👤 Kiran D Kaur

Chronic Unpredictable Mild Stress (CUMS) is a well-established model for inducing behavioral, cognitive, neurochemical, and metabolic impairments associated with neurobehavioral alterations. This study assessed the neuroprotective, antidepressant, and metabolic regulatory effects of Lonafarnib, a selective farnesyltransferase inhibitor, in mice subjected to chronic unpredictable mild stress (CUMS) for 28 days. The in silico docking analysis revealed encouraging binding energies of Lonafarnib with AChE (- 11.58 kcal/mol), CRF1 (- 10.94 kcal/mol), BDNF (- 5.99 kcal/mol), 5HT1A (- 10.48 kcal/mol), and 5HT2A (- 10.77 kcal/mol). This suggests a potential structural compatibility with cholinergic, serotonergic, neurotrophic, and stress-related proteins as preliminary results which requires experimental validation. The in -vivo study of Lonafarnib (20 or 40 mg/kg, i.p.) were effective in preventing the neurobehavioral alterations in CUMS mice. As, the behavioral evaluations demonstrated that CUMS resulted in anxiety-like behaviors, depressive-like behaviors, and cognitive impairments (p < 0.0001), all of which were significantly alleviated by Lonafarnib, particularly at a dosage of 40 mg/kg. The administration of Lonafarnib resulted in significant improvements in behavioral performance, a reduction in oxidative and inflammatory markers (IL-6, TNF-α), stabilization of HPA-axis related parameters, normalization of corticosterone, glucose, and lipid profiles, along with an increase in BDNF levels. Histological findings also indicated the preservation of neuronal structure within the hippocampus. In conclusion, these findings suggest that Lonafarnib may offer protective advantages against neurobehavioral and metabolic dysfunction caused by CUMS. However, a comprehensive mechanistic validation of prenylation-dependent signaling pathways is essential for further investigation. Show less

Interleukin 1 receptor-associated kinase 1, 4 (IRAK 1/4) inhibitor exerts anti-inflammatory and immuno-modulatory effects; however, its role in high-fat diet-induced vascular dysfunction and cognitive impairment is not known, and therefore investigated in the present study. Animals were fed either a high-fat diet (60% Kcal fat) or a chow diet (10% Kcal fat) for 12 weeks to induce hyperlipidemia and weight gain. High-fat diet-fed animals were then treated with vehicle, IRAK1/4 inhibitor (2.2 mg/kg, i.p.) and a reference drug, Orlistat (20 mg/kg, oral gavage), for 4 additional weeks. Protein levels were assessed by ELISA or Western blotting, and mRNA by RT-PCR. IRAK1/4 inhibitor and reference drug, Orlistat treatment, prevented HFD-induced increase in body weight gain, fasting blood glucose and plasma lipids, improved discrimination between the familiar and the novel arm in the Y-Maze test, alleviated percent avoidance in two-way active avoidance, and freezing percent in contextual fear conditioning test. The treatments attenuated the levels of systemic inflammatory cytokines IL-1β, CRP, as well as TNF-α, IL-6 and protein expression of Iba-1, GFAP, HIF-1α, and restored the BDNF levels in the pre-frontal cortex of HFD-fed treated mice. IRAK 1/4 inhibitor exerted these effects by blocking proteasomal degradation of IκB-α protein in the pre-frontal cortex of HFD-treated mice. In addition, the treatments prevented HFD-induced increase in vascular ICAM-1, VCAM-1, MCP-1, COX-1 and COX-2 mRNA expression, and restored vascular eNOS mRNA levels as well as the Acetylcholine (300 ρM-300 μM) induced relaxations of PE (1 µM) pre-contracted aortic rings. IRAK1/4 inhibitor attenuates HFD-induced inflammation, vascular dysfunction and cognitive impairment in obese mice. Show less

T2D mellitus (T2DM) is increasingly prevalent in South Asia, often affecting individuals with normal BMI, a phenotype described as metabolically obese but normal weight (MONW). While randomized trials demonstrate that low-carbohydrate diets can induce remission, long-term, real-world evidence in non-obese, predominantly vegetarian South Asian populations remains scarce. To evaluate the long-term efficacy and safety of a culturally adapted low-carbohydrate diet in an N-of-1 longitudinal study with systematic, multi-domain follow-up. A 49-year-old male with new-onset T2D (HbA1c 7.2%) began a phased initiation (~100 g/day carbohydrate), nutritional ketosis (<30 g/day carbohydrate), and long-term stabilization (~100 g/day). Assessments included continuous glucose monitoring (CGM) periodically, standardized mixed-meal challenges, advanced lipid and apolipoprotein panels including ApoB and lipoprotein(a) [Lp(a)], hs-CRP, liver and renal function, and serial cardiovascular, skeletal, and ophthalmic imaging over 10-years. The study was monitored through regular physician assessments and follow-up. HbA1c remained between 4.7 and 5.3% without medication for a decade. CGM showed >90% time-in-range with reduced variability (CV decreased from approximately 18-12%), Lp(a) decreased (43.4 → 25.3 mg/dL), and hs-CRP remained <1 mg/L. Coronary artery calcium (CAC) remained 0 across three scans, with CT angiography confirming CAD-RADS 0. CIMT showed no stenosis. Bone mineral density and ophthalmic imaging showed no deterioration. This report offers a detailed N-of-1 longitudinal characterization of decade-long, medication-free remission of T2D in a metabolically obese normal weight South Asian male. Observations at approximately 100 g per day carbohydrate intake suggest that moderate carbohydrate restriction may represent a physiologically plausible and culturally compatible approach for long-term metabolic management in similar phenotypes. While broader applicability requires validation in larger cohorts, these findings provide a rationale for further evaluation of moderate carbohydrate restriction as a feasible dietary strategy in South Asian and comparable settings. Show less

Individuals with Alzheimer's disease (AD) are at an increased risk of bone fracture, while osteoporosis in women is one of the earliest predictors of AD. Yet the mechanisms linking cognitive decline and skeletal deterioration remain poorly defined. Proteomic analysis of cortical bone from aged 21-month-old mice revealed strong enrichment of neurodegeneration-associated proteins, including apolipoprotein E (Apoe) and amyloid precursor protein. Apoe localized specifically to osteocytes, with expression in aged female bone nearly twice that of young 4-month-old male bone. Because human APOE alleles confer different age-related AD risks, we examined their roles in bone using humanized APOE2, APOE3, and APOE4 knock-in mice and analyzed bone and hippocampus from the same animals. APOE4 produced marked sex-specific effects on the bone transcriptome and proteome compared with APOE2 or APOE3. Strikingly, APOE4-associated proteomic disruptions were stronger in female bone than in the hippocampus. Functionally, APOE4 caused bone fragility in females without altering cortical structure. These deficits stemmed from impaired osteocyte perilacunocanalicular remodeling. Our findings identify APOE4 as a molecular driver of early osteocyte dysfunction and reduced bone quality, disproportionately affecting females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment and treatment for bone fragility, in females. Show less

Anti-amyloid-β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real-world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care. Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019-Mar 2025) assessed trends in AD-relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid-beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated. Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (-25/quarter), and plasma p-tau The adoption of anti-Aβ therapies coincided with a rapid shift in diagnostic workflows. Show less

Alzheimer's Disease (AD) is a disabling neurodegenerative illness characterized by Amyloid-beta (Aβ) plaque deposition, tau tangles, and neuroinflammation. These pathological characteristics lead to progressive cognitive decline, and drug therapeutic approaches are bedeviled by extreme difficulty with the Blood-Brain Barrier (BBB) that prevents most drugs from effectively crossing into the brain. Extracellular vesicle-based nanomedicine is a prospective approach to overcome this hurdle. Extracellular vesicles are endogenously derived extracellular vesicles that can cross the BBB and deliver a variety of therapeutic cargos, including small interfering RNAs (siRNAs), microRNAs (miRNAs), proteins, and other small molecules. Since they can cross the BBB and exhibit low immunogenicity and toxicity, extracellular vesicles represent a promising strategy for drug delivery against AD. Recent studies have highlighted the potential of extracellular vesiclebased treatments to deliver anti-amyloid and anti-tau therapies, neuroprotectants (e.g., antioxidants), and immune-modulatory factors. Engineered extracellular vesicles containing siRNA against βsecretase eta-site app cleaving enzyme 1 (BACE1), anti-tau oligonucleotides, and anti-inflammatory cytokines have shown promising preclinical efficacy by reducing Aβ deposition, tau aggregation, and neuroinflammation. These changes have been associated with enhanced cognitive function. Besides, extracellular vesicle-based systems were investigated for gene-editing therapeutics with Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/ Cas9) and Antisense Oligonucleotides (ASOs). Besides scalability concerns, cargo-loading efficiency, and long-term toxicity, extracellular vesicle-based nanomedicine is an innovative platform for targeted drug deli. Show less

In this study, we evaluated the therapeutic potential of DMB, a berberine derivative known for its enhanced bioavailability and reduced toxicity. DMB was synthesized and administered orally at doses of 5 and 10 mg/kg in an in vivo rat model of insulin resistance-induced Alzheimer's disease (AD). This model was established using a combination of a high-fat diet (HFD), streptozotocin (35 mg/kg; intraperitoneally), and amyloid-β Show less

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, abnormal social interactions, and restricted, repetitive behaviors. Pathogenic mutations in UBE3B result in neurodevelopmental disease, including intellectual disability, lack of speech, and ASD. UBE3B is an E3 ubiquitin ligase that tags substrate proteins with ubiquitin, marking them for proteasomal degradation. The ubiquitin-proteasome system (UPS) regulates several signaling pathways critical for neurodevelopment, including neurogenesis and synaptogenesis, and mutations in various UPS genes have been identified in ASD and related neurodevelopmental disorders. To investigate the function of UBE3B in the brain and how its disruption gives rise to neurodevelopmental abnormalities, we generated a central nervous system-specific conditional Ube3b knockout (cKO) mouse model and evaluated the resulting neurobehavioral phenotypes. We found that Ube3b cKO mice exhibit severe deficits in vocalization, social behavior, learning and memory, and motor skills. Assessment of in vivo neuronal phenotypes revealed defects in dendritic morphogenesis, reduced excitatory synapse density, diminished spontaneous cortical circuit activity, decreased AMPA receptor surface expression, and hyperexcitability of excitatory cortical neurons. Using quantitative proteomics, we profiled the proteome and ubiquitome of neural stem cells and identified 116 proteins that exhibited increased protein levels and reduced ubiquitination following loss of UBE3B. These proteins were highly enriched for ones involved in synaptic processes, and we confirmed interaction of UBE3B with several key synaptic proteins, including ATP1A1, DOCK7, NLGN2, and STX12. Collectively, our findings identify a role for UBE3B in regulating social, cognitive, and motor functions, and neuronal morphogenesis and activity by fine-tuning the synaptic proteome. Show less

Visceral leishmaniasis (VL) is a neglected tropical disease with high mortality and limited treatment options. Amphotericin B (AmB) remains the most effective drug but is constrained by dose-dependent toxicity. Immunotherapy using parasite-derived components may potentiate host defenses and host protective responses and attenuate drug-induced cytotoxicity. This study investigated the therapeutic efficacy and immune response-modulating mechanism of AmB in combination with ultradiluted Leishmania antigen (udLA) in a murine model of VL. BALB/c mice were experimentally infected with L.donovani promastigotes and subsequently treated with AmB, udLA, or their combination. Parasite burden in hepatic and splenic tissues was quantified via Leishman-Donovan Units and quantitative PCR. Cellular immune responses were characterized by flow cytometric analysis of CD4 All therapeutic regimens significantly reduced parasite load relative to untreated controls, with the AmB+udLA combination achieving up to 96% reduction. Combination therapy elicited pronounced expansion of CD4 Co-administration of AmB with ultradiluted Leishmania antigen markedly enhances antileishmanial efficacy through potentiation of Th1-biased immune response and activation of macrophage effector mechanisms, while concurrently minimizing drug induced toxicity. These findings underscore the potential of udLA as a rational safer strategy for the management of VL. Show less

Visceral leishmaniasis, caused by the protozoan parasite Leishmania donovani is one of the most life threatening neglected tropical disease with no licensed human vaccine and increasing risks of resistance to chemotherapeutic agents. Current vaccine approaches are hindered by suboptimal immunogenecity, underscoring the need for potent adjuvant that can steer a durable and protective immune response. Here, we reported for the first time immunotherapeutic potential of a synthetic TLR7/8 agonist, 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4 aminedihydrochloride (p-AM-BBIQ), in combination with heat-killed L. donovani antigen (HKA) in a murine model. Mice immunized with the adjuvanted formulation exhibited significant reduction in splenic parasite load, alongside enhanced production of nitric oxide and reactive oxygen species. Trancriptional profiling revealed increased upregulation of iNOS and Nf-κB, indicating activation of innate immune response. Flow cytometric analysis demonstrated increased frequencies of CD4 Show less

Elevated lipoprotein(a) [Lp(a)] is associated with an increased risk of aortic stenosis and Atherosclerotic Cardiovascular Disease (ASCVD), including myocardial infarction. Therefore, Lp(a) has emerged as a potential target for reducing residual cardiovascular risk. Conventional lipid-lowering interventions, including lifestyle modifications such as diet and exercise and statin therapies, have not been shown to effectively reduce Lp(a) levels. Ezetimibe, which inhibits cholesterol absorption and can reduce LDL-C, does not significantly affect Lp(a) levels, even when used in combination with statins. PCSK9 inhibitors have been found to reduce Lp(a) levels but to a lesser extent than their effect on LDL-C, and the clinical significance of the 15- 20% reduction in Lp(a) they offer is not entirely clear. Emerging therapies to lower Lp(a) focus on inhibiting apo(a) synthesis. One such agent is Olpasiran, a small interfering RNA (siRNA) that degrades apo(a) mRNA, preventing subsequent production of the protein. Its efficacy was studied in the OCEAN(a)-DOSE trial that included patients with established ASCVD and Lp(a) > 150 nmol/L and demonstrated greater than 95% reduction in Lp(a). A phase 3 outcomes trial is currently underway. In this review article, we delve further into lowering of Lp(a) with Olpasiran by detailing its pharmacological properties, its efficacy based on data from clinical trials, and ongoing research. The study also contextualizes it within the broader therapeutic landscape alongside other agents targeting Lp(a), such as Pelacarsen and Lepodisiran. Show less

Cancer is among the leading causes of death in the USA and worldwide. Solid tumors require the formation of new blood vessels (angiogenesis) for their growth. The endothelium plays a crucial role in angiogenesis and tumor progression. Hypoxic stress generated by tumors can activate stress kinases such as mixed lineage kinases (MLKs). Publicly available datasets on lung adenocarcinoma, along with our experimental findings, indicate that MLK2 and MLK3 are expressed in human lung tumors. In this study, using three distinct mouse models of tumor development, we demonstrated that MLK2 (MAP3K10) and MLK3 (MAP3K11) are essential for tumor growth and angiogenesis. Furthermore, MLK2 and MLK3 are highly expressed in the endothelium and are necessary for endothelial proliferation, migration, and angiogenesis. In the endothelium, MLKs regulate the expression of angiogenic growth factors and metalloproteinases, including Pgf, Vegfa, Angptl4, Adam8, and Mmp9. Additionally, the MLK family of kinases acts through the long noncoding RNA (lncRNA) H19 to control the expression of these pro-angiogenic factors in the endothelium. Collectively, these findings suggest that the MLK-H19 axis coordinates endothelial function, angiogenesis, and tumor growth. Show less

Sex hormone-binding globulin (SHBG), which regulates androgen and estrogen bioavailability, has been linked to cognitive decline, but its relationship with temporal lobe changes-an area vulnerable in early Alzheimer's disease (AD)-remains unclear. This study aimed to investigate whether plasma SHBG levels are associated with temporal lobe volume and cognitive performance across the cognitive spectrum from normal aging to AD. Participants included individuals with AD (n = 85), mild cognitive impairment (MCI; n = 304), and cognitively normal controls (CN; n = 50). Cognitive performance was assessed using the ADAS-Cog 11, MMSE, and CDR-SB. Temporal lobe volumes were derived from MRI scans using tensor-based morphometry (TBM), and plasma SHBG levels were measured using a validated immunoassay. Multiple regression analyses adjusted for age, sex, education, handedness, and APOE ε4 status were conducted, followed by mediation analysis to test indirect effects through temporal lobe volume. After covariate adjustment, elevated plasma SHBG levels were significantly associated with reduced temporal lobe volume in the MCI group. Across both MCI and AD participants, greater temporal lobe volume correlated with better cognitive performance on all tests. Mediation analysis indicated that in MCI, the relationship between higher plasma SHBG and poorer cognitive outcomes was significantly mediated by reduced temporal lobe volume. These findings suggest that elevated SHBG may contribute to early cognitive impairment in MCI through its impact on temporal lobe integrity, highlighting SHBG as a potential target in the prodromal stages of AD. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction and neuronal loss, with glutamate excitotoxicity playing a central role in its pathology. The astrocytic glutamate transporter EAAT2, responsible for maintaining synaptic glutamate homeostasis, is significantly downregulated in AD. Restoration of EAAT2 expression presents a promising therapeutic strategy. This study explores the potential of modulating the Wnt/β-catenin signaling pathway to enhance EAAT2 levels by targeting the Axin-1/β-catenin interaction. Through virtual screening of 120,993 compounds from the Asinex-CNS database, five lead candidates were identified based on molecular docking, MMGBSA scores, and drug-likeness parameters. Advanced in-silico analyses-including Principal Component Analysis, Dynamic Cross-Correlation Mapping, molecular dynamics simulations, and MM/PBSA binding free energy calculations-highlighted BAS 04937103 as the most promising compound for disrupting β-catenin degradation. In vitro validation using C6 glioma cells and primary astrocytic cultures demonstrated that BAS 04937103 enhanced β-catenin stabilization and nuclear translocation, reduced Axin-1 expression, and significantly upregulated EAAT2 levels. These molecular effects corresponded with decreased extracellular glutamate concentrations, improved glutamate uptake, and reduced oxidative stress. Collectively, these findings establish BAS 04937103 as a novel modulator of the Axin/β-catenin interaction with therapeutic potential in mitigating glutamate-mediated neurotoxicity in Alzheimer's disease. Show less

BACE-1 is a prime therapeutic target for treatment of Alzheimer disease as it cleaves the β-site of APP leading to formation of amyloid plaques. A dataset of 229 benzo-fused heterocyclic compounds reported as BACE-1 inhibitors was utilized to develop various QSAR models (regression and classification) utilizing Monte Carlo algorithm. The dataset was randomly split into different sets for generation of models. The IIC and CCC were calculated to increase the predictive ability of generated models. Among various models, split-1 of Model-1 demonstrated the highest robustness and predictive accuracy for pIC Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and tau tangles, leading to cognitive decline and dementia. Insulin-like Growth Factor-1 (IGF-1) is similar in structure to insulin and is crucial for cell growth, differentiation, and regulating oxidative stress, synaptic plasticity, and mitochondrial function. IGF-1 exerts its physiological effects by binding to the IGF-1 receptor (IGF-1R) and activating PI3K/Akt pathway. In addition to the physiological activities in the brain, numerous studies point to a potential protective role of the IGF-1 pathway in the pathogenesis of neurodegenerative diseases, such as AD. Interestingly, patients with AD often exhibit altered insulin and IGF-1 levels, along with an inadequate insulin response. Dysregulation of IGF-1 signaling contributes to hyperphosphorylation of tau, NFT accumulation, increased β- and γ-secretase activity, elevated Aβ production, and impaired Aβ clearance, highlighting the need to explore the role of this signaling for potential therapeutic targets of AD. This review explores the role of IGF signaling in AD pathology, highlighting IGF-1 as a promising therapeutic target due to its significant involvement in disease mechanisms. Modulating IGF-1 activity could help mitigate neurodegeneration and preserve cognitive function in AD. A comprehensive understanding of the mechanisms underlying IGF-1 dysregulation is crucial for developing targeted therapeutic strategies to address the complex and multifaceted nature of AD. Show less

Osteoglophonic Dysplasia (OGD) is an autosomal dominant skeletal dysplasia characterized by impaired bone growth resulting in short stature, severe craniofacial abnormalities, and in some patients FGF23-mediated hypophosphatemia. It is caused by gain-of-function variants in FGFR1, particularly in or near the transmembrane domain of the receptor. We used CRISPR in mice to knock-in the FGFR1 p.N330I variant, chosen based on its association with FGF23 excess. Skeletal phenotyping of this Show less

Osteoglophonic dysplasia (OGD) is a rare skeletal disorder caused by certain variants in FGFR1. The FGFR1 gene encodes a receptor vital for osteogenesis in the axial and craniofacial skeleton. Key OGD features include craniosynostosis, craniofacial dysmorphism, impacted teeth, rhizomelic shortening, and nonossifying fibromas. Patients may have hypophosphatemia due to high FGF23 levels. We report two OGD patients with the c.1141T > C FGFR1 variant [p.(Cys381Arg)], initially diagnosed with Pfeiffer syndrome. Both showed classic symptoms as well as signs not previously reported, including elevated frontal temperature and overlapping toes. This report emphasizes distinguishing OGD from similar disorders and expanding the clinical phenotype. Show less

Drug resistant Tuberculosis (DR-TB) continues to be a major concern for public health, particularly in countries like India with high disease burden. Recognizing resistance trends and appropriate therapeutic approach is critical for improving patient outcomes and updating national treatment protocols. This study aims to analyze drug resistance patterns and assess treatment modifications made in accordance with National Tuberculosis Elimination Programme (NTEP). The study was conducted in our institute in western Maharashtra over a period of 18 months after approval from ethics committee which included microbiologically confirmed pulmonary and extrapulmonary DR-TB cases and resistance patterns were studied using molecular and phenotypic drug susceptibility testing (DST) including line probe assays (LPA). Initial treatment regimens and subsequent modifications were documented and assessed. Out of 83 DR-TB patients the most prevalent pattern was Isoniazid monoresistance (H Mono DRTB) (45.78 %), followed by Rifampicin resistant TB (RR-TB) (21.69 %) and Pre - extensively drug resistant TB (Pre XDR-TB) (24.10 %). Majority were initiated on an All Oral Longer Regimen (49.40 %) or an H Mono/Poly DR-TB regimen (48.19 %). Modifications were required in 28.92 % of the cases with fluoroquinolones being the most frequently substituted drug due to resistance. Out of 83 individuals, only 55 were assigned outcomes since the remaining were on treatment. Among these 55, 72.7 % were assigned outcome as cured, 5.4 % as treatment completed, 10.9 % defaulted, 3.6 % as treatment failed and 7.27 % died. The study highlights the evolving resistance pattern in DR-TB patients and need for patient specific treatment to achieve optimal outcomes. It also provides valuable insights for effective management protocols, contributing to improved patient prognosis and informing public health strategies. Show less

Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder typically involving the bone marrow with infiltration by small lymphocytes and plasma cells. Studies have identified MYD88 L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas. Detection rates for this mutation have varied depending on the analytic methodology, with previous data suggesting that routine next-generation sequencing (NGS) does not demonstrate the required sensitivity to reliably detect MYD88 L265P. NGS has become part of routine clinical testing because it allows detection of variants across multiple genes. To study the utility of NGS in the detection of MYD88 L265P, we performed droplet digital PCR (ddPCR) and routine NGS on a cohort of 34 cases of lymphoid neoplasms (22 LPL, 4 CLL, 1 MCL, 1 MGUS, 2 plasma cell myeloma, and 4 negative bone marrow cases). We utilized manual review and BAMtools to assess MYD88 L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.4 % variant allele frequency (VAF) with 10 ng DNA input. MYD88 L265P VAF detection by NGS and ddPCR was comparable down to 0.5 % VAF (R Show less

Many emerging service delivery models triage genetic counselor time with patients to postgenetic testing, including population genomic screening followed by genetic counseling (GC). To prime patients and help genetic counselors tailor such visits, a previsit (PV) chatbot was created to assess patient understanding, emotional response to, and family communication about genetic results. This study explored patients' perceptions of the PV chatbot and how they would use it. User testing was conducted via videoconference with patients who had completed GC. A codebook thematic analysis informed by Proctor's Conceptual Model of Implementation Research in a postpositivist paradigm was conducted. In total, 16 participants completed user testing, of whom 12 were women and 4 were men with a mean age of 55.4 (range 32-69). Participants had a variety of genetic results out of 78 genes among cancer (PMS2 n = 2; PALB2 n = 4; BRCA2 n = 1) and cardiovascular (LDLR n = 1; MYBPC3 n = 1; DSP n = 1; TTN n = 5; MYH7 n = 1) conditions. Participants reported high acceptability (M = 4.53/5, SD = 0.45) and feasibility (M = 4.43/5, SD = 1.04) of the chatbot. Participants reported liking the chatbot because of its ease of use and anticipated benefit to GC. Participants viewed the chatbot as complementary to GC and shared that the chatbot would have helped prepare them for GC in ways they may not have considered, including inviting a family member to join the appointment. Participants desired more personalization within the chatbot, including responsiveness to their personal/family history, optional supplementary education, and more emotionally supportive language. Some participants described challenges with certain aspects of the chatbot, including the repetitiveness and phrasing of validated scaled measures. Overall, participants perceived the PV chatbot to be of value in educating and preparing them for GC and reflected on how the PV chatbot may have enhanced GC. Many of the perceived benefits of this chatbot are applicable across GC settings. 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

Several new treatments have recently been shown to have heart and kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, it is unclear how the different molecular pathways affected by the therapies may overlap. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone in mice with comorbid diabetes, focusing on the regulation of expression of the glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor (GIPR) and glucagon receptor (GCGR), which are targets of approved or investigational therapies in diabetes. Male C57BL/6J mice were fed a high fat diet for 26 weeks. Twelve weeks into the high fat diet feeding period, mice received an intraperitoneal injection of streptozotocin before being followed for the remaining 14 weeks (DMHFD mice). After 26 weeks, mice were fed a high fat diet containing finerenone (100 mg/kg diet) or high fat diet alone for a further 2 weeks. Cell culture experiments were performed in primary vascular smooth muscle cells (VSMCs), NRK-49 F fibroblasts, HK-2 cells, and MDCK cells. DMHFD mice developed albuminuria, glomerular mesangial expansion, and diastolic dysfunction (decreased E/A ratio). Glp1r and Gcgr were predominantly expressed in arteriolar VSMCs and distal nephron structures of mouse kidneys respectively, whereas Gipr was the predominant of the three transcripts in mouse hearts. Kidney Glp1r and Gcgr and cardiac Gipr mRNA levels were reduced in DMHFD mice and this reduction was negated or attenuated with finerenone. Mechanistically, finerenone attenuated upregulation of the profibrotic growth factor Ccn2 in DMHFD kidneys, whereas recombinant CCN2 downregulated Glp1r and Gcgr in VSMCs and MDCK cells respectively. Through its anti-fibrotic actions, finerenone reverses Glp1r and Gcgr downregulation in the diabetic kidney. Both finerenone and GLP-1R agonists have proven cardiorenal benefits, whereas receptor co-agonists are approved or under development. The current findings provide preclinical rationale for the combined use of finerenone with the GLP-1R agonist family. They also provide mechanism of action insights into the potential benefit of finerenone in people with diabetes for whom GLP-1R agonists or co-agonists may not be indicated. Show less

Obesity is one of the critical public health problems in our society. It leads to various health conditions, such as type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidaemia, and non-alcoholic fatty liver disease. With the rising incidence of obesity, there is a growing demand for new therapies which can effectively manage body weight and improve health. Currently under development, multi-receptor agonist drugs may offer a promising solution to meet this unmet medical need. Retatrutide is a novel triple receptor agonist peptide that targets the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). This novel drug has the potential to treat metabolic abnormalities associated with obesity as well as diseases resulting from it due to its distinct mechanism of action. The Phase III trial of this pipeline drug for treating type 2 diabetes mellitus, non-alcoholic fatty liver disease, and obesity started on August 28, 2023. The results of a Phase II clinical trial have demonstrated significant weight reduction in overweight and obese adults. Specifically, the trial reported an average weight loss of 17.5% and 24.4% at 24 and 48 weeks, respectively. These findings hold promise for the development of effective weight loss interventions in this population group. There is a need for more phase III studies to provide sufficient clinical evidence for the effectiveness of retatrutide, as current evidence is limited to phase II studies and has yet to prove its worth in a larger population. Here, we aimed to provide an overview of retatrutide's safety and effectiveness in treating obesity. 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

Based on the biochemical understanding of Alzheimer's disease, here, we report the design, synthesis, and biological screening of a series of compounds against this neuro-disorder. Adopting the multitarget approach, the catalytic processes of BACE-1 and AChE were targeted, and thereby, compounds Show less

The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation and survival. Previously, the role of cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast cancer aggressiveness, but the molecular basis of this observation is not clearly understood, which this study aims to elucidate. CETP knock-down resulted in a >50% decrease in cell proliferation in both 'estrogen receptor-positive' (ER+; Michigan Cancer Foundation-7 (MCF7) breast cancer cells) and 'triple-negative' breast cancer (TNBC; MDA-MB-231) cell lines. Intriguingly, the abrogation of CETP together with the combination treatment of tamoxifen (5 μM) and acetyl plumbagin (a cholesterol-depleting agent) (5 μM) resulted in twofold to threefold increase in apoptosis in both cell lines. CETP knockdown also showed decreased intracellular CE levels, lipid raft and lipid droplets in both cell lines. In addition, RT Show less

Cytokines and chemokines are vital in maintaining a healthy state by efficiently controlling invading microbes. In addition, the dysregulation of these immune mediators can contribute to viral infection pathology. We comprehensively analyzed the profiles of host immunomodulators in response to infections with members of several virus families, particularly if the SARS-CoV-2 infection produces a unique immune profile compared with other viral infections. Multiplex microbead immunoassay results from 219 datasets with a range of viruses were curated systematically. The curated immunoassay data, obtained using Luminex technology, include 35 different viruses in 18 different viral families; this analysis also incorporated data from studies performed in 7 different cell model systems with 28 different sample types. A multivariate statistical analysis was performed with a specific focus involving many investigations (>10), which include the viral families of Coronaviridae, Orthomyxoviridae, Retroviridae, Flaviviridae, and Hantaviridae. A random forest-based classification of the profiles indicates that IL1-RA, C-X-C motif chemokine ligand 9, C-C motif chemokine ligand 4, interferon (IFN)-λ1, IFN-γ-inducing protein 10, and interleukin (IL)-27 are the top immunomodulators among human samples. Similar approaches only between Coronaviridae (COVID-19) and Orthomyxoviridae (influenza A/B) indicated that transforming growth factor-β, IFN-λ1, IL-9, and eotaxin-1 are important features. In particular, the IFN-λ1 protein was implicated as one of the significant immunomodulators differentiating viral family infection. It is evident that Coronaviridae infection, including SARS-CoV-2, induces a unique cytokine-chemokine profile and can lead to specific immunoassays for diagnosing and prognosis of viral diseases based on host immune responses. Alternatively, we can use diagnosing and prognosing. It is also essential to note that meta-analysis-based predictions must be appropriately validated before clinical implementation. Show less

In this study, comparative analysis of skeletal muscle transcriptome was carried out for four biological replicates of Aseel, a fighter type breed and Punjab Brown, a meat type breed of India. The profusely expressed genes in both breeds were related to muscle contraction and motor activity. Differential expression analysis identified 961 up-regulated and 979 down-regulated genes in Aseel at a threshold of log Show less