Biology subjects

Nazir, S.

Publications and source records attributed to Nazir, S..

9 recordsLinked to original sources

bioRxiv2026

Multicellular signaling and partial recovery define reverse cardiac remodeling

Heart failure results from maladaptive multicellular remodeling triggered by sustained biomechanical stress. Although mechanical unloading can promote reverse remodeling, recovery is frequently incomplete and its mechanistic basis remains unclear. Using a reversible murine pressure-overload model combined with bulk and single-nucleus transcriptomics, we demonstrate that reverse remodeling represents an actively maintained yet constrained multicellular state. Unloading improved cardiac function and partially restored extracellular matrix and metabolic programs, whereas inflammatory and mitochondrial dysfunction signatures persisted. Cardiomyocytes and endothelial cells largely re-established homeostatic transcriptional states, while fibroblasts retained activated programs that dominated residual pathology. Multicellular factor analysis delineated a reversible metabolic stress program and a persistent inflammatory-mitochondrial program coordinated across cardiac cell types. Cell-cell communication analysis identified lymphatic endothelial cells as key instructive regulators of recovery. Notably, lymphatic-derived Reelin directly suppressed pathological fetal gene activation in murine and human cardiomyocytes, uncovering a previously unrecognized lymphoangiocrine mechanism that constrains myocardial recovery in chronic heart failure.

molecular biology↗

bioRxiv2025

True Digestibility and Growth Response of Coated Essential Amino Acid Supplementation in Plant-Based Feeds for Rainbow Trout (Oncorhynchus mykiss)

In order to assess the efficacy of using essential amino acids to support the inclusion of high plant based proteins in diets for rainbow trout, a 56-day growth and feed utilisation study was conducted with juvenile (60g) rainbow trout (Oncorhynchus mykiss) under controlled conditions. Fish were fed diets where a predominately white fishmeal based control diet was compared to diets where full fat soyabean meal (FFS) as well as maize gluten meal (MGM) were incorporated respectively at significant levels (up to 75% of the fishmeal). Ten essential amino acids (EAAs) supplemented these diets in both standard and coated forms to evaluate their potential to rebalance the dietary EAA profiles more precisely. All diets were adjusted to be isonitrogenous and isolipidic. In addition to the growth trial, a low purified protein diet was fed to the fish separately (at a mean weight of 200g) to collect faeces for determining endogenous protein loss as well as the individual experimental diets described. As such it was possible to calculate the true digestibility for essential amino acids. The results indicated that corrective amino acid fortification of high plant diets, especially MGM could significantly (P<0.05) improve trout performance and raise their nutritional value. This was confirmed by final body weight, specific growth rate, feed conversion ratio and protein utilisation values. The true digestibility of the EAAs were similar and the values of each digestible EAA but coated EAAs were slightly superior in their digestibility coefficients. Coated EAAs improved digestibility coefficients by 2-5% and FCR by 8% compared to crystalline forms and also improved their utilisation leading to better trout performance with respect to growth, feed conversion efficiency and Nitrogen (crude protein) retention (P<0.05). The findings are discussed in the context of sustainable feeds and the circular bioeconomy for fish farming.

physiology↗

bioRxiv2025

CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction (HFrEF) is marked by a shift in cardiac energy metabolism from fatty acid oxidation to glucose utilization. This "fuel switch" promotes accumulation of glucose byproducts that modify calcium-handling proteins and impair cardiac function, yet the initiating signals remain unclear. We identify Ca2+/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [18F]FDG-PET imaging showed a six-fold increase in myocardial glucose uptake after pressure overload in control mice, but not in cardiomyocyte-specific Camk2d/Camk2g double knockouts (cDKO), even before functional decline. cDKO hearts retained lipid reserves, indicating preserved fatty acid metabolism. Transcriptomics revealed strong CAMK2-dependent induction of Nr4a1 and early repression of genes for fatty acid uptake and {beta}-oxidation preceding upregulation of genes for glucose utilization. Cardiomyocyte-specific Nr4a1 knockout mice closely mimicked the metabolic protection seen in cDKO, while NR4A1 overexpression in human iPSC-derived cardiomyocytes suppressed fatty acid metabolism. NR4A1 directly bound and repressed the FATP1 (Slc27a1) promoter, thereby secondarily enhancing glucose utilization. Together, these findings define a CAMK2-NR4A1 signaling axis that drives lipid depletion and metabolic remodeling, establishing it as a causal mechanism linking energy substrate switching to HFrEF.

physiology↗

bioRxiv2025

Treatment with the ribosome biogenesis inhibitor CX-5461 increases platelet count in humans and enhances murine megakaryopoiesis

Thrombocytopenia is a common and serious complication of anticancer therapies. Here, we identify a novel thrombopoietic activity of the first-in-class ribosome biogenesis inhibitor CX-5461. In a phase I trial, 56% (9/16) of patients exhibited up to a 34% increase in platelet count following a single dose of CX-5461. In mice, CX-5461 elicited a rapid, reversible, and sustained [~]1.7-fold increase in platelet numbers without altering platelet function, lifespan, or inflammatory cytokines. Bone marrow analysis revealed a specific expansion of megakaryocytes (MKs), increased Sca1 MKs, and selective enrichment of MK-biased multipotent progenitor 2, independent of thrombopoietin (TPO) or c-mpl signalling. CX-5461 also mitigated carboplatin-induced thrombocytopenia, accelerating platelet recovery. Single-cell RNA sequencing and RNA velocity analysis confirmed enhanced differentiation of MK progenitors. These findings demonstrate that inhibition of ribosome biogenesis promotes TPO-independent megakaryopoiesis and identifies a previously unrecognised therapeutic opportunity to support platelet recovery in cancer treatment and potentially other thrombocytopenic states.

cell biology↗

bioRxiv2025

A bioprinting approach for high-throughput production of micropatterned neuroepithelial tissues and modeling TSC2-deficient brain malformations

In vitro human pluripotent stem cell-derived models have been crucial in advancing our understanding of the mechanisms underlying neurodevelopment, though knowledge of the earliest stages of brain formation is lacking. Micropatterning of cell populations as they transition from pluripotency through the process of neurulation can produce self-assembled neuroepithelial tissues (NETs) with precise spatio-temporal control, enhancing the fidelity of hPSC models to the early developing human brain and their use in phenotypic assessments. Here, we introduce an accessible, customizable and scalable method to produce self-assembled NETs using bioprinting to rapidly deposit reproducibly sized extracellular matrix droplets. Matrix addition to the media provides a scaffold that promotes 3D tissue folding, reflecting neural tube development. We demonstrate that these scaffolded NETs (scNETs) exhibit key architectural and biological features of the human brain during normal and abnormal development, notably hyperproliferation and structural malformations induced by TSC2-deficiency, and provide a robust drug screening tool.

neuroscience↗

bioRxiv2023

Enhancing farmed striped catfish (Pangasianodon hypophthalmus) robustness using dietary β-glucan

{beta}-glucan is a well-documented feed additive for its potent immunostimulatory properties in many farmed fish species. This study examined how it can also be a promising growth promoter, modulate antioxidant enzyme activities, and act as an anti-stress agent in striped catfish (Pangasianodon hypophthalmus). A 12-week feeding experiment was untaken to determine the effects of dietary {beta}-glucan supplementation at graded levels (0, 0.5, 1.0, and 1.5 g kg-1). Measured indicators suggest that a dietary inclusion level of 1.5 g kg-1 {beta}-glucan gave the highest positive responses: weight gain (120.10 g fish-1), survival (98.30 %), and lower FCR (1.70) (P<0.05). Whole body proximate analysis had only revealed that crude protein was significantly affected by the dietary inclusion of {beta}-glucan (P<0.05), with the highest protein content (19.70 %) being in fish that were fed with 1.5 g kg-1 {beta}-glucan. Although other inclusion levels (i.e., 0.5 and 1 g kg-1) of {beta}-glucan did not enhance body protein content (P>0.05). The assessment of fatty acid composition in muscle, liver, and adipose tissues showed modifications with the inclusion of {beta}-glucan. Antioxidative-related enzyme activities (inc. catalase, glutathione peroxidase, and superoxide dismutase) that were measured in the liver had higher levels when fed with {beta}-glucan inclusion diets (P<0.05). Following the feed trial, fish were subjected to crowding stress treatment. It was subsequently found that catfish fed with {beta}-glucan-based diet groups had lower levels of blood stress-related indicators compared to the control group with no dietary {beta}-glucan. The use of 1.5 g kg-1 of dietary {beta}-glucan resulted in the lowest measured levels of cortisol (43.13 ng mL-1) and glucose (50.16 mg dL-1). This study has demonstrated that the dietary inclusion of {beta}-glucan can have functional benefits beyond the immunological enhancements in striped catfish. Furthermore, its use can increase production levels and mitigate the stress associated with intensive farming practices.

zoology↗

bioRxiv2023

Genetic Loss of Nicotinamide Nucleotide Transhydrogenase Prevents from Cardiometabolic Heart Failure with Preserved Ejection Fraction

RationaleHeart failure with preserved ejection fraction (HFpEF) represents a common clinical endpoint of cardiometabolic diseases which impair myocardial diastolic relaxation. Although myocardial redox perturbations are known to accompany HFpEF, the specific role of mitochondrial oxidative stress has not been demonstrated yet. ObjectiveBased on an observation that C57BL6/N - but not C57BL6/J - mice develop diastolic dysfunction when provided an ad libitum high-fat and 0.5% N({omega})-nitro-L-arginine methyl ester (HFD+L-NAME) diet, we conducted a multi-cohort murine study to determine whether the loss of Nicotinamide Nucleotide Transhydrogenase (NNT), a mitochondrial transhydrogenase that couples NADPH:NADP+ to NADH:NAD+ homeostasis, protects mice from developing cardiometabolic alterations. Methods and ResultsTwo cohorts of 12-week-old male and female mice possessing wild-type (Nnt+/+) or deleted (Nnt-/-) NNT were challenged by HFD+L-NAME for 9 weeks (n = 6-10). Male Nnt+/+ mice developed obesity (23.2% {Delta}, P = 0.003), arterial hypertension (24 {+/-} 5 {Delta} mmHg, P = 0.023), impaired glucose tolerance (P = 0.006), and reduced maximal treadmill running distance (-172 {+/-} 73.1 {Delta} m, P = 0.006) following 9 weeks HFD+L-NAME, whereas male Nnt-/- mice did not. Female mice were protected from cardiometabolic dysfunction regardless of Nnt genotype. Cardiac functional and morphologic characterization revealed similar NNT-dependent and sex-specific increases in E/e (42.8 vs. 21.5, P < 0.001) and E/A (2.3 vs 1.4, P = 0.007) ratios, diastolic stiffness (0.09 vs 0.04 mmHg/L, P = 0.02), and myocardial fibrosis (P = 0.02). Unsupervised transcriptomic analysis identified distinct genetic and dietary signatures, wherein Nnt+/+ exhibited disproportionate perturbations in various mitochondrial oxidative pathways following HFD+L-NAME. Our search for putative transcriptional regulators identified NNT-dependent suppression of NAD+ dependent deacetylase Sirt3. ConclusionsTaken together, these observations support that the genetic disruption of Nnt protects against both cardiac and metabolic consequences of HFD+L-NAME, thus highlighting a novel etiology-specific avenue for HFpEF therapeutics.

physiology↗

bioRxiv2021

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

A major therapeutic obstacle in diabetes mellitus is the metabolic or hyperglycemic memory: the persistence of impaired organ function despite improvement of blood glucose. Therapies reversing the hyperglycemic memory and thus improving already established organ-dysfunction are lacking, but urgently needed considering the increasing prevalence of diabetes mellitus worldwide. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with sustained induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, in several independent human samples and in in vitro models. Tubular p21 expression and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans, suggesting that p21 may be a biomarker indicating persistent ("memorized") kidney damage. Glucose-mediated p21 induction and tubular senescence were enhanced in mice with reduced levels of the disease resolving protease activated protein C (aPC). Mechanistically, glucose-induced and sustained tubular p21 expression is linked with demethylation of its promoter and reduced DNMT1 expression. aPC reverses already established p21 expression independent of its anticoagulant function through receptor signaling. Accordingly, new pharmacological approaches specifically mimicking aPC signaling (3K3A-aPC, parmodulin-2) enabled the reversal of glucose-mediated sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence contributes to the hyperglycemic memory but can be therapeutically targeted. Single sentence summaryaPC signaling targets persistent p21 expression and tubular senescence and reverses the hyperglycemic memory in diabetic kidney disease.

molecular biology↗

bioRxiv2020

Forensic features and genetic legacy of the Baloch population of Pakistan and the Hazara population across Durand-line revealed by Y chromosomal STRs

Hazara population across Durand-line has experienced extensive interaction with Central Asian and East Asian populations. Hazara individuals have typical Mongolian facial appearances and they called themselves descendants of Genghis Khans army. The people who speak the Balochi language are called Baloch. Previously, a worldwide analysis of Y-chromosomal haplotype diversity for rapidly mutating (RM) Y-STRs and with PowerPlex Y23 System (Promega Corporation Madison, USA) kit was created with collaborative efforts, but Baloch and Hazara population from Pakistan and Hazara population from Afghanistan were missing. A limited data with limited number of markers and samples is available which poorly define these populations. So, in the current study, Yfiler Plus PCR Amplification Kit loci were examined in 260 unrelated Hazara individuals from Afghanistan, 153 Hazara individuals, and 111 Balochi individuals from Baluchistan Pakistan. For the Hazara population from Afghanistan and Pakistan overall, 380 different haplotypes were observed on these 27 Y-STR loci, gene diversities ranged from 0.51288 (DYS389I) to 0.9257 (DYF387S1) and haplotype diversity was 0.9992 +/- 0.0004. For the Baloch population, every individual was unique at 27 Y-STR loci, gene diversity ranged from 0.5718 (DYS460) to 0.9371(DYF387S1). Twelve haplotypes shared between 178 individuals while only two haplotypes among these twelve were shared between 87 individuals in Hazara populations. Rst and Fst pairwise genetic distance analyses, multidimensional scaling (MDS) plot, Neighbor-joining (NJ) tree, linear discriminatory analysis (LDA), and median-joining network (MJNs) were performed, which shed light on the history of Hazara and Baloch populations. Interestingly null alleles were observed at DYS448 with specific mutation patterns in Hazara populations. The results of our study showed that the Yfiler Plus PCR Amplification Kit marker set provided substantially stronger discriminatory power in the Baloch population of Pakistan and the Hazara population across the Durand-line.

evolutionary biology↗