👤 Debabrata Mukherjee

Clusterin, a multifunctional glycoprotein involved in proteostasis, amyloid-β clearance, and neuroinflammation, has been proposed as a biomarker in Alzheimer's disease (AD), but its stage-specific links to brain structure, tau pathology, and cognition remain unclear. This study evaluated plasma clusterin across the AD spectrum, its associations with brain volumes and CSF tau/p-tau, and whether structural brain measures mediate its cognitive effects. Data from 333 participants (CN = 38, MCI = 207, AD = 88) were analyzed using FDR-corrected regression, Pearson correlations, and mediation analyses, adjusting for demographic factors and APOE ɛ4 status. Results showed that plasma clusterin was highest in mild cognitive impairment (MCI) compared to cognitively normal (CN) and AD, suggesting a peak during early neurodegeneration. In CN participants, higher clusterin was associated with lower whole-brain volume, but it was not significantly related to hippocampal volumes or tau/p-tau. In MCI, clusterin was modestly associated with reduced whole-brain volume and elevated CSF tau, while associations with hippocampal volumes and p-tau were nonsignificant. In AD, higher clusterin was significantly associated with smaller left and right hippocampal volumes, with a trend toward lower whole-brain volume; no significant associations with tau or p-tau were observed. Based on the mediation analysis, in CN participants, no significant mediation effects of brain volumes were observed between plasma clusterin and cognitive function. In the MCI group, higher plasma clusterin was associated with lower whole-brain volume, and this volumetric measure showed significant indirect effects linking plasma clusterin to cognitive performance, consistent with indirect-only (full mediation) patterns. This suggests an indirect association whereby higher clusterin may be linked to poorer cognitive function through its association with reduced global brain volume. Likewise, in the AD group, higher clusterin levels were associated with lower whole-brain and right hippocampal volumes. Both measures significantly mediated the relationship between clusterin and cognitive performance, indicating that higher clusterin may be linked to poorer cognitive function through its association with reductions in global and region-specific brain volumes. Future studies should clarify the temporal and mechanistic pathways linking clusterin to neurodegeneration to determine its value as a biomarker and therapeutic target. Show less

Brain vascular aging is increasingly recognized as a critical therapeutic target for age-related cognitive decline. Oxidative stress, bioenergetic dysfunction, and molecular damage play central roles in the progression of vascular aging, contributing to cerebrovascular dysfunction and impaired cognitive function. While naturally occurring polyphenols such as resveratrol (RSV) have demonstrated potential in mitigating aging-related pathologies, their poor bioavailability and limited brain targeting efficiency significantly constrain their therapeutic impact. As a result, high doses or advanced drug delivery strategies are necessary to achieve meaningful physiological effects. We introduce a novel nanocarrier system designed to enhance RSV delivery to the cerebral endothelium by leveraging the natural formation of an apolipoprotein E (ApoE)-enriched protein corona around fusogenic liposomes (FL) Show less

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers. Show less

Understanding the genetic foundations of dementia is critical to unraveling its complex molecular basis. Given that a clinical diagnosis of Alzheimer's disease (AD) dementia often results from interplay between multiple underlying neuropathologic co-morbidities, previous genome-wide association studies (GWAS) of clinically diagnosed AD are restricted in their ability to translate genetic associations to potential targeted therapeutics. The current study seeks to address these limitations by presenting the largest GWAS to date (n=12,509) of neuropathologic hallmarks of AD and AD related dementias (ADRDs). We further performed a candidate-variant analysis using loci previously identified in GWAS of clinically diagnosed AD dementia and Parkinson's disease (PD). Finally, we conducted heritability and genetic correlation analyses using linkage disequilibrium (LD) score regression. We found broad genome-wide significant associations with Clinically diagnosed Alzheimer's disease (AD) dementia is commonly associated with its hallmark pathologic changes plus neuropathologic features of prevalent co-morbid diseases such as cerebrovascular disease, Lewy body disease, and more recently discovered abnormalities in protein called TDP-43 (collectively, AD related dementias; ADRD). As a result, previous studies that associated clinical diagnosis of AD with specific genes may not tell us the whole story. For this study, we gathered autopsy and genetic data to identify relationships between genes and dementia-associated brain changes. We found some relationships between these diseases and genes that had been previously identified as contributing to clinical dementia, as well as some new relationships that had been previously unknown. We also found that some genes that had previously been identified in relation to AD were associated with different dementia-associated brain lesions. Finally, we found that the various brain lesions differ in the proportion that can be attributed to genetic vs. environmental differences. These results support that the pathway to a diagnosis of dementia can be caused by multiple factors and are an important step in beginning to identify individually based dementia treatments. Show less

BackgroundOthers have examined heterogeneity in Alzheimer's disease (AD); however, few have used longitudinal data while accounting for variation in disease stage. We used latent classes to model heterogeneity in the trajectories of three cognitive domains (memory, language, and executive functioning) starting at AD dementia diagnosis.ObjectiveOur aim was to describe the patterns of heterogeneity in cognitive decline across cognitive domains during the course of AD and to contextualize our findings by assessing associations with demographic factors and neuropathological measures.MethodsWe used cognitive data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study in a multi-dimensional joint latent class mixed model, which allowed us to estimate cognitive trajectories that varied across cognitive domains and latent classes. We accounted for the uncertainty in latent class assignment and corrected for multiple hypotheses when assessing the association of the latent classes with demographic and neuropathological variables.ResultsWe identified five latent classes differentiated by level of impairment (high to low) and rate of decline (slow to fast). Within each latent class, the pattern of decline did not differ substantially across cognitive domains. Classes were associated with Show less

"SuperAgers" are oldest-old adults (ages 80+) whose memory performance more closely resembles middle-aged adults. The present study examined apolipoprotein E (APOE) allele frequency in non-Hispanic Black (NHB) and non-Hispanic White (NHW) SuperAgers compared to controls and Alzheimer's disease dementia cases. In 18,080 participants from eight cohorts, harmonized clinical diagnostics and memory, executive function, and language domain scores were used to identify SuperAgers, cases, and controls across age-defined bins. NHW SuperAgers had significantly lower frequency of APOE-ε4 alleles and higher frequency of APOE-ε2 alleles compared to all cases and controls, including oldest-old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance. We demonstrated strong evidence that APOE allele frequency relates to SuperAger status. Further research is needed with a larger sample of NHB SuperAgers to determine if mechanisms conferring cognitive resilience differ across race groups. Apolipoprotein E (APOE) allele frequency differs between SuperAgers and cases APOE allele frequency differs between non-Hispanic White SuperAgers and controls The relationship of APOE and non-Hispanic Black SuperAger status is unclear. Show less

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive neuronal degeneration, predominantly caused by the accumulation of amyloid-beta (Aβ) and neuroinflammatory processes. Hypoxia, characterized by diminished oxygen levels, intensifies these mechanisms by stimulating hypoxia-inducible factor 1-alpha (HIF-1α), potentially enhancing BACE1 enzyme activity and resulting in increased Aβ synthesis and render neurons especially susceptible to hypoxia, exacerbating disease progression. Existing therapies are constrained by inadequate medication distribution across the blood-brain barrier and associated adverse effects. This study aims to identify potential therapeutic agents targeting HIF-1 We used Results identified several compounds with strong binding affinities and favorable ADMET profiles as potential inhibitors of HIF-1 Show less

Considering the multi-targeted drug approach, Enhydra fluctuans and Ipomoea aquatica were comprehensively investigated for their acetylcholinesterase, butyrylcholinesterase, and β-secretase enzyme inhibitory potential, which are linked to Alzheimer's disease. The results showed that I. aquatica produced more prominent anti-cholinesterase potential compared to E. fluctuans. But E. fluctuans showed more potent BACE1 inhibitory potential compared to I. aquatica. For the safety study, the extracts were tested for heavy metal content estimation, CYP450 isozyme inhibitory potential, and cytotoxicity in human hepatocellular carcinoma cells. Antioxidant capacity, total phenolics, and total flavonoids were significantly correlated with the anti-cholinesterase activity, where I. aquatica showed more protuberant potential compared to E. fluctuans. The UPLC-QTOF-MS analysis tentatively identified phytometabolites from the phenylethanoid glycosides and chlorogenic acids class in both the extracts. Further, in silico toxicity prediction, molecular docking, and dynamic simulation studies provided additional evidence on the safety profile and interaction potential of phytometabolites with AChE, BChE, and BACE1 enzymes. Show less

Dendritic cells (DCs) encounter Leishmania differentially, and the conflict can restrict or disseminate the parasite infection, either by activating or dampening the protective T cell responses and inducing the regulatory T cells. The outcome of this conflict depends on the species of Leishmania, infection tenure, DC subtypes, and, importantly, the DC-stimulating chemical and physical mediators. The critical balance between splenic cDC1 (CD8α Show less

Epithelial-mesenchymal transition (EMT) and cell migration are two essential cellular processes involved in normal biological events such as embryogenesis, organ development, and wound healing, and are also associated with pathological conditions like cancer metastasis. Recent studies have indicated that the microtubule cytoskeleton and its associated proteins play significant roles in these processes. In this study, we investigated how fidgetin, a microtubule-severing and depolymerizing enzyme, affects EMT and cell migration by depleting it in MDA-MB-231 breast cancer cells. Our data show that depletion of endogenous fidgetin reduces the cell migration rate in both wound-healing and single-cell motility assays. During EMT, transcription factors such as Snail, Slug (Snail2), Twist, and Zeb play pivotal roles by regulating the expression of EMT-related genes. In this study, we found that fidgetin depletion reduces the expression of Slug and Zeb1 in MDA-MB-231 breast cancer cells under both basal and EMT-induced conditions. Consistent with these findings, we observed that fidgetin depletion downregulates N-cadherin and vimentin expression in EMT-induced MDA-MB-231 cells, thereby influencing cell motility. Further investigations revealed that fidgetin also affects microtubule plus-end tracking proteins (+TIPs). Specifically, we detected reduced expression of CLIP-170 in fidgetin-depleted cells. Immunofluorescence analysis showed that EB1 comets occupied a smaller area at microtubule plus ends upon fidgetin depletion. Additionally, the size of focal adhesions was significantly increased, although no changes were observed in the expression levels of focal adhesion kinase (FAK). Our findings indicate that microtubule regulation by fidgetin influences cancer cell motility by altering the expression of EMT-promoting transcription factors and modulating the accumulation of focal adhesion and EB1 proteins. These results suggest that fidgetin could be a promising therapeutic target in cancer. Show less

Traditional risk reduction strategies like diet, exercise, and existing lipid- lowering medications have minimal impact on Lp(a) levels. Recent therapies targeting Lp(a) at the level of mRNA transcription of apo(a) or binding of apo(a) to apoB-100 have demonstrated substantial reductions of Lp(a). Lepodisiran is a GalNAc-conjugated small interfering RNA (siRNA) developed to inhibit LPA transcription, reducing apo(a) synthesis and circulating Lp(a) levels. This is an updated review of the mechanism of action, pharmacokinetics, clinical efficacy, and safety of Lepodisiran, as well as its effects on lipoprotein(a), with potential applications in treating patients with elevated cardiovascular risk. We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Lepodisiran," "small interfering RNA therapies," and "lipoprotein(a)". Lepodisiran demonstrated a dose-dependent and sustained reduction in Lp(a) levels, achieving a maximum reduction of up to 97% at the highest dose in a Phase 1 trial. A Phase 2 placebo-controlled trial similarly showed robust and durable decline in Lp(a) with a favorable safety profile. Lepodisiran is a promising therapy, with sustained Lp(a) reduction and good safety. Ongoing phase 3 trials are poised to provide robust data on its long-term safety, clinical efficacy, and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes. Lepodisiran demonstrates potent and sustained reductions in Lp(a) levels with a favorable safety profile, making it a promising therapeutic candidate for Lp(a)-mediated cardiovascular risk. Ongoing long-term outcome studies are essential to confirm its clinical benefit. Show less

The Sahiwal are among the most prominent international transboundary dairy cattle distributed in large numbers between India and Pakistan. With the elapse of more than seven decades after the independence and limited cross-border exchange of Sahiwal germplasm, one thought-provoking question arises as to whether natural and artificial selection could alter the genomic signature patterns in the Sahiwal, reared for different purposes in these two countries. Deciphering the genetic mechanisms that underlie economic traits is essential for advancement and long-term breeding plans that are reflected in the distinct selection signatures they carry. To identify these genomic signatures, three medium-density SNP datasets of Sahiwal from three geographical locations of India and Pakistan were analyzed, using De-Correlated Composite of Multiple Selection Signals technique to identify the major candidate genes. In the genome of Sahiwal, a total of 70 genomic regions with 261 protein-coding genes were found. Milk production (NEK11, HMGCS1, BTN1A1,KCNH3), reproduction (SH3BGR, PSMG1, BRWD1,B3GALT5) and immune response genes (BPIFB1, MCOLN2) were more closely related to the Indian Sahiwal. Pakistani Sahiwal had genes closely linked with the dual-purpose meat (RALGAPA2, RIN2, CFAP61), and milk (SLC24A3 GALNT17, BACH2) traits. Our findings revealed differential patterns of selection signatures in transboundary Sahiwal cattle. Show less

Elevated levels of lipoprotein(a) have been linked to an increased risk of Atherosclerotic Cardiovascular Disease (ASCVD). Conventional lipid-lowering medications have modest to no impact on Lp(a) levels. Emerging RNA-based modalities significantly decrease Lp(a) by silencing the apo(a) mRNA at the post-transcriptional level. Pelacarsen (TQJ230) is a GalNAc-conjugated novel Antisense Oligonucleotide (ASO) that selectively inhibits apo(a) synthesis in hepatocytes. This updated review aims to elucidate the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of Pelacarsen (TQJ230), with a focused appraisal of its potential role in the prevention of Atherosclerotic Cardiovascular Disease (ASCVD). We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Pelacarsen", "antisense oligonucleotide" OR "ASO", and "lipoprotein(a)" from inception to March 2025. Pelacarsen demonstrated a dose-dependent sustained reduction in Lp(a) levels, achieving up to a 97% reduction at the highest dose in Phase 1 and 2 trials. It was well-tolerated with a favorable safety profile. Phase 3 trials are underway to provide robust data on its long-term safety and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes. Pelacarsen (TQJ230) is a potent Lp(a)-lowering agent with promising efficacy and a favorable safety profile. However, its definitive role in reducing atherosclerotic cardiovascular events remains to be established. Ongoing Phase 3 trials will be critical in determining whether its lipid-lowering effects translate into meaningful long-term cardiovascular outcomes. Show less

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. To assess the role of ANGPTL4 in COVID-19-related outcomes. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients. Show less

The exact molecular mechanism underlying the heterogeneous drug response against breast carcinoma remains to be fully understood. It is urgently required to identify key genes that are intricately associated with varied clinical response of standard anti-cancer drugs, clinically used to treat breast cancer patients. In the present study, the utility of transcriptomic data of breast cancer patients in discerning the clinical drug response using machine learning-based approaches were evaluated. Here, a computational framework has been developed which can be used to identify key genes that can be linked with clinical drug response and progression of cancer, offering an immense opportunity to predict potential prognostic biomarkers and therapeutic targets. The framework concerned utilizes DeSeq2, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Cytoscape, and machine learning techniques to find these crucial genes. Total RNA extraction and qRT-PCR were performed to quantify relative expression of few hub genes selected from the networks. In our study, we have experimentally checked the expression of few key hub genes like APOA2, DLX5, APOC3, CAMK2B, and PAK6 that were predicted to play an immense role in breast cancer tumorigenesis and progression in response to anti-cancer drug Paclitaxel. However, further experimental validations will be required to get mechanistic insights of these genes in regulating the drug response and cancer progression which will likely to play pivotal role in cancer treatment and precision oncology. Show less

Inhibition of PKC (PKCi) signaling maintains pluripotency of embryonic stem cells (ESCs) across different mammalian species. However, the position of PKCi maintained ESCs in the pluripotency continuum is largely unknown. Here we demonstrate that mouse ESCs when cultured continuously, with PKCi, for 75 days are retained in naïve state of pluripotency. Gene expression analysis and proteomics studies demonstrated enhanced naïve character of PKCi maintained ESCs in comparison to classical serum/LIF (S/L) supported ESCs. Molecular analysis revealed that activation of PKCζ isoform associate with primed state of pluripotency, present in epiblast-like stem cells generated in vitro while inhibition of PKCζ phosphorylation associated with naïve state of pluripotency in vitro and in vivo. Phosphoproteomics and chromatin modification enzyme array based studies showed loss in DNA methyl transferase 3B (DNMT3B) and its phosphorylation level upon functional inhibition of PKCζ as one of the crucial components of this regulatory pathway. Unlike ground state of pluripotency maintained by MEK/GSK3 inhibitor in addition to LIF (2i/LIF), loss in DNMT3B is a reversible phenomenon in PKCi maintained ESCs. Absence of phosphorylation of c-MYC, RAF1, SPRY4 while presence of ERF, DUSP6, CIC and YAP1 phosphorylation underlined the phosphoproteomics signature of PKCi mediated maintenance of naïve pluripotency. States of pluripotency represent the developmental continuum and the existence of PKCi mediated mouse ESCs in a distinct state in the continuum of pluripotency (DiSCo) might contribute to the establishment of stages of murine embryonic development that were non-permissible till date. Show less

Acute respiratory infection by influenza virus is a persistent and pervasive public health problem. Antiviral innate immunity initiated by type I interferon (IFN) is the first responder to pathogen invasion and provides the first line of defense. We discovered that Axin1, a scaffold protein, was reduced during influenza virus infection. We also found that overexpression of Axin1 and the chemical stabilizer of Axin1, XAV939, reduced influenza virus replication in lung epithelial cells. This effect was also observed with respiratory syncytial virus and vesicular stomatitis virus. Axin1 boosted type I IFN response to influenza virus infection and activated JNK/c-Jun and Smad3 signaling. XAV939 protected mice from influenza virus infection. Thus, our studies provide new mechanistic insights into the regulation of the type I IFN response and present a new potential therapeutic of targeting Axin1 against influenza virus infection. Show less

Microbial fuel cell (MFC) is an emerging technology which has been immensely investigated for wastewater treatment along with electricity generation. In the present study, the treatment efficiency of MFC was investigated for hydrocarbon containing wastewater by optimizing various parameters of MFC. Mediator-less MFC (1·2 l) was constructed, and its performance was compared with mediated MFC with Escherichia coli as a biocatalyst. MFC with electrode having biofilm proved to be better compared with MFC inoculated with suspended cells. Analysis of increasing surface area of electrode by increasing their numbers indicated increase in COD reduction from 55 to 75%. Catholyte volume was optimized to be 750 ml. Sodium benzoate (0·721 g l Show less

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3. Show less

Macroautophagy/autophagy is a cellular catabolic process that results in lysosome-mediated recycling of organelles and protein aggregates, as well as the destruction of intracellular pathogens. Its role in the maintenance of the intestinal epithelium is of particular interest, as several autophagy-related genes have been associated with intestinal disease. Autophagy and its regulatory mechanisms are involved in both homeostasis and repair of the intestine, supporting intestinal barrier function in response to cellular stress through tight junction regulation and protection from cell death. Furthermore, a clear role has emerged for autophagy not only in secretory cells but also in intestinal stem cells, where it affects their metabolism, as well as their proliferative and regenerative capacity. Here, we review the physiological role of autophagy in the context of intestinal epithelial maintenance and how genetic mutations affecting autophagy contribute to the development of intestinal disease. Show less

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment. Show less

Microbial Fuel Cell (MFC) is an innovative bio-electrochemical approach which converts biochemical energy inherent in wastewater into electrical energy, thus contributing to circular economy. Five electrogenic bacteria, Kocuria rosea (GTPAS76), two strains of Bacillus circulans (GTPO28 and GTPAS54), and two strains of Corynebacterium vitaeruminis (GTPO38 and GTPO42) were isolated from a common effluent treatment plant (CETP) and were used individually as well as in consortium form to run double chambered "H" type microbial fuel cell. Individually they could produce voltage in the range of 0.4-0.7 V in the MFC systems. Consortium developed using GTPO28, GTPO38, GTPAS54 and GTPAS76 were capable of producing voltage output of 0.8 V with 81.81 % and 64 % COD and BOD reduction, respectively. The EPS production capacity and electricity generation by the isolated bacteria correlated significantly (r = 0.72). Various parameters like, effect of preformed biofilm, length of salt bridge and its reuse, aeration, substrate concentration and external resistance were studied in detail. The study emphasizes on improving the commercialization aspect of MFC with repeated use of salt bridge and improving wastewater treatment potential after optimization of MFC system. Polarization curve and power density trends were studied in optimized MFC. A maximum power density and current density achieved were 18.15 mW/m Show less

During definitive erythropoiesis, maturation of erythroid progenitors into enucleated reticulocytes requires the erythroblastic island (EBI) niche comprising a central macrophage attached to differentiating erythroid progenitors. Normally, the macrophage provides a nurturing environment for maturation of erythroid cells. Its critical physiologic importance entails aiding in recovery from anemic insults, such as systemic stress or acquired disease. Considerable interest in characterizing the central macrophage of the island niche led to the identification of putative cell surface markers enriched in island macrophages, enabling isolation and characterization. Recent studies focus on bulk and single cell transcriptomics of the island macrophage during adult steady-state erythropoiesis and embryonic erythropoiesis. They reveal that the island macrophage is a distinct cell type but with widespread cellular heterogeneity, likely suggesting distinct developmental origins and biological function. These studies have also uncovered transcriptional programs that drive gene expression in the island macrophage. Strikingly, the master erythroid regulator EKLF/Klf1 seems to also play a major role in specifying gene expression in island macrophages, including a putative EKLF/Klf1-dependent transcription circuit. Our present review and analysis of mouse single cell genetic patterns suggest novel expression characteristics that will enable a clear enrichment of EBI subtypes and resolution of island macrophage heterogeneity. Specifically, the discovery of markers such as Epor, and specific features for EKLF/Klf1-expressing island macrophages such as Sptb and Add2, or for SpiC-expressing island macrophage such as Timd4, or for Maf/Nr1h3-expressing island macrophage such as Vcam1, opens exciting possibilities for further characterization of these unique macrophage cell types in the context of their critical developmental function. Show less

Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRβ agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRβ-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRβ and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRβ agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation. Show less

Mutations in at least 13 different genes (called CLNs) underlie various forms of neuronal ceroid lipofuscinoses (NCLs), a group of the most common neurodegenerative lysosomal storage diseases. While inactivating mutations in the CLN1 gene, encoding palmitoyl-protein thioesterases-1 (PPT1), cause infantile NCL (INCL), those in the CLN3 gene, encoding a protein of unknown function, underlie juvenile NCL (JNCL). PPT1 depalmitoylates S-palmitoylated proteins (constituents of ceroid) required for their degradation by lysosomal hydrolases and PPT1-deficiency causes lysosomal accumulation of autofluorescent ceroid leading to INCL. Because intracellular accumulation of ceroid is a characteristic of all NCLs, a common pathogenic link for these diseases has been suggested. It has been reported that CLN3-mutations suppress the exit of cation-independent mannose 6-phosphate receptor (CI-M6PR) from the trans Golgi network (TGN). Because CI-M6PR transports soluble proteins such as PPT1 from the TGN to the lysosome, we hypothesized that CLN3-mutations may cause lysosomal PPT1-insufficiency contributing to JNCL pathogenesis. Here, we report that the lysosomes in Cln3-mutant mice, which mimic JNCL, and those in cultured cells from JNCL patients, contain significantly reduced levels of Ppt1-protein and Ppt1-enzyme activity and progressively accumulate autofluorescent ceroid. Furthermore, in JNCL fibroblasts the V0a1 subunit of v-ATPase, which regulates lysosomal acidification, is mislocalized to the plasma membrane instead of its normal location on lysosomal membrane. This defect dysregulates lysosomal acidification, as we previously reported in Cln1 Show less

Insulin resistance (IR) is an important determinant of type-2 diabetes mellitus (T2DM). Free fatty acids (FFAs) induce IR by various mechanisms. A surfeit of circulating FFA leads to intra-myocellular lipid accumulation that induces mitochondrial ROS generation and worsens IR. However, the molecular mechanisms behind are unclear. We identified thioredoxin interacting protein (TxNIP), which is overexpressed in T2DM, to be a promoter of ROS-induced IR. We observed upregulation of TxNIP upon palmitate treatment in skeletal muscle cells that led to ROS generation and Glut-4 downregulation resulting in impaired glucose-uptake. FFA-induced overexpression of TxNIP gene was mediated through the activation of its bona-fide trans activator, ChREBP. Further, Palmitate-induced impairment in AMPK-SIRT-1 pathway resulted in overexpression of ChREBP. While Fenofibrate, abrogated PA-induced TxNIP expression and ROS generation in skeletal muscle cells, Saroglitazar, a dual PPARα/γ-agonist, not only inhibited PA-induced TXNIP expression but also led to greater improvement in glucose uptake. Taken together, TxNIP appears to be an important factor in FFA-induced ROS generation and IR in skeletal muscle cells, which can be modulated for the management of this complex disorder. Show less