👤 Vinod Nayak

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

Mania, a core feature of bipolar disorder, is characterized by impulsivity, hyperactivity, and mood disturbances. Impulsivity has been linked to lipid metabolism, particularly cholesterol and apolipoproteins. This study investigates the relationship between lipid profile, apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), and impulsivity in first-episode mania patients. A case-control study was conducted at Sriram Chandra Bhanja (SCB) Medical College, Cuttack, involving 60 patients with first-episode mania and 60 age-matched healthy controls. Lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), ApoA1, and ApoB, were measured. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Independent samples t-tests and Pearson's correlation were used for statistical analysis. Mania patients had significantly lower TC (156.58 ± 14.00 mg/dL vs. 175.93 ± 23.59 mg/dL, p < 0.001), LDL (75.00 ± 9.24 mg/dL vs. 83.58 ± 16.86 mg/dL, p = 0.001), and TG (74.03 ± 11.94 mg/dL vs. 96.43 ± 29.48 mg/dL, p < 0.001) compared to controls. ApoB levels were higher in mania patients (795.95 ± 725.44 mg/dL vs. 549.53 ± 796.67 mg/dL, p = 0.079), though not statistically significant. BIS-11 scores negatively correlated with cholesterol levels, particularly TC and LDL, suggesting an association between hypercholesterolemia and increased impulsivity. Lower cholesterol levels, particularly LDL, are significantly associated with impulsivity in first-episode mania patients. These findings highlight the potential role of lipid metabolism in psychiatric disorders and suggest lipid monitoring in high-risk individuals. Show less

Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE-1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35 % inhibitory activity at 10 μM. Notably, pyrazole-5-carbohydrazide 29 (5784196) exhibited BACE-1 inhibition with an IC Show less

Agrin, encoded by AGRN , plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS. We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants. Perinatal phenotyping revealed FADS in the family, and genomic testing identified novel null variants in AGRN . First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1₉₅₂₊₃del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN. This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN . Show less

This study seeks a comprehensive exploration of genome-wide selective processes impacting morphometric traits across diverse cattle breeds, utilizing an array of statistical methods. Morphometric traits, encompassing both qualitative and quantitative variables, play a pivotal role in characterizing and selecting livestock breeds based on their external appearance, size, and physical attributes. While qualitative traits, such as color, horn structure, and coat type, contribute to adaptive features and breed identification, quantitative traits like body weight and conformation measurements bear a closer correlation with production characteristics. This study employs advanced genotyping technologies, including the Illumina BovineSNP50 Bead Chip and next-generation sequencing methods like Reduced Representation sequencing, to identify genomic signatures associated with these traits. We applied four intra-population methods to find evidence of selection, such as Tajima's D, CLR, iHS, and ROH. We found a total of 40 genes under the selection signature, that were associated with morphometric traits in five cattle breeds (Kankrej, Tharparkar, Nelore, Sahiwal, and Gir). Crucial genes such as ADIPDQ, DPP6, INSIG1, SLC35D2 in Kankrej, LPL, ATP6V1B2, CDC14B in Tharparkar, HPSE2, PLAG1 in Nelore, PCSK1, PRKD1 in Sahiwal, and GNAQ, HPCAL1 in Gir were identified in our study. This approach provides valuable insights into the genetic basis of variations in body weight and conformation traits, facilitating informed selection processes and offering a deeper understanding of the evolutionary and domestication processes in diverse cattle breeds. Show less

Primary cilia (PC) are cellular organelles that regulate the cellular homeostasis. They are the seats of many oncogenic pathways and indirectly regulate the epithelial-mesenchymal transition (EMT) and extracellular matrix, both critical for the tumor microenvironment (TME). Though there are a few studies highlighting the alteration of PC in the tumor cells of various malignancies, none depict the PC in the stromal cells in the urothelial carcinoma of the urinary bladder (UC), the stromal cells being an essential component of TME. Therefore, we intend to evaluate the PC in the stromal cells at the tumor-stromal interface in UC. Immunohistochemistry for acetylated-α-tubulin (for PC), Ki67, E-cadherin, and SNAI1 was performed in 141 cases of UC and 5 normal controls, and primary cilium: nucleus (C:N) ratio was counted in the stromal cells at the tumor-stromal interface. The C:N ratio was correlated with various clinical and histopathological parameters. The C:N ratio showed significant diminution from normal control (mean=0.75) to low-grade UC (mean=0.24) ( P =0.001) to high-grade UC (mean value=0.17) ( P =0.001). There was a significant diminution of the C:N ratio from the noninvasive to invasive UC ( P =0.025). The C:N ratio did not show any correlation with EMT although negatively correlated with the Ki67 index ( r =-0.32; P =0.001), and a higher ratio showed a trend with a higher recurrence-free survival ( P =0.07). The diminution of the PC in the stromal cells at the tumor-stromal interface is an early event and correlates with an aggressive tumor biology of UC. Show less

The present study was carried out to compare the proteomic profiles of spermatogenic cells of crossbred and zebu cattle in an effort to understand the possible reasons for a higher incidence of sub-fertility in crossbred bulls. The spermatogenic cells collected from the testes of pre-pubertal (6 mo) and adult (24 mo) crossbred and zebu males through fine needle aspiration were proliferated in vitro, and proteomic profiling was done using a shotgun proteomics approach. The age- and species-specific variations in the expression level of proteins were identified in spermatogenic cells. The number of differentially expressed proteins (DEPs) identified in pre-pubertal zebu and crossbred was 546, while 579 DEPs were identified between adult zebu and crossbred bulls. Out of these, 194 DEPS were common to these groups and 40 DEPs displayed a fold change ≥2. However, only 20 proteins exhibited similar expression variation trends (upregulated or downregulated) among pre-pubertal as well as adult zebu and crossbred bulls. Out of these 20 DEPs, 13 proteins were upregulated, and 7 proteins were downregulated in spermatogenic cells of zebu compared to crossbred bulls. Among the upregulated proteins were RPLP2, PAXIP1, calumenin, prosaposin, GTF2F1, TMP2, ubiquitin conjugation factor E4A, COL1A2, vimentin, protein FAM13A, peripherin, GFPT2, and GRP78. Seven proteins that were downregulated in zebu bulls compared to crossbred included APOA1, G patch domain-containing protein 1, NAD P transhydrogenase mitochondrial, glutamyl aminopeptidase, synaptojanin 1 fragment, Arf GAP with SH3 domain ANK repeat and PH domain-containing protein 1, and protein transport protein sec16B. It was inferred that the proteins associated with sperm function and fertilization processes, such as calumenin, prosaposin, vimentin, GRP78, and APOA1 could be studied further to understand the precise cause of subfertility in crossbred bulls. Show less

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regulatory network encompassing the known associations among regulators of EMT (epithelial-mesenchymal transition) and PD-L1, an established immune-suppressor. Our simulations for the network consisting of SLUG, ZEB1, miR-200, CDH1 and PD-L1, integrated with single-cell and bulk RNA-seq data analysis, elucidate that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to be immune-evasive. Specifically, in breast cancer, we show the co-existence of hybrid E/M phenotypes, enhanced resistance to anti-estrogen therapy and increased PD-L1 levels. Our results underscore how the emergent dynamics of interconnected regulatory networks can coordinate different axes of cellular fitness during metastasis. Show less

Retinoic acid-inducible gene I-like receptors (RLRs) are important cytosolic pattern recognition receptors (PRRs) that sense viral RNA before mounting a response leading to the activation of type I IFNs. Several viral infections induce epithelial-mesenchymal transition (EMT), even as its significance remains unclear. Here, we show that EMT or an EMT-like process is a general response to viral infections. Our studies identify a previously unknown mechanism of regulation of an important EMT-transcription factor (EMT-TF) Snail during RNA viral infections and describe its possible implication. RNA viral infections, poly(I·C) transfection, and ectopic expression of RLR components induced Snail levels, indicating that RLR pathway could regulate its expression. Detailed examination using mitochondrial antiviral signaling protein knockout (MAVS-KO) cells established that MAVS is essential in this regulation. We identified two interferon-stimulated response elements (ISREs) in the Show less

Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition. Pathogenic variants in DOK7 are known to cause myasthenic syndrome, congenital, 10 (MIM#254300) and, rarely (reported in a single family) lethal FADS. Herein, we describe a biallelic variant c.1263dupC in DOK7, known to cause congenital myasthenic syndrome 10, causing lethal FADS in a consanguineous family. The present report illustrates wide phenotypic variability caused by biallelic pathogenic variants in DOK7. We also describe the second family with FADS due to pathogenic variants in DOK7. Show less

Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144-1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM₀₀₀₁₅₈₎. Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum. Show less

Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition. We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616). Maternal genotypes were imputed using IMPUTE. After running 33 separate FA fraction phenotypes, we found that SNPs known to be associated with serum FAs in the AA is the primary FA in breast milk influenced by genetic variation at the Show less

We report on two unrelated fetuses born to nonconsanguineous couples with fetal akinesia deformation sequence (FADS). The fetuses shared facial features, micrognathia, fetal finger pads, bulbous digital tips, pterygia, clubfeet, ventriculomegaly, and cerebellar anomalies. Both had loss/absence of Purkinje cells in cerebellum. The first family had a similarly affected previous pregnancy suggesting an autosomal recessive inheritance. The second fetus, in addition to the findings in the first, had cleft palate and defective lobulation of lungs. These fetuses appear to have the Pena-Shokeir phenotype (PSP) or FADS. These two cases seem to define a newly recognizable subtype of FADS with bulbous digital tips, prominent digit pads and cerebellar anomalies, and highlight the phenotypic diversity of syndromes with multiple congenital contractures manifesting in utero. Show less