first-line LPA, resistance to fluoroquinolones (FQ) and second-line injectable drugs (SLID) by second-line LPA in sputum smear-positive specimens (direct testing) and cultured isolates (indirect testing). LPA uses a DNA-based reverse hybridization method, which determines the drug resistance profile through the pattern of binding of DNA amplicons to probes that target specific areas of the MTb genome for MTb detection and to most common mutations conferring resistance to various drugs and/or the corresponding wild-type DNA sequence. LPA is endorsed by the National Tuberculosis Elimination Programme (NTEP), but very limited data are available, especially from high-burden areas such as Bihar, where a rapid, accurate, cost-effective technique like LPA can play a crucial role in early diagnosis and initiation of treatment and ultimately contribute to the effective elimination of the disease. This cross-sectional study was performed at Indira Gandhi Institute of Medical Sciences, Patna, a tertiary care centre, and aimed at the molecular characterization of Rifampicin resistant tuberculosis (RR-TB) isolates using the line probe assay method. The study was conducted between November 2022 and May 2024 with 116 samples obtained from both pulmonary tuberculosis(PTB) and extrapulmonary tuberculosis(EPTB) cases that were found to be rifampicin-resistant on CBNAAT (Cartridge based nucleic acid amplification test-Gene Xpert Mtb/RIF). In this study, 116 patients were enrolled, of whom 80(68.9 %) were pre-XDR-TB cases and 36(31 %) were MDR-TB cases. The most common pattern of mutation associated with rifampicin rpoB gene was WT8 MUT3 S531L and, Isoniazid inhA gene was WT1 MUT1 c-15 t. High-level isoniazid resistance involving KatG mutation was present in 111 (95.7 %) cases and the most common mutation associated was MUT1 -S315T1. Overall prevalence of fluoroquinolone resistance in this study was 68.9 %. There is a wide prevalence of high-level isoniazid resistance and fluoroquinolone resistance among RR-TB patients, indicating the rapid emergence and transmission of resistant strains in the community. This underscores the need for enforced interventions, such as screening for MDR-TB before starting therapy and surveillance of fluoroquinolone susceptibility. Molecular characterization of RR-TB strains by Line probe assay method can play a critical role in the rapid determination of pattern of resistance in the circulating strains and hence guide tailored therapy at the earliest opportunity especially in high burden setting with limited infrastructure. Show less

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

Lung cancer is one of the most common cancer and the leading cause of cancer-related death worldwide. Early detection of lung cancer can help reduce the death rate; therefore, the identification of potential biomarkers is crucial. Thus, this study aimed to identify potential biomarkers for lung cancer by integrating bioinformatics analysis and machine learning (ML)-based approaches. Data were normalized using the robust multiarray average method and batch effect were corrected using the ComBat method. Differentially expressed genes were identified by the LIMMA approach and carcinoma-associated genes were selected using Enrichr, based on the DisGeNET database. Protein-protein interaction (PPI) network analysis was performed using STRING, and the PPI network was visualized using Cytoscape. The core hub genes were identified by overlapping genes obtained from degree, betweenness, closeness, and MNC. Moreover, the MCODE plugin for Cytoscape was used to perform module analysis, and optimal modules were selected based on MCODE scores along with their associated genes. Subsequently, Boruta-based ML approach was utilized to identify the important genes. Consequently, the core genes were identified by the overlapping genes obtained from PPI networks, module analysis, and ML-based approach. The prognostic and discriminative power analysis of the core genes was assessed through survival and ROC analysis. We extracted five datasets from USA cohort and three datasets from Taiwan cohort and performed same experimental protocols to determine potential biomarkers. Four genes (LPL, CLDN18, EDNRB, MME) were identified from USA cohort, while three genes (DNRB, MME, ROBO4) were from Taiwan cohort. Finally, two biomarkers (EDNRB and MME) were identified by intersecting genes, obtained from USA and Taiwan cohorts. The proposed biomarkers can significantly improve patient outcomes by enabling earlier detection, precise diagnosis, and tailored treatment, ultimately contributing to better survival rates and quality of life for patients. Show less

Many traditional treatments include honey owing to its magnificent health beneficiary effects. Recent studies have demonstrated the potent anti-diabetic activity of honey. However, its actual mechanism of action remains elusive. Moreover, being rich in sugar (75%-80%), its role in maintaining glucose homeostasis remains questionable. Although the polyphenol content of honey aids its hypoglycaemic activity, the small quantity of bioactive compounds in honey (0.5%-1.0%) may not be solely responsible for this. In the current study, an attempt was made to understand the role of Indian lychee honey (LyH) in regulating blood glucose levels under diabetic conditions. This study investigated whether LyH, although rich in sugars, can be used as an alternative to regulate glucose and lipid homeostasis under insulin-resistant conditions by regulating the ChREBP/Glut4 signalling pathway. This study was first performed Show less

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder characterized by left ventricular hypertrophy and variable clinical manifestations, including asymptomatic states and sudden cardiac death (SCD). Data on its phenotype and genotype in the Indian population remain limited. We studied 113 patients diagnosed with HCM. All underwent clinical assessment, 24-h Holter monitoring, echocardiography, and cardiac MRI. Genetic testing was performed in 80 patients. Clinical and imaging features were compared between genotype-positive and genotype-negative groups. The mean age was 47 ± 10.8 years, with 82.6 % being males. Dyspnoea and chest pain were the most frequent symptoms. Obstructive HCM was seen in 70 (61.9 %) patients. Cardiac MRI showed late gadolinium enhancement >15 % in 13 (23.2 %) and apical aneurysms in 2 (3.5 %). Genetic mutations were detected in 40 (50 %) patients, with MYBPC3 (33 %) and MYH7 (26.8 %) being most common. Genotype-positive individuals more frequently had chest pain, a family history of SCD, and more severe hypertrophy. In this Indian HCM cohort, the condition predominantly affected males. Genotype-positive patients exhibited more severe hypertrophy and adverse clinical profiles, underscoring the importance of genetic screening in risk stratification. Show less

The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/autophagy by stabilizing and sequestering KIT in the paranuclear compartment via binding VPS39. KIT engaged with phosphorylated BECN1, thereby enhancing its association with BCL2 while diminishing its interaction with the PIK3C3 complex. This process ultimately resulted in the suppression of autophagy. Depletion of KIT triggered both autophagy and apoptosis, and decreased LT expression. Conversely, blocking autophagy in KIT-depleted cells restored LT levels and rescued apoptosis. Additionally, stimulating autophagy efficiently increased cell death and inhibited tumor growth of MCC xenografts in mice. These insights into the interplay between MCPyV LT and autophagy regulation reveal important mechanisms by which viral oncoproteins are essential for MCC cell viability. Thus, autophagy-inducing agents represent a therapeutic strategy in advanced MCPyV-associated MCC. Show less

Centrioles have a unique, conserved architecture formed by three linked, 'triplet', microtubules arranged in ninefold symmetry. The mechanisms by which these triplet microtubules are formed remain unclear but likely involve the noncanonical tubulins delta-tubulin and epsilon-tubulin. Previously, we found that human cells lacking delta-tubulin or epsilon-tubulin form abnormal centrioles, characterized by an absence of triplet microtubules, lack of central core protein POC5, and a futile cycle of centriole formation and disintegration (Wang et al., 2017). Here, we show that human cells lacking either TEDC1 or TEDC2 have similar abnormalities. Using ultrastructure expansion microscopy, we observed that mutant centrioles elongate to the same length as control centrioles in G2 phase and fail to recruit central core scaffold proteins. Remarkably, mutant centrioles also have an expanded proximal region. During mitosis, these mutant centrioles further elongate before fragmenting and disintegrating. All four proteins physically interact and TEDC1 and TEDC2 can form a subcomplex in the absence of the tubulins, supporting an AlphaFold Multimer model of the tetramer. TEDC1 and TEDC2 localize to centrosomes and are mutually dependent on each other and on delta-tubulin and epsilon-tubulin for localization. Our results demonstrate that delta-tubulin, epsilon-tubulin, TEDC1, and TEDC2 function together to promote robust centriole architecture, laying the foundation for future studies on the mechanisms underlying the assembly of triplet microtubules and their interactions with centriole structure. Show less

Mutations in Cullin-3 (CUL3) cause hypertension (HTN). We examined the role of smooth muscle cell (SMC) CUL3 in the regulation of renin gene expression. Mice with SMC-specific CUL3 deletion (S-CUL3-KO) developed severe HTN with paradoxically preserved levels of plasma angiotensin peptides and renal renin expression. Cre-recombinase was active in juxtaglomerular (JG) cells, resulting in decreased CUL3 expression. We evaluated components of the renin cell baroreceptor and revealed preserved Lamin A/C but decreased integrin β1 expression in S-CUL3-KO. We hypothesized that Rab proteins are involved in integrin β1 downregulation. Silencing either Rab21 or Rab5 in CUL3-deficient HEK293 cells increased integrin β1 protein. Coimmunoprecipitation revealed a direct interaction between Rab5 and CUL3. CUL3 deficiency increased Rab5, suggesting it is regulated by a CUL3-mediated mechanism and that CUL3 deficiency results in loss of Rab protein turnover, leading to enhanced integrin β1 internalization. We conclude that the loss of integrin β1 from JG cells impairs the mechanosensory function of the renin cell baroreceptor, which underlies the persistent renin expression observed in hypertensive S-CUL3-KO mice. These findings provide insights into the molecular mechanisms of HTN, revealing that dysregulation of Rab proteins and integrin β1 in the kidney due to CUL3 deficiency contributes to the development of HTN. Show less

Cervical Cancer is the second most common gynecological malignancy affecting a large group of women worldwide. The molecular mechanism of cervical cancer progression is still not very clear. As a result, diagnosis of cervical cancer occurs at a very advanced stage when the disease has spread to its malignant stage, causing death in the majority of women. EMT is a major culprit associated with the malignant transformation of tumor cells during cancer progression and metastasis. Hence, identification of new biomarkers to detect cervical cancer at an early stage is essential to minimize incidence and mortality. The present study aims to identify Common Differentially Expressed Genes (DEGs) and early biomarkers associated with EMT in cervical cancer. The Datasets were downloaded from the Gene Expression Omnibus (GEO) database, with Accession numbers GSE26511, GSE67522, and GSE9750. Then, the Gene Ontology (GO), KEGG pathway enrichment analysis, and protein-protein interactions (PPI) were done. Further hub genes were identified by molecular interaction networks using Cytoscape from the constructed network of DEGs. Afterwards, survival analysis was performed to assess the prognostic significance of eight hub genes associated with EMT in cervical cancer. A total of 11,339 overlapping DEGs were identified from all three datasets, among all the total 61 DEGS, and 8 hub genes were linked to the EMT pathway. Our study suggests that these eight hub genes, CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2, may be critically associated with EMT progression. Among the eight identified EMT hub genes, CDH2 (N-cadherin) demonstrated a significant association with overall survival, while FN1 (fibronectin) was notably linked to disease-free survival, underscoring their prognostic value in cervical cancer. Based on these findings, our study suggests that CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2 hold potential diagnostic and prognostic significance in the progression of cervical cancer. Show less

Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD) are severe psychiatric conditions that share overlapping clinical symptoms, yet they differ in their underlying molecular mechanisms. Despite extensive research, the biological foundations of these disorders remain incompletely understood. In this study, we performed a large-scale transcriptomic analysis by integrating 557 publicly available RNA-seq datasets from post-mortem brain tissues, spanning multiple regions, to better understand the shared and distinct molecular features of these disorders. Using systematic bioinformatic approaches, we identified differentially expressed genes (DEGs) and investigated associated biological pathways, regulatory transcription factors, and drug-gene interactions. Our analysis revealed notable overlap in gene expression profiles, particularly between SCZ and BD, suggesting common molecular pathways underlying these disorders. At the same time, each disorder also demonstrated unique transcriptional patterns, supporting the existence of disorder-specific mechanisms. Brain region-specific analyses further highlighted spatial heterogeneity in gene expression, with significant differences observed in regions such as the hippocampus and dorsolateral prefrontal cortex (DLPFC). The transcription factor enrichment analysis revealed distinct regulatory programs driving each disorder: MDD pathology appears regulated by ASCL3, MYOG, HNF1B, RUNX3, FOXA1 and STAT4; BD exhibited predominant control by immune-regulatory factors including FOSL1, FOSL2, PLSCR1, RELB, BATF3, IRF and NFKB1; while SCZ demonstrated unique regulation through ATF5, CREB3L3, SNAI1, NFIL3, CEBPB, RELB and IRF transcription factors. Moreover, our drug-gene interaction analysis uncovered promising therapeutic targets, with several differentially expressed genes showing potential for drug repurposing, particularly in relation to antipsychotics and immunomodulatory agents. Our comprehensive transcriptomic analysis reveals both shared molecular mechanisms and distinct immune signatures across schizophrenia, bipolar disorder, and major depressive disorder, advancing our understanding of psychiatric pathophysiology while highlighting the heterogeneous nature of these conditions. These findings establish a critical foundation for developing targeted, patient-specific therapeutic interventions that address the underlying biological complexity of major psychiatric disorders. Show less

Parkinson's disease (PD) is a genetically complex neurodegenerative disorder. Up to 15% of cases are considered monogenic. However, research on monogenic PD has largely focused on populations of European ancestry, leaving gaps in our understanding of genetic variability in other populations. This study addresses this gap by analysing the allele frequencies of pathogenic and likely pathogenic variants in known monogenic PD genes across eight global populations, using data from the gnomAD database. We compiled a list of 27 genes associated with Mendelian PD from the Online Mendelian Inheritance in Man (OMIM) database, and identified pathogenic and likely pathogenic variants using ClinVar. We then performed pairwise comparisons of allele frequencies across populations included in the gnomAD database. Variants with significant frequency differences were further assessed using in silico pathogenicity predictions. We identified 81 variants across 17 genes with statistically significant allele frequency differences between at least two populations. Variants in Our findings reveal substantial population-specific differences in the allele frequencies of pathogenic variants linked to monogenic PD, emphasising the need for broader genetic studies beyond European populations. These insights have important implications for PD research, genetic screening, and understanding the pathogenesis of PD in diverse populations. Show less

The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important physiological roles including glucose homeostasis and appetite suppression. Stabilized agonists of the GLP-1 receptor (GLP-1R) and dual agonists of GLP-1R and GIP receptor (GIPR) for the management of type 2 diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase-4 (DPP4), that catalyzes rapid removal of the two N-terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide makes them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza-amino acids, that are bioisosteric replacements for α-amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza-amino acid can populate the same conformational space that GLP-1 adopts when bound to the GLP-1R. The insertion of an aza-amino acid at the second position from the N-terminus in semaglutide and in a dual agonist of GLP-1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variation that may influence downstream signaling. Show less

Glucose-dependent insulinotropic peptide (GIP) is a 42-amino acid peptide hormone that regulates postprandial glucose levels. GIP binds to its cognate receptor, GIPR, and mediates metabolic physiology by improved insulin sensitivity, β-cell proliferation, increased energy consumption, and stimulated glucagon secretion. Dipeptidyl peptidase-4 (DPP4) catalyzes the rapid inactivation of GIP within 6 min Show less

Variants in melanocortin 4 receptor ( We compared the severity of obesity and cardiometabolic risk markers in children with A retrospective chart review was performed in children with obesity who underwent multigene panel testing for monogenic obesity. Data on a total of 104 children were examined, with 93 (89%) identified as White. Thirty-nine (37.5%) patients had clinically reported variants in the Variants in the Show less

Familial hypercholesterolemia (FH) is a frequently underdiagnosed genetic disorder characterized by elevated low-density lipoprotein (LDL) levels. Genetic testing of LDLR, APOB, and PCSK9 genes can identify variants in up to 80% of clinically diagnosed patients. However, limitations in time, scalability, and cost have hindered effective next-generation sequencing of these genes. Additionally, pharmacogenomic variants are associated with statin-induced adverse effects in FH patients. To address these challenges, we developed a multiplex primer-based amplicon sequencing approach for FH genetic testing. Multiplex primers were designed for the exons of the LDLR, APOB, and PCSK9 genes, as well as for pharmacogenomic variants rs4149056 (SLCO1B1:c.521T > A), rs2306283 (SLCO1B1:c.388A > G), and rs2231142 (ABCG2:c.421C > A). Analytical validation using samples with known pathogenic variants and clinical validation with 12 FH-suspected probands were conducted. Library preparation was based on a bead-based tagmentation method, and sequencing was conducted on the NovaSeq 6000 platform. Our approach ensured no amplicon dropouts, with over 100× coverage on each amplicon. Known variants in 2 samples were successfully detected. Further, we identified one heterozygous LDLR (p.Glu228Ter) variant and 2 homozygous cases of LDLR (p.Lys294Ter) and LDLR (p.Ser177Leu) variants in patients. Pharmacogenomic analysis revealed that overall 3 patients may require reduced statin doses. Our approach offered reduced library preparation time (approximately 3 h), greater scalability, and lower costs (under $50) for FH genetic testing. Our method effectively sequences LDLR, APOB, and PCSK9 genes including pharmacogenomic variants that will guide appropriate screening and statin dosing, thus increasing both efficiency and affordability. Show less

Gallbladder cancer (GBC) is a common gastrointestinal malignancy noted for its aggressive characteristics and poor prognosis, which is mostly caused by delayed detection. However, the scarcity of information regarding somatic mutations in Indian patients with GBC has hampered the development of efficient therapeutic options. In the present study, the authors attempted to bridge this gap by revealing the mutational profile of GBC. To evaluate the somatic mutation profile, whole exome sequencing (WES) was performed on 66 tumor and matched blood samples from individuals with GBC. Somatic variant calling was performed using GATK pipeline. Variants were annotated at pathogenic and oncogenic levels, using ANNOVAR, VEP tools and the OncoKB database. Mutational signature analysis, oncogenic pathway analysis and cancer driver genes identification were performed at the functional level by using the maftools package. Our findings focused on the eight most altered genes with pathogenic and oncogenic mutations: TP53, SMAD4, ERBB3, KRAS, ARID1A, PIK3CA, RB1, and AXIN1. Genes with pathogenic single nucleotide variations (SNVs) were enriched in oncogenic signaling pathways, particularly RTK-RAS, WNT, and TP53 pathways. Furthermore, our research related certain mutational signatures, such as cosmic 1, cosmic 6, and cosmic 18, 29, to known characteristics including patient age and tobacco smoking, providing important insights into disease etiology. Given the scarcity of exome-based sequencing studies focusing on the Indian population, this study represents a significant step forward in providing a framework for additional in-depth mutational analysis. Genes with substantial oncogenic and pathogenic mutations are promising candidates for developing targeted mutation panels, particularly for GBC detection. Show less

Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviates intestinal pathologies in mice suffering from colitis. Deficiency of RelB:p52 diminishes transcription of Axin1, a critical component of the β-catenin destruction complex, reinforcing β-catenin-dependent expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid synthesis. DC-specific impairment of noncanonical NF-κB signaling leads to increased colonic numbers of Tregs and IgA+ B cells, which promote luminal IgA production and foster eubiosis. Experimentally introduced β-catenin haploinsufficiency in DCs with deficient noncanonical NF-κB signaling moderates Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, inflammatory bowel-disease patients also display a deleterious noncanonical NF-κB signaling signature in intestinal DCs. In sum, we establish how noncanonical NF-κB signaling in dendritic cells can subvert retinoic acid synthesis to fuel intestinal inflammation. Show less

Despite significant research efforts, Alzheimer's disease (AD), the primary cause of dementia in older adults worldwide, remains a neurological challenge for which there are currently no effective therapies. There are substantial financial, medical, and personal costs associated with this condition.Important pathological features of AD include hyperphosphorylated microtubule-associated protein Tau, the formation of amyloid β (Aβ) peptides from amyloid precursor protein (APP), and continuous inflammation that ultimately results in neuronal death. Important histological markers of AD, amyloid plaques, and neurofibrillary tangles are created when Aβ and hyperphosphorylated Tau build-up. Nevertheless, a thorough knowledge of the molecular players in AD pathophysiology is still elusive. Recent studies have shown how noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate gene expression at the transcriptional and posttranscriptional levels in a variety of diseases, including AD. There is increasing evidence to support the involvement of these ncRNAs in the genesis and progression of AD, making them promising as biomarkers and therapeutic targets. As a result, therapeutic approaches that target regulatory ncRNAs are becoming more popular as potential means of preventing the progression of AD. This review explores the posttranscriptional relationships between ncRNAs and the main AD pathways, highlighting the potential of ncRNAs to advance AD treatment. In AD, ncRNAs, especially miRNAs, change expression and present potential targets for therapy. MiR-346 raises Aβ through APP messenger Ribonucleic Acid (mRNA), whereas miR-107 may decrease Aβ by targeting beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). They are promising early AD biomarkers due to their stability in cerebrospinal fluid (CSF) and blood. Furthermore, additional research is necessary to determine the role that RNA fragments present in AD-related protein deposits play in AD pathogenesis. Show less

As per the National Survey on Drug Use and Health, 10.5% of Americans aged 12 years and older are suffering from alcohol use disorder, with a wide range of neurological disorders. Alcohol-mediated neurological disorders can be linked to Alzheimer's-like pathology, which has not been well studied. We hypothesize that alcohol exposure can induce astrocytic amyloidosis, which can be corroborated by the neurological disorders observed in alcohol use disorder. In this study, we demonstrated that the exposure of astrocytes to ethanol resulted in an increase in Alzheimer's disease markers-the amyloid precursor protein, Aβ1-42, and the β-site-cleaving enzyme; an oxidative stress marker-4HNE; proinflammatory cytokines-TNF-α, IL1β, and IL6; lncRNA BACE1-AS; and alcohol-metabolizing enzymes-alcohol dehydrogenase, aldehyde dehydrogenase-2, and cytochrome P450 2E1. A gene-silencing approach confirmed the regulatory role of lncRNA BACE1-AS in amyloid generation, alcohol metabolism, and neuroinflammation. This report is the first to suggest the involvement of lncRNA BACE1-AS in alcohol-induced astrocytic amyloid generation and alcohol metabolism. These findings will aid in developing therapies targeting astrocyte-mediated neurological disorders and cognitive deficits in alcohol users. Show less

Steroidal alkaloids are secondary metabolites that are often found in plants, fungi and sponges. These compounds are considered as a source of bioactive compounds for the treatment of chronic diseases, such as neurological disorder like Alzheimer's disease (AD). Some examples of alkaloid derivatives currently used to treat AD symptoms include galantamine, huperzine A, and other alkaloids. AD is a multifactorial disease caused by multiple factors such as inflammation, oxidative stress, and protein aggregation. Based on the various important neuroprotective activities and different pharmacological effects of steroidal alkaloids with polypharmacological modulatory effects, they can lead to the development of new drugs for the treatment of AD. There are limited studies on the involvement of steroidal alkaloids in AD. Therefore, the mechanisms and neuroprotective abilities of these compounds are still poorly understood. The purpose of this review article is to provide an overview of the mechanism, toxicity and neuroprotective benefits of steroidal alkaloids and to discuss future possibilities to improve the application of steroidal alkaloids as anti-AD agents. The therapeutic value and limitations of the steroidal alkaloid are investigated to provide new perspectives for future clinical development studies. Show less

The β-secretase β-site APP cleaving enzyme (BACE1) is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, nonhuman primates, and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for safer prevention of Alzheimer's disease. Show less

The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and β-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aβ aggregation inhibition in a self- and AChE-induced Aβ aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aβ-induced cognitive deficits in the Aβ-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aꞵ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aβ and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD. Show less

Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), β secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Aβ aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC Show less