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Ahmed, T.

Publications and source records attributed to Ahmed, T..

At least 19 recordsLinked to original sources

Capsule types driving carbapenem-resistant Klebsiella pneumoniae in Pakistan are largely absent from the phage literature

Phage therapy is increasingly proposed for carbapenem-resistant Klebsiella pneumoniae, but most Klebsiella phages bind a single capsule type, so a phage is useful only where its capsule type circulates. We asked whether published phages cover the capsule types found in Pakistani patients. We typed 254 clinical K. pneumoniae genomes from Pakistan and curated the phage and depolymerase literature into 34 phage-capsule records covering 27 phages and 15 capsule types. Nearly half the cohort was unmatched: 121 of 254 isolates (47.6%), spanning 51 of 66 capsule types, belong to types for which no phage has been described, and 67 of those isolates carry a carbapenemase. Collapsing each BioProject to one isolate per type raises the unmatched fraction to 51.8%. To ask why, we typed 475 genomes sampled on identical criteria from India, Bangladesh and Nepal, China, Europe and the USA. Two capsule types separated sharply. KL81 accounted for 6.3% of South Asian genomes and none of 275 from China, Europe or the USA, and has no published phage; KL107 showed the reverse, 9.8% in those regions and absent from South Asia. Both survived collapsing (P = 0.0014 and P = 0.0002). Six further differences did not, and are attributable to clonal expansion within single studies. Phages are isolated against locally available hosts, so the capsule types entering the global phage collection track the regions doing the isolating. KL81 is a defined target for phage isolation in South Asia.

microbiology↗

RGC-specific reversal of lipid peroxidation drives neuroprotection and vision restoration in optic nerve ischemia by targeting GPX4

Nonarteritic anterior ischemic optic neuropathy (NAION) is the leading cause of acute optic nerve related vision loss in older adults, yet no disease modifying therapy exists. Although ischemia is a defining feature of NAION, prior therapeutic efforts targeting vascular insufficiency or nonspecific oxidative stress have failed to prevent irreversible retinal ganglion cell (RGC) degeneration, underscoring an unresolved mechanistic gap between ischemic insult and permanent axonal failure. In this endeavour, we identify lipid peroxidation as an important driver of neurodegeneration in NAION. Analyses of human NAION retina, together with a rigorously validated mouse model, demonstrated a remarkable activation of phospholipid peroxidation within the retina following ischemic injury. RGC-specific overexpression of glutathione peroxidase 4 (GPX4), the only known enzyme capable of directly detoxifying phospholipid hydroperoxides within biological membranes, confers striking protection of RGC survival, axonal integrity, and visual function. We further demonstrate that mitochondrial-targeted GPX4 provides superior protection, suggesting mitochondria as a critical locus of lipid peroxidation-driven vulnerability in NAION. Leveraging real-time multiparametric in vivo imaging to directly interrogate axonal metabolism and function, we demonstrate that RGC-specific GPX4 overexpression robustly restores axonal and retinal mitochondrial abundance, improves ATP bioenergetics, and suppresses superoxide stress following optic nerve ischemia. Mitochondria-targeted GPX4 expression further restores axonal transport and retinofugal projections to central visual targets, thereby stabilizing visual pathway connectivity. Notably, these neuroprotective effects are recapitulated by Ebselen, a clinically tested GPX mimetic, identifying lipid peroxide detoxification as a translatable and imaging-validated therapeutic strategy. Collectively, this work establishes ischemia-induced lipid peroxidation as an essential driver of neurodegeneration in NAION and identifies GPX4 as a key molecular determinant of retinal ganglion cell resilience.

neuroscience↗

Small intestinal microbiota of undernourished women perturbs placental development in mice

Children of undernourished women have impaired pre- and postnatal growth. Undernourished women and children have a high incidence of environmental enteric dysfunction (EED), an enteropathy characterized by gut barrier dysfunction and systemic inflammation. Here, we employ gnotobiotic mice to compare the effects of bacterial consortia cultured from the duodenal microbiota of Bangladeshi women with EED and their healthy counterparts. Female mice harboring the EED-derived consortium exhibited fetal and placental growth restriction. Transcriptomic and proteomic analyses disclosed pronounced effects of the EED-derived consortium on the decidual component of the maternal-fetal interface involving tissue-resident uterine natural killer (uNK) cells and disruption of TGF-{beta} signaling between uNK and decidual stromal cells. Co-housing mice with EED and healthy consortia ameliorated these effects, disclosing bacterial targets to improve prenatal development.

systems biology↗

Intestinal fructose metabolism drives unsaturated fat absorption and synergizes with GLP-1 receptor agonism to promote weight loss

High-fat, high-sucrose (HFHS) diets are established risk factors for obesity. In the intestine, sucrose is hydrolyzed into glucose and fructose, with fructose being taken up by epithelial cells and phosphorylated by ketohexokinase (KHK). We hypothesized that KHK is required for the obesogenic effects of HFHS diets and performed genetic and pharmacologic experiments in mice using diet-induced obesity (DIO) models. We show that genetic loss of KHK prevents HFHS-induced weight gain and intestinal villus elongation. Moreover, pharmacologic inhibition of KHK (KHKi) promotes weight and fat loss during continued HFHS feeding in DIO mice and enhances weight loss and weight maintenance during and after incretin-mimetic therapy. The anti-obesogenic effects of KHKi were associated with delayed intestinal lipid absorption, reprogramming of lipid metabolism in the distal intestinal epithelium, and reduced absorption of unsaturated dietary fats. Together, these findings identify fructose metabolism as a key regulator of intestinal lipid handling and suggest that fructose promotes obesity, in part, by enhancing intestinal lipid absorption and metabolism.

cell biology↗

Xenium In Situ Profiling Uncovers HSPG-Dependent SULF1/VEGFR2 Signaling Mediating Vascular Remodeling in Moyamoya Disease

BackgroundMoyamoya disease (MMD) is characterized by progressive arterial stenosis and abnormal collateral formation, but the spatial organization of vessel-wall abnormalities remains incompletely understood. MethodsWe combined Xenium in situ spatial transcriptomics and multiplex immunofluorescence in superficial temporal artery samples from patients with MMD and controls, and performed gain- and loss-of-function experiments in human brain microvascular endothelial cells (HBMECs). Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), tube-formation, Transwell migration, and cell scratch assays were used to assess signaling and endothelial phenotypes. ResultsMMD vascular tissue showed intimal hyperplasia, altered spatial cellular architecture, and enrichment of extracellular matrix- and proteoglycan-related programs, with upregulation of sulfatase 1 (SULF1). In HBMECs, SULF1 knockdown reduced, whereas SULF1 overexpression enhanced, vascular endothelial growth factor A165 (VEGF-A165)-induced vascular endothelial growth factor receptor 2 (VEGFR2), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT) phosphorylation, migration, tube formation, and angiogenesis- and adhesion-related gene expression. Heparinase III attenuated the signaling effects associated with SULF1 overexpression. ConclusionThese findings suggest that SULF1-associated extracellular matrix alterations may contribute to local vessel-wall remodeling and enhanced endothelial responsiveness in MMD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/721514v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@f1fa1aorg.highwire.dtl.DTLVardef@5ac693org.highwire.dtl.DTLVardef@1a2e755org.highwire.dtl.DTLVardef@1a858_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

Spatial Multi-Omics Reveals Extracellular Matrix Remodeling and VSMC Phenotypic Switching in Moyamoya Disease

BackgroundMoyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by steno-occlusive lesions and intimal hyperplasia. Although vascular smooth muscle cell (VSMC) phenotypic switching is implicated in its pathogenesis, the precise spatial interplay between extracellular matrix (ECM) remodeling and local metabolic alterations within the distinct vascular microenvironments remains unknown. MethodsSuperficial temporal artery (STA) samples from patients with MMD and controls were analyzed by histology, immunofluorescence, spatial transcriptomics, spatial proteomics, and spatial metabolomics. Single cell RNA sequencing was used to profile the cellular landscape of STA tissues. To functionally validate the identified pathway, human brain vascular smooth muscle cells (HBVSMCs) were stimulated with fibronectin 1 (FN1), and patient derived induced pluripotent stem cell smooth muscle cells (iPSC-SMCs) were generated for migration and protein expression assays following ITGA5 silencing or focal adhesion kinase (FAK) inhibition. ResultsMMD STA samples exhibited marked intimal hyperplasia with medial thinning and intimal accumulation of -SMA positive cells. Spatial transcriptomic and proteomic analyses identified an intimal remodeling program characterized by increased FN1, EFEMP1, fibronectin, ITGA5, and FAK, together with reduced MYH11. FN1 stimulation promoted smooth muscle cell migration, ECM associated protein expression, and FAK phosphorylation, whereas ITGA5 knockdown or FAK inhibition attenuated these effects. Patient derived MMD iPSC-SMCs showed similar abnormalities, including enhanced migration, increased FAK activation, reduced contractile markers, and increased ECM associated proteins. Spatial metabolomics and integrated multi-omics analyses further revealed that these changes were coupled to a metabolically depleted intimal niche enriched for reduced acyl-CoA related metabolites. ConclusionsIntegrated spatial multi-omics identifies coupled ECM remodeling and metabolic alteration in the hyperplastic intima of MMD. Within this context, the FN1-ITGA5-FAK axis emerges as a plausible mediator of smooth muscle remodeling that warrants further validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/721225v1_ufig1.gif" ALT="Figure 1"> View larger version (90K): org.highwire.dtl.DTLVardef@3f6e19org.highwire.dtl.DTLVardef@554d49org.highwire.dtl.DTLVardef@451dd9org.highwire.dtl.DTLVardef@1aac1e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

New host and geographic range expansion of Lemuricola nycticebi in the Bengal slow loris

PurposeThe Bengal slow loris (Nycticebus bengalensis) is a globally Endangered nocturnal primate with limited health data across its South and Southeast Asian range. MethodsDuring necropsies of two deceased individuals from northeastern Bangladesh, numerous live adult pinworms were recovered. ResultsMorphological examination combined with mitochondrial cox1 gene sequencing identified the parasites as Lemuricola (Protenterobius) nycticebi. Both hosts exhibited severe gastrointestinal and peritoneal lesions consistent with high-intensity helminth infection. This represents the first confirmed record of L. nycticebi in the Bengal slow loris and extends the parasites known geographic range by approximately 3,400 km. ConclusionOur findings highlight an overlooked parasitic threat to slow lorises. Given that many Bengal slow lorises are rescued or confiscated from the illegal wildlife trade and forest-edge areas in Bangladesh every year and subsequently released into the wild, the results underscore the need for systematic health assessments, including parasitic screening, before repatriation into the wild.

zoology↗

JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake

Lung cancer is the leading cause of cancer-related death and is frequently accompanied by reduced food intake and cachexia, a debilitating syndrome characterized by weight loss and skeletal muscle wasting. We sought to identify contributors to cachexia using a murine model of lung cancer that reproduces key features of this syndrome. A multiplex cytokine screening approach, integrated with western blot and transcriptomic analyses, identified tumor-derived inflammatory mediators and downstream signaling pathways associated with cachexia. Notably, IL-6 superfamily members were elevated in the tumor and plasma of mice and patients with cachexia. The JAK-STAT3 signaling was upregulated in liver and skeletal muscle, driving the acute phase response and impairing lipid metabolism. Pharmacologic inhibition of JAK1/2 with ruxolitinib improved body weight, fat mass, and overall survival without altering tumor burden. These effects were driven primarily by blunted hypothalamic leptin receptor signaling, which increased food intake early in the disease course. In the liver, JAK inhibition reduced STAT3 activity, restored fatty acid oxidation, and decreased the production of acute-phase proteins. These findings support JAK inhibition as a therapeutic strategy for lung cancer-associated cachexia. Statement of SignificanceCancer cachexia is a lethal complication of lung cancer that lacks effective treatment. We show that JAK inhibition by ruxolitinib restores weight, fat mass, and prolongs survival in murine models of lung cancer. These effects were independent of tumor burden, underscoring the relevance of addressing cachexia to improve survival in cancer patients and supporting clinical testing of JAK inhibition for cancer cachexia

cancer biology↗

Think Before You List: Integrative Systematics of an 'Endemic and Critically Endangered' Butterfly in the Sundarbans

Accurate species delineation is fundamental to understanding evolutionary relationships and guiding effective conservation measures. While the IUCN Red List serves as a critical conservation tool, its reliability hinges on precise systematic species identification and comprehensive distribution data. However, taxonomic inconsistencies remain a major challenge, particularly for poorly studied taxa in complex ecoregions like the Sundarbans mangrove forest. Here, we investigated the taxonomic identity of the Sundarbans Crow, Euploea crameri nicevillei (Moore, 1890), which is considered the only endemic and critically endangered butterfly of Bangladesh, reported only from the Sundarbans mangroves. The taxonomic status of this butterfly has long been debated, with authors regarding it as a morph of Euploea core (Cramer, 1780), while others designated it as a distinct subspecies of E. crameri (Lucas, 1853). Thus, we applied an integrative taxonomic approach incorporating morphological and molecular evidence with field observations and found that the E. crameri nicevillei is conspecific with the E. core. Based on its distinctive external wing morphology and geographic distribution, we recognize it as a valid subspecies of that, E. core nicevillei (Moore, 1890), stat. nov. Furthermore, this subspecies has a wider geographical range than previously assumed. These results suggest that its earlier designation as endemic and critically endangered was premature, emphasizing the importance of rigorous integrative systematics and the need to reassess its conservation status in Bangladesh.

zoology↗

Using gnotobiotic mice to decipher effects of gut microbiome repair in undernourished children on tuft and goblet cell function

Studies have implicated perturbations in the postnatal development of the gut microbiome as a contributing factor to childhood undernutrition. Compared to a standard ready-to-use supplementary food, a microbiome-directed complementary food (MDCF-2) designed to repair these perturbations produced superior improvements in ponderal and linear growth in clinical trials of Bangladeshi children with moderate acute malnutrition. Here, reverse translation experiments are performed where intact fecal microbiomes collected from trial participants prior to and at the end of treatment are introduced into female gnotobiotic mice just after delivery of their pups. Pups received diets designed to resemble those consumed by children in the trials to recreate "unrepaired" and "repaired" gut ecosystems. Analyses of the abundances of bacterial strains (metagenome-assembled genomes), their expressed genes and metabolic products, combined with assessments of ponderal growth and intestinal epithelial lineage transcriptomes (single-nucleus RNA-Seq with follow-up immunocytochemistry) disclosed effects of MDCF-2 associated microbiome repair that cannot be determined, in part because no treatment control arms cannot be ethically incorporated into these trials. Specifically, microbiome repair in these mice produced significant increases in ponderal growth, changes microbial gene expression consistent with a less virulent gut ecosystem and changes in expression of (i) components of gut epithelial cell junctions in the enterocytic and goblet cell lineages, (ii) pathways for synthesis and secretion of eicosanoid immune effectors in chemosensory tuft cells, and (iii) goblet cell pathways involved in glycosylation and secretion of mucin. Experiments of the type described can help formulate and test hypotheses about how microbiome repair affects host biology. SIGNIFICANCE STATEMENTUndernutrition is a global health problem. Recent clinical trials of a gut microbiome-directed complementary food (MDCF-2) designed to repair the perturbed gut microbiomes of undernourished Bangladesh children produced superior growth outcomes versus a standard nutritional supplement. Given ethical considerations and tissue sampling constraints associated with these types of studies, we colonized gnotobiotic mice postnatally with microbiome samples obtained from trial participants before and after treatment to model "unrepaired" and "repaired" gut ecosystems. Using a multi-omics approach, we uncover heretofore unappreciated changes in expressed chemosensory tuft cell, mucus-producing goblet cell and absorptive enterocytic functions and interactions accompanying microbiome repair. Extending microbiome clinical trials back to preclinical models ( reverse translation) provides mechanistic insights that can inform design/interpretation of future interventions.

microbiology↗

Environmental and Maternal Imprints on Infant Gut Metabolic Programming

Early life is a critical period for immune and metabolic programming, but developmental patterns remain underexplored in populations from low- and middle-income countries. Here, we profiled the microbiome and metabolome of 55 Bangladeshi mother-infant dyads over the first six months of life. Importantly, we observed an increase in microbially-derived bile amidates and N-acyl lipids with age in conjunction with reads matching the bile salt hydrolase/transferase (bsh) gene. While microbial source tracking confirmed maternal fecal seeding, a substantial environmental contribution was also highlighted. Differences in infant fecal metabolic profiles were associated with delivery mode, maternal milk composition, household assets, and household-level water treatment. C-section delivery and untreated drinking water were linked to transient metabolic differences, including increases in bile amidates, N-acyl lipids, and other host-microbe co-metabolic products, including acylcarnitines. Multi-omics analysis revealed specific microbial-metabolite relationships, highlighting how early environmental and maternal living circumstances shape metabolic gut programming through the microbiome.

microbiology↗

The Immune-Modulatory Function of Megakaryocytes in the Hematopoietic Niche of Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and neoplastic hematopoietic stem cell (HSC) expansion. Using a murine model with MK-specific JAK2V617F expression, we establish an MPN aging model where mutant MKs drive HSC expansion and a progressive decline in wild-type HSC function. Compared to wild-type MKs, JAK2V617F MKs exhibit heightened inflammation and innate immune activation with aging, including increased antigen presentation, elevated pro-inflammatory cytokines, skewed T cell populations, and impaired T cell functions in the marrow niche. Enhanced MK immunomodulatory function is linked to mutant cell expansion and MPN progression in a chimeric murine model with co-existing wild-type and JAK2V617F mutant HSCs. LINE-1 (long-interspersed element-1), a retrotransposon linked to innate immune activation and aging, is upregulated in mutant MKs during aging in murine models. We validated that LINE-1-encoded protein ORF1p is expressed in marrow MKs in 12 of 13 MPN patients but absent in control samples from patients undergoing orthopedic surgery (n=5). These findings suggest that MKs reprogram the marrow immune microenvironment, impairing normal HSC function while promoting neoplastic expansion in MPNs. LINE-1 activation in mutant MKs may be a key driver of immune dysregulation in MPNs. Key PointsO_LIJAK2V617F mutant MKs reprogram the marrow immune microenvironment to promote neoplastic HSC expansion in MPNs. C_LIO_LILINE-1 activation in diseased MKs triggers chronic inflammation and immune dysfunction in MPNs. C_LI

cancer biology↗

Assessment of the Anticancer Activity of Aegle marmelos Leaf Extracts Against Ehrlich's Ascites Carcinoma (EAC) Cell Line in Swiss Albino Mice

Cancer remains a significant health threat globally, and as a result, the demand for safer and more effective alternatives keeps growing. In this current study, we have assessed the anticancer activity of Aegle marmelos extract on Ehrlich Ascites Carcinoma (EAC) cells on Swiss Albino mice. Three extracts were prepared: a methanolic (APME), chloroform (APCE), and n-hexane (APHE) extract. These extracts were administered intraperitoneally in doses of 50 mg/kg and 100 mg/kg per dose on 6 consecutive days to mice. The anticancer activity was assessed from viable tumor cell count, with percentage (%) inhibition of cell growth, and changes in body weight of the mice that had been treated with extracts. Of all the extracts, APHE exhibited the most tumor growth inhibition (62.2% at 100 mg/kg), followed by APME (59.25%) and APCE (54.86%), compared to the standard chemotherapy drug doxorubicin (81.6% inhibition at 0.8 mg/kg/day). Mice treated with the extracts experienced less weight loss than the control group, with an approximate effect of 0.50 {+/-} 0.06 g/day. A Brine Shrimp Lethality Bioassay demonstrated a cytotoxic dose-dependent impact, with LC50 values of 18.38, 36.79, and 46.45 micrograms per milliliter for n-hexane, methanolic, and chloroform extracts, respectively. The tumor suppression and cytotoxicity effects of Aegle marmelos extracts are probably attributable to the bioactive compounds such as flavonoids, alkaloids, and essential oils that have known apoptotic and antiproliferative activities. The extracts were not as effective as doxorubicin; however, the extracts natural composition and ability to reduce weight loss due to cancer indicate potential to be used in combination with or as an alternative to cancer-treating medications. Further research includes that mechanistic studies and clinical trials are needed to confirm their therapeutic potential.

cancer biology↗

Capturing dynamic phage-pathogen coevolution by clinical surveillance

Bacteria harness diverse defense systems that protect against phage predation1, many of which are encoded on horizontally transmitted mobile genetic elements (MGEs)2. In turn, phages evolve counter-defenses3, driving a dynamic arms race that remains underexplored in human disease contexts. For the diarrheal pathogen Vibrio cholerae, a higher burden of its lytic phage, ICP1, in patient stool correlates with reduced disease severity4. However, direct molecular evidence of phage-driven selection of epidemic V. cholerae has not been demonstrated. Here, through clinical surveillance in cholera-endemic Bangladesh, we capture the acquisition of a parasitic anti-phage MGE, PLE11, that initiated a selective sweep coinciding with the largest cholera outbreak in recent records. PLE11 exhibited potent anti-phage activity against co-circulating ICP1, explaining its rapid and dominating emergence. We identify PLE11-encoded Rta as the novel defense responsible and provide evidence that Rta restricts phage tail assembly. Using experimental evolution, we predict phage counteradaptations against PLE11 and document the eventual emergence and selection of ICP1 that achieves a convergent evolutionary outcome. By probing how PLEs hijack phage structural proteins to drive their horizontal transmission while simultaneously restricting phage tail assembly, we discover that PLEs manipulate tail assembly to construct chimeric tails comprised of MGE and phage-encoded proteins. Collectively, our findings reveal the molecular basis of the natural selection of a globally significant pathogen and its virus in a clinically relevant context.

microbiology↗

Effects of intergenerational transmission of small intestinal bacteria cultured from stunted Bangladeshi children with enteropathy

Environmental enteric dysfunction (EED), a small intestinal disorder found at a high prevalence in stunted children, is associated with gut mucosal barrier disruption and decreased absorptive capacity1-4. To test the hypothesis that intergenerational transmission of a perturbed small intestinal microbiota contributes to undernutrition by inducing EED5, we characterized two consortia of bacterial strains cultured from duodenal aspirates from stunted Bangladeshi children with EED - one of which induced local and systemic inflammation in female gnotobiotic mice. Offspring of dams colonized with the inflammatory consortium exhibited impaired prenatal and postnatal growth, as well as immunologic changes phenocopying features of EED in children. Dam-to-pup transmission of the inflammatory consortium produced, in recently weaned offspring, alterations in inter-cellular signaling pathways related to intestinal epithelial cell renewal, barrier integrity and immune function. Cohousing of mice harboring the inflammatory or non-inflammatory consortia and subsequent screening of candidate disease-promoting bacterial isolates identified Campylobacter concisus, an organism typically found in the oral microbiota, as a contributor to enteropathy. The C. concisus strain induced, in a host nitric oxide synthase (NOS)-dependent manner, pro-inflammatory cytokine signaling. Moreover, host-derived nutrients generated by NOS augmented C. concisus growth. This preclinical model should facilitate identification of small intestinal microbiota-targeted therapeutics for (intergenerational) undernutrition.

systems biology↗

Effects of fasting on heat-stressed broiler chickens: part I- growth performance, meat quality, gut histomorphological and microbial responses

The current study aimed to optimize the fasting duration in order to mitigate the detrimental effects of heat stress on broilers raised in hot and humid climatic environments. A total of 500 broiler DOCs were assigned to five distinct treatment groups: T= Non-fasted controlled temperature (24-26) (NF-CT), T1= Non-fasted heat stressed (30-38) (NF-HS), T2= 6 hours fasted heat stressed (6-h FHS), T3= 8 hours fasted heat stressed (8-h FHS), and T4= 10 hours fasted heat stressed (10-h FHS). Each treatment was replicated five times, with 20 birds in each replicate group. As expected, the birds in NF-CT group showed significantly better performances for all the growth parameters, although birds who fasted for 8-h under heat stress exerted better growth and FCR in comparison to the other HS groups. Fasting of birds under heat stress significantly showed the lowest mortality. Like the NF-CT group, birds in 8-h FHS achieved significantly higher dressing percentage, breast meat, liver yields, and the lowest abdominal fat. Fasting for 8- and 10-h significantly increased breast meat pH and water holding capacity and thus reduced cooking loss. Fasting also improved the breast meat color quality by increasing redness (a*) and reducing the hue angle values comparable with the NF-CT group. A significantly upward trend in villi height (VH), width (VW) and crypt depth (CD) of gut segments was also observed in the birds of the 8-h FHS group. Total bacterial and coliform counts in cecum contents were reduced significantly with the increase in the fasting period. Benefit-cost analysis showed better profitability in the 8-h FHS group than other HS groups. Taken altogether, it can be concluded that broiler chicken exposed to 8-h fasting period is an effective approach to mitigate heat stress under hot and humid climatic conditions.

zoology↗

WT1 targeting multi-epitope vaccine design for glioblastoma multiforme using immuno-informatics approaches

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer classified as grade 4 glioma with a median survival rate of 12-14 months. Currently there is no cure and the conventional treatment outcomes are poor making it imperative to develop novel treatments. WT1, also known as Wilms Tumor 1, is a protein that is often found to be overexpressed in GBM and has minimal expression in normal tissues has become a promising target for immunotherapy for its oncogenicity and immunogenicity. This study aimed to develop a multi-epitope vaccine using immuno-informatics approaches that specifically targets the WT1 protein. The WT1 sequence was used to predict B and T cell epitopes which showed probable antigenic, non-allergic and non-toxic properties. Using suitable linker and adjuvants the vaccine construct (370 amino acids) was prepared which were then analyzed for solubility, physicochemical properties, molecular docking to show receptor interactions and molecular dynamics to show stability of the vaccine-receptor complexes. Subsequently, the vaccine sequence was back translated (1110 nucleotides), codon adaptation, pET-28a (+) vector in-silico cloning, and immune response simulations were performed. The designed vaccine lays groundwork for future in-vitro and in-vivo studies and potentially develop it into a novel treatment option for GBM patients.

bioinformatics↗

The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney

Due to aging, the efficiency of kidney function begins to decrease. Dysfunction in mitochondria and their cristae is a hallmark of aging. Therefore, age-related decline in kidney function could be attributed to changes in mitochondrial ultrastructure, increased reactive oxygen species, and alterations in metabolism and lipid composition. We sought to understand how mitochondrial ultrastructure is altered over time in tubular kidney cells. A serial block facing-scanning electron microscope and manual segmentation using the Amira software were employed to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we demonstrate that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney during aging. Disruption of the MICOS complex resulted in altered mitochondrial metabolic function and increased ROS levels. We found significant, detrimental structural changes in the mitochondria of aged kidney tubules, suggesting a potential mechanism underlying the increased frequency of kidney disease with aging. We hypothesize that disruption of the MICOS complex exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, which impacts kidney health. Impact and ImplicationsDue to aging, the efficiency of kidney function begins to decrease, and the risk of kidney diseases may increase; however, the specific regulators of mitochondrial age-related changes are poorly understood. This study demonstrates that the MICOS complex may be a target for mitigating age-related mitochondrial changes. The MICOS complex is associated with oxidative stress and calcium dysregulation, which also arise in many kidney pathologies. HighlightsO_LIAging alters the MICOS mRNA levels and disease markers. C_LIO_LIAging reduces cristae architecture, mitochondrial volume and complexity in murine kidney ultrastructure C_LIO_LIReducing MIC60 and CHCHD6 lowers Ca2+ uptake and retention and induces oxidative stress in HEK cells. C_LIO_LIMetabolomic Profiling revealed that NAD+ and amino acid metabolism were altered in aged kidneys. C_LIO_LIMICOS deficiency alters the reduced basal, ATP-linked, maximal capacity and spare capacity. C_LIO_LIDecreased modeled expression of CHCHD6 in individuals of European genetic ancestry is linked to chronic kidney disease, whereas decreased modeled expression of OPA1 in individuals of African genetic ancestry is associated with chronic kidney disease. C_LI Graphical AbstractKidney aging causes a decline in the MICOS complex, concomitant with metabolic, lipidomic, and mitochondrial structural alterations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/598108v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@1a868f0org.highwire.dtl.DTLVardef@1817bfborg.highwire.dtl.DTLVardef@1f2a1a3org.highwire.dtl.DTLVardef@520692_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗