👤 Medha Kaushik

Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633-0.773; juvenile USVs, d = 1.103-1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36% reduction in overall brain volume (FDR 10%). Placentas from both groups showed reduced LIX (CXCL5), but distinct immune shifts also emerged: MIA placentas exhibited elevated IL-4 and IL-1β, whereas hyperandrogenized placentas showed increased TNFα. In neonatal brains, both conditions were associated with reduced IL-2, with MIA additionally decreasing IL-17A and IL-12p70, suggesting suppression of Th1/Th17-type cytokine signaling that normally supports proinflammatory and immune-neural interactions. DRD2 and BDNF protein were upregulated in hyperandrogenized fetal brains but downregulated with MIA. These results suggest that hyperandrogenization and MIA act through distinct mechanisms, producing subtle neurodevelopmental and behavioral differences consistent with human ASD subtypes. 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

Alzheimer's disease (AD) and vascular dementia (VaD) account for most dementia cases. AD biomarkers remain costly and invasive, and no specific biomarkers exist for VaD. We analyzed plasma and brain proteomics in the UK Biobank (N=53,000) and ROSMAP (N=512) to identify shared and distinct proteomic signatures of AD and VaD and assess the influence of the APOE ε4 variant. We identified 55 AD-associated and 49 VaD-associated proteins, with 13 shared. AD proteins were enriched in glycosaminoglycan binding and cholesterol metabolism; VaD proteins in virus receptor activity, cytokine activity and metalloproteinases. Both showed IGF pathway dysregulation. APOE ε4 stratification revealed distinct AD proteomic signatures beyond GFAP and NeFL. Mendelian randomization suggested causal links for SNAP25 in AD, EDA2R and TIMP4 in VaD, and PVR in both. Findings underscore the importance of APOE genotype and highlight SNAP25, EDA2R, TIMP4, and PVR as potential biomarkers and therapeutic targets. Show less

Behavioral Tagging (BT) is a well-established phenomenon under in vivo conditions to understand molecular framework of long-term memory (LTM) consolidation. BT has been extensively explored using different learning tasks and novelties at the behavioral level, while at the molecular level, handful of plasticity related proteins (PRPs) such as PKMζ, CREB, BDNF have been explored in various manners thereof. Hence, the quest for novel PRPs in BT becomes a necessity, since repeated studies of known PRPs results in scientific stagnation and cessation of further exploration. Emerging literature suggests potential role of BACE1 and endogenous Aβ in maintenance of synaptic plasticity and long-term potentiation. The present study aims to characterize the effects of BACE1 inhibition using minocycline on novel object recognition (NOR) LTM through environment enrichment (EE) mediated BT. BACE1 is responsible for endogenous Aβ generation, hence its inhibition also subdues the Aβ synthesis. Our results significantly demonstrate the active involvement of BACE1 and endogenous Aβ in facilitating NOR-LTM consolidation through EE mediated BT for the first time under in vivo conditions. Interestingly, EE exposure was found to induce the synthesis of BACE1 and endogenous Aβ in BT paradigm along with their potential interplay with PKMζ signaling to facilitate NOR-LTM consolidation. Taken together, our results provide first hand evidence of the role of BACE1 and endogenous Aβ as novel PRP complex in EE mediated BT phenomenon. The results provide significant advance in our understanding of LTM consolidation process and paves the way for exploration of novel molecular pathways involved in the process. Show less

India accounts for 26 % of global tuberculosis (TB) cases, with delayed diagnosis of Mycobacterium tuberculosis (MTB) and drug resistance exacerbating disease transmission. Conventional drug susceptibility testing (DST) remains time-consuming, while molecular tools like the Xpert MTB/RIF assay-though rapid-are limited to detecting MTB and rifampicin (RIF) resistance. Testing for isoniazid (INH) and second-line drugs requires the costly Xpert MTB/XDR assay. Although line probe assays (LPAs) identifies first- and second-line drug resistance, their accessibility is restricted to specialized laboratories. This underscores the need for a rapid, cost-effective alternative to diagnose resistance to INH and fluoroquinolones (FQs). A cross-sectional study was performed at the Department of Microbiology, AIIMS Bhubaneswar, and the Intermediate Reference Laboratory (IRL), Cuttack, from March 2022 to April 2023. MTB isolates (n = 123) were analyzed using LPAs (Hain Lifescience's Genotype MTBDRplus and Genotype MTBDRsl) and multiplex allele-specific (MAS) PCR. The MAS-PCR targeted mutations in katG codon 315 and the inhA-15 promoter region for INH resistance, and gyrA codon 94 for FQ resistance. MAS-PCR identified INH resistance in 28/123 (22.76 %) isolates. Compared to LPA, MAS-PCR demonstrated sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 80.77 %, 93.81 %, 77.78 %, 94.79 %, and 91.06 %, respectively, for INH resistance. For FQ resistance, MAS-PCR identified 19/123 (15.44 %) resistant isolates, with sensitivity, specificity, PPV, NPV, and accuracy of 87.50 %, 95.33 %, 73.68 %, 98.08 %, and 94.31 %, respectively, relative to LPA. MAS-PCR offers a rapid, technically feasible, and cost-effective method for detecting resistance to INH and FQs. Its high accuracy and affordability position it as a viable alternative in resource-limited settings, facilitating timely TB diagnosis and resistance management. Show less

To screen for variants in the MC4R and LEP genes in 46 patients with clinical suspicion of non-syndromic early onset severe obesity (NEOSO). Children with early onset obesity satisfying WHO criteria of obesity were studied. The MC4R and LEP genes were sequenced using a PCR amplicon based NGS on Illumina MiSeq next generation sequencer using an in-house developed protocol. Of the 46 children tested, four were found to have novel pathogenic/likely-pathogenic variants (one in the MC4R gene and three in the LEP gene). In three out of the 4 families, the presence of the variants was confirmed using standard bidirectional capillary sequencing in the probands. Four children with novel likely pathogenic variants in the MC4R and LEP genes are reported. Genetic analysis is crucial in children with early onset obesity and should be considered. Show less

The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC. Show less

In the present study, expression level of various ATP-binding cassette (ABC) viz., ABCA1, ABCA7, ABCG1, ABCG2, and ABCG5; associated transcription factors viz., SREBF1, LXRα (NR1H3), PPARA, and Solute Carriers (SLC); or Glucose transporters (GLUT) viz., SLC2A1(GLUT1), SLC2A4 (GLUT4), SLC2A8 (GLUT8), and SLC2A12 (GLUT12) superfamily of transporters were compared across physiological stages of buffalo mammary gland. The relative expression of ABCA1, and ABCG1 was significantly (p < 0.05) higher in mammary gland of heifer followed by involution and lactation stages. Similarly, ABCA7 gene expression was highest in heifer mammary gland followed by lactation and involution stages. ABCG2 gene expression was significantly (p < 0.05) high in lactating mammary gland in comparison to involution and heifer stages. On the other hand, ABCG5 gene expression was highest in involuting mammary gland followed by lactation and involution stages. Additionally, the expression of LXRα SREBF1, and PPARA which are known to regulate some of the ABC tranporters were also analyzed. The expression of LXRα gene was high in involuting as compared to lactating mammary gland. In contrast, SREBF1 and PPARA expression was significantly (p < 0.05) high in lactating mammary gland. Among the several SLC transporters studied, SLC2A1, SLC2A4, and SLC2A8 showed significant (p < 0.05) higher expression during lactation stage, whereas SLC2A12 expression was greater during heifer stage suggesting SLC2A1, SLC2A4, and SLC2A8 to be the major transporters associated with glucose uptake in buffalo mammary gland. The expression profile of (lactoferrin) LTF, known to be expressed at high level in mammary gland during involution was also studied. As expected, its expression was significantly (p < 0.05) higher during involution in comparison to lactating mammary gland.in buffaloes as well. The inclusion of LTF as a control gene further provided the confidence in the buffalo mammary gland expression data generated in the present study. This study thus helped to provide information about the distinct expression pattern of various transporters and their regulators in buffalo mammary gland during different physiological states. Show less

This study was undertaken to further examine the role of the host response to parvovirus B19 in the development of symptoms and consequences of viral persistence. Genomic DNA from 42 patients with symptomatic B19 infection was analyzed using the HuSNP assay (Affymetrix), and the results were compared with those from analysis of 53 healthy control individuals. Fifty-seven single-nucleotide polymorphisms were identified that were significantly associated with symptomatic infection. Total RNA from peripheral blood mononuclear cells from 57 B19-seropositive and 13 B19-seronegative donors was analyzed by hybridization to a single-color microarray representing 9522 human genes. Ninety-two genes were shown to be differentially expressed. Differential expression was confirmed in 6 of 38 genes (SKIP, MACF1, SPAG7, FLOT1, c6orf48, and RASSF5) tested using real-time quantitative polymerase chain reaction in a different group of healthy subjects. Genes identified in both studies play a functional role in the cytoskeleton, integrin signaling, and oncosuppression, themes that have been shown to be important in parvovirus infections. Show less