Biology subjects

Naz, S.

Publications and source records attributed to Naz, S..

11 recordsLinked to original sources

bioRxiv2026

GDF3 is an endogenous antagonist of the ActE-ALK7/ACVR2 pathway in adipocytes

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) arise, in part, from excessive free fatty acid flux from adipose tissue to the liver. Activin E (ActE, encoded by INHBE) suppresses adipocyte lipolysis through the type I receptor ALK7 (ACVR1C). Loss-of-function variants in INHBE and ACVR1C reduce waist-to-hip ratio in humans, yet genetic knockouts in mice produce insulin resistance and hepatic steatosis, suggesting discrepancies between human and mouse biology. We identify GDF3, a TGF-{beta} superfamily ligand upregulated in obese adipose tissue, as the principal endogenous antagonist of ActE/ALK7 signaling. Human transcriptomic datasets reveal coordinated dysregulation: hepatic INHBE expression and circulating ActE protein are elevated in obesity, while adipose ACVR1C is downregulated and GDF3 is reciprocally upregulated. Using ALK7-selective reporter assays, we show GDF3 inhibits ActE-driven SMAD2/3 signaling as a competitive antagonist rather than the weak agonist previously proposed. ActE suppressed beta-adrenergic-stimulated lipolysis in mouse and human adipocytes and primary human adipose tissue; GDF3 overexpression abolished this effect. In diet-induced obese mice, inducible Gdf3 deletion reduced adipose lipolysis, resolved hepatic steatosis and fibrosis, and improved insulin sensitivity, benefits abolished by Inhbe knockdown, confirming dependence on ActE signaling. Predicted loss-of-function variants in INHBE show only nominal, WHR-dependent associations with type 2 diabetes risk, potentially confounded by hematological effects on HbA1c. Gdf3 deficiency synergized with the clinical-stage anti-activin receptor antibody Bimagrumab to amplify fat-mass loss and improve glucose homeostasis in multiple MASH models. These findings establish GDF3 as an endogenous antagonist of ActE-ALK7 signaling and nominate GDF3 inhibition as a therapeutic strategy for MASLD/MASH.

physiology↗

bioRxiv2025

Microgradients in porosity and canal diameter in femur bone

Bone exhibits hierarchical structural gradients that optimize mechanical performance and regenerative potential. Longitudinal and radial variations in cortical porosity and canal architecture influence load distribution, vascularization, and remodeling. Understanding these gradients is essential for designing scaffolds and implants that mimic native bone structure and function. This study quantified longitudinal and radial microgradients in cortical porosity and canal diameter along the rabbit femur and explored their implications for bone regeneration and repair implant design. Rabbit femora were divided into proximal, mid-shaft, and distal regions. High-resolution micro-computed tomography quantified cortical thickness, porosity, and canal diameter along radial and longitudinal axes in micron-scale resolutions. Compressive mechanical testing of cortical slices determined local moduli, which were correlated with microstructural parameters to establish structure-function relationships. Cortical thickness peaked at the mid-shaft and decreased toward both ends. Porosity and canal diameter increased radially toward the medullary cavity and longitudinally toward the bone ends. Upto 500 micron cortical thickness from the outer surface toward modullary cavity, porosity and canal diameter ranged, respectively, from ~5% and 40 {micro}m at the mid-shaft to ~40% and 110 {micro}m at the ends. At 750 micron cortical thickness, porosity and canal diameter ranged, respectively, from ~5% and 50 {micro}m at the mid-shaft to ~80% and 200 {micro}m at the ends. As expected, compressive moduli declined linearly with increasing porosity and canal size. The mid-shaft, with the lowest porosity and smallest canals, exhibited the highest modulus of around 15{square}MPa, which decreased to 5{square}MPa toward the ends. The rabbit femur displays distinct longitudinal and radial microgradients in porosity and canal architecture that govern local stiffness. These gradients define structural benchmarks for designing functionally graded tissue engineering scaffolds and bone implants that replicate native tissue structure and stiffness transitions to promote osteoconduction, osteoinduction, osteogenesis in bone regeneration and improve osseointegration of bone implants.

bioengineering↗

bioRxiv2025

Metabolic, epigenetic and transcriptomic alterations in postnatal 16p11.2 deficient murine astrocytes

Autism Spectrum Disorders (ASD) are associated with metabolic dysregulation. While astrocytes are integral to cerebral metabolism, their molecular and functional changes in ASD are poorly known. Using early postnatal primary cortical astrocytes from a mouse model of 16p11.2 deletion ASD syndrome (16p11.2df/+ mice), we observed core molecular alterations with sex-specific profiles, suggesting divergent energetic pathways and epigenetic regulation. Targeted metabolomics revealed opposing phenotypes in male versus female 16p11.2df/+ astrocytes, particularly for alpha-ketoglutaric acid. Functionally, 16p11.2df/+astrocytes exhibited elevated phosphorylation in low glucose culture conditions, and reduced glycolysis in high glucose. Epigenetic profiling of male 16p11.2df/+astrocytes revealed differentially hydroxymethylated and methylated regions, with foci on chromosomes 3 and 13. Finally, bulk RNA sequencing in male and female mutant astrocytes indicated differential gene expression with profound sex differences, mostly affecting pathways related to cellular morphology. By establishing 16p11.2df/+ astroglial molecular signatures, this study refines our understanding of glial changes in ASD.

cell biology↗

bioRxiv2025

Oral administration of engineered recombinant outer membrane vesicles-based nano-vaccine formulation triggers robust mucosal and systemic humoral immunity against poultry pathogens

Although vaccination is an integral part of poultry health management, affordable, scalable, and easily administrable new-generation vaccine discovery platforms are required to combat emerging infectious diseases. Oral vaccines offer an alternative to injectable options owing to their ease of administration; however, existing platforms fail to confer robust protective systemic and mucosal immunity. Here, we used engineered outer membrane vesicles (rOMVs) displaying the desired vaccine antigens, and derived from hypervesiculating probiotic E coli Nissle 1917 (EcN) [36], which elicits both mucosal and systemic immunity when administered orally. Using such approach, we attempted to formulate rOMV based single Oral vaccine against Newcastle Disease Virus (NDV) and Infectious Bursal Disease Virus (IBDV), which pose significant risks to the poultry sector. We engineered rOMVs to display the antigenic regions of immunodominant Hemagglutinin-Neuraminidase (HN) and Viral Protein 2 (VP2) of NDV and IBDV, respectively, on their surface, with sizes less than 150 nm and considerable polydispersity. The Oral administration of these rOMVs expressing the HN and VP2 induced a robust immune response which shows enhanced production of high-titer antigen-specific sIgA and IgG, which were able to neutralize the virus effectively in an in-vitro infection model system. While the poultry pathogens such as NDV and IBDV served as a model, the rOMV-based platforms hold considerable potential for the development of a multivalent oral biotherapeutic agent, including vaccines against a wide range of emerging human and animal pathogens by engineering rOMVs to display immunodominant antigenic portions, demonstrating its capability as a next-generation oral vaccine discovery platform.

immunology↗

bioRxiv2025

ALOX12B overexpression in the skin drives inflammasome/Th17 signaling axis to promote inflammation in the mouse model and human patients

Inflammation plays a pivotal role in the etiopathogenesis of chronic inflammatory skin diseases. However, the underlying mechanism remains unclear. Here, we employed Gene expression meta-analysis and clinical validation strategy to dissect the global architecture of immune dysregulation responsible for inflammatory conditions in the skin. Using such approaches, we identified a gene signature comprising of ALOX12B, which is significantly upregulated in psoriatic and atopic dermatitis patient skin samples, and correlates with increased levels of pathological IL-1{beta} and Th17 responses. Surprisingly, ALOX12B is predominantly expressed in the skin. Furthermore, skin-specific overexpression of human ALOX12B in transgenic mice resulted in psoriasis-like inflammatory symptoms, including epidermal hyperplasia, immune cell infiltration, and elevated IL-1{beta}/Th17 responses. ALOX12B is a non-heme iron-containing enzyme that catalyses the production of 12R-HETE from polyunsaturated fatty acids such as arachidonic acid. Mechanistically, we found that ALOX12B/12R-HETE accumulation in the skin acts as an intrinsic danger signal that triggers enhanced IL-1{beta} processing and secretion via ROS generation and NLRP3 inflammasome activation. Increased IL-1{beta} levels in turn drive IL-17 producing T-cell polarization. We further designed a novel first-in-class, potent ALOX12B inhibitor, 6a, which exhibited favorable topical pharmacokinetic and safety profiles. The topical application of 6a reduced inflammation-associated pathologies in Tg-hALOX12B mice by suppressing 12R-HETE-induced IL-1{beta} production and ROS generation. These findings revealed a novel mechanism mediated by ALOX12B/12R-HETE overexpression that controls skin inflammation, thereby providing a promising therapeutic target for treating inflammatory skin diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/658245v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@13cdf3forg.highwire.dtl.DTLVardef@164cac3org.highwire.dtl.DTLVardef@3c0364org.highwire.dtl.DTLVardef@2ca91_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO The proposed mechanism through which ALOX12B modulates the inflammatory pathway in psoriasiform-like inflammatory conditions in the skin. The study provides insight into the role of ALOX12B in skin inflammation. Increased levels of ALOX12B expression in the skin result in 12R-HETE accumulation, which subsequently triggers the IL-1/Th17 inflammatory cascade through ROS generation and inflammasome activation. IL-1 produced by the activated inflammasome leads to the polarization of naive T-cells to activated IL-17 producing CD4+ T-cells, which are involved in the skin-inflammation related pathologies such as keratinocyte proliferation, and cellular infiltration. Hence, we propose ALOX12B as a novel potential therapeutic target for psoriasis-like inflammatory skin disorders. Additionally, we designed a novel first-in-class ALOX12B inhibitor, 6a; which shows a substantial alleviation in ALOX12B enzymatic activity, thereby reducing cellular ROS, which in turn results in reduced levels of IL-1, as a result inhibiting IL-1/Th17 inflammatory pathway and subsequent reduction in pathological inflammatory skin conditions. A portion of the image was created using Biorender.com C_FIG HighlightsO_LIALOX12B is a key gene upregulated in the skin during psoriasis and atopic dermatitis. C_LIO_LITransgenic mice overexpressing ALOX12B in the skin developed Psoriasis-like inflammatory symptoms. C_LIO_LIMechanistically, ALOX12B, through 12R-HETE, enhanced IL-1{beta} production via ROS generation and NLRP3 inflammasome activation. Further elevated IL-1{beta} production promotes Th17 cell polarization. C_LIO_LINovel first-in-class ALOX12B inhibitor alleviates inflammatory symptoms in a transgenic mouse model. C_LIO_LIStudy reveals a crucial ALOX12B/12R-HETE-inflammasome-IL-17 axis involvement in inflammatory skin diseases. C_LI

immunology↗

bioRxiv2025

Purinergic receptor activation rectifies autism-associated endothelial dysfunction

Early cerebrovascular alterations affect brain maturation by impacting trophic support and energy supply. Recent evidence in a 16p11.2 deletion mouse model of autism spectrum disorder (ASD) revealed brain endothelial abnormalities postnatally. Yet, the endothelial alterations eliciting these changes remain unknown. Isolation of brain endothelial cells (ECs) from 14-day old male 16p11.2-deficient and wild-type mice revealed that 16p11.2 deletion-induced endothelial dysfunction is linked to a bioenergetic failure, with reduced intracellular ATP. Intra- or extra-cellular ATP supplementation rescued the function of 16p11.2-deficient ECs in vitro via P2 purinergic receptor activation, specifically P2Y2 receptors. Activating P2Y2 receptors restored cerebrovascular reactivity in 16p11.2-deficient parenchymal arterioles ex vivo and rescued 16p11.2 deletion-associated mouse behaviors. Taken together, this study demonstrates that metabolic reprogramming of brain ECs via purinergic receptor engagement represents a possible therapeutic avenue for ASD.

cell biology↗

bioRxiv2024

Trace Elements in Fish: Assessment of bioaccumulation and associated health risks.

Industrial and agricultural water run-off are polluting the aquatic ecosystem by depositing different toxic trace elements (TTEs) in riverine system. It has become a global concern impacting not only the well-being of aquatic organisms but human health as well. Current study evaluated the impact of four TTEs (Cadmium (Cd), copper (Cu), lead (Pb), and nickel (Ni)) in three organs (liver, gills, and muscles) of five fish species viz, Rita rita, Sperata sarwari, Wallago attu, Mastacembelus armatus, and Cirrhinus mrigala collected from right and left banks of Punjnad headworks during winter, spring and summer. We investigated accumulation (mg/kg) of these TTEs in fish in addition to the human health risk assessment by estimating exposure hazards, hazardous index (THQ and TTHQ) and metal pollution index (MPI). The obtained results showed that W. attu accumulated significantly more TTEs (p < 0.00) as compared to other fish. Among seasons, summer had significantly more (p < 0.00) accumulation of TTEs than other seasons. Lead (Pb) accumulation was highest across TTEs in fish liver as compared to gills and muscles. Right bank showed higher accumulation (p < 0.00) of all TTEs in all fish species in contrast to the left bank. The human health risk assessment showed that Cd and Pb had higher exposure levels than Cu and Ni. Furthermore, the THQ was in the order of Cd > Pb > Ni > Cu. All fish species had THQ 1 for Cd and Pb and TTHQ > 1 for all fish. MPI index showed moderate to high level of TTE contamination if all fish species. The study concluded that right bank has higher metal accumulation than left bank. However, fish consumption from both of the study site was not safe for human consumption.

zoology↗

bioRxiv2023

De novo Genome Assembly, Functional Annotation and SSR Mining of Citrus reticulata (Kinnow) from Pakistan

Citrus reticulata (Blanco) fruit is native to South East Asia which owns many of the nutritional, medicinal and economic advantages, locally known as "Kinnow" and one of the priced mandarin varieties (Dancy, Fuetrells Early and Honey) of Citrus genera renowned for its exclusive taste, vitamin richness, thin peel, long shelf-life and seedless characteristics in Pakistan. However, genetic improvement and breeding strategies of this valued variety are lacking due to the in-housed insufficient genomic and technical resources. Therefore, the current research was initiated to provide the base-line de-novo genome assembly of C. reticulata (seedless kinnow) at a depth of 151x with Illumina paired-end short-read sequencing technology using HiSeq 2500. Whole-genome sequencing resulted in 139,436,350 raw reads ([~]20.09 GB) of data, however, after removing the low-quality reads (1.08%), duplicated sequences (10.5%) and Illumina adaptors, 137,901,462 clean reads were obtained with ([~]18.87 GB) of clean data which was further used for downstream variant calling analysis. In total, 348,861 scaffolds were generated with N50 value of 4827 which constitute 263,018,9 contigs ranging from 71-36,213 with total of 179,984,763 nucleotides. The GC content of the final draft assembly at 71-mer was 34.1%. Moreover, annotation was performed with "Hayai-Annotation Plants" tool which marked the whole-genome mapping with three main functional databases of interpro, Pfam and gene ontology. Additionally, in-silico identification of 111,032 Simple Sequence Repeats (SSR) was also accomplished with the help of GMATA tool, which may be used for further screening and genetic improvement of the citrus varieties by means of this current assembly as a resource of local reference genome.

bioinformatics↗

bioRxiv2022

Whole-Genome Sequencing and Variant Discovery of Citrus reticulata 'Kinnow' from Pakistan

Citrus is a source of many nutritional and medicinal advantages, which is cultivated worldwide with major citrus groups of sweet oranges, mandarins, grapefruits, kumquats, lemons and limes. Pakistan produces all of its major citrus groups with mandarin (Citrus reticulata) being the prominent group that includes local commercial cultivars such as Feutrals Early, Dancy, Honey and Kinnow. The present study was designed to understand the genetic architecture of this unique variety of Citrus reticulata -Kinnow. The whole-genome resequencing and variant calling was performed to map the genomic variability that might be responsible for its particular characteristics like taste, seededness, juice content, thickness of peel and its shelf-life. A total of 139,436,350 raw sequence reads using Illumina platform were generated with 20.9 Gb data in Fastq format having 98% effectiveness and 0.2% base call error rate. Overall, a total of 3,503,033 SNPs, 176,949 MNPs, 323,287 INS and 333,083 DEL were identified using GATK4 variant calling pipeline against Citrus clementina as a reference genome. Further, g:Profiler bioinformatics tool was applied for annotating the newly found variants, harbor genes/transcripts and their involved pathways. A total of 73,864 transcripts harbors 4,336,352 variants, most of the observed variants were predicted in non-coding regions and 1,009 transcripts were found well annotated by different databases. Out of total aforementioned transcripts, 588 involved in biological processes, 234 in molecular functions and 167 transcripts involved in cellular components in Citrus reticulata. In a nutshell, 18,153 high-impact variants and 216 genic-variants found in the current study which may be used for marker assisted breeding programs of Kinnow to identify this particular variety among others and to propagate its valued traits to improve the contemporary citrus varieties as well. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/519411v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1568ae1org.highwire.dtl.DTLVardef@b7d20eorg.highwire.dtl.DTLVardef@3fc3a9org.highwire.dtl.DTLVardef@46ba89_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

NHA1 is a cation/proton antiporter essential for the water-conserving functions of the rectal complex in Tribolium castaneum

More than half of all extant metazoan species on earth are insects. The evolutionary success of insects is intrinsically linked with their ability to osmoregulate, suggesting that they have evolved unique physiological mechanisms to maintain water balance. In beetles (Coleoptera)--the largest group of insects--a specialized rectal ( cryptonephridial) complex has evolved that recovers water from the rectum destined for excretion and recycles it back to the body. However, the molecular mechanisms underpinning the remarkable waterconserving functions of this system are unknown. Here, we introduce a transcriptomic resource, BeetleAtlas.org, for red flour beetle Tribolium castaneum, and demonstrate its utility by identifying a cation/H+ antiporter (NHA1) that is enriched and functionally significant in the Tribolium rectal complex. NHA1 localizes exclusively to a specialized cell type, the leptophragmata, in the distal region of the Malpighian tubules associated with the rectal complex. Computational modelling and electrophysiological characterization in Xenopus oocytes show that NHA1 acts as an electroneutral K+/H+ antiporter. Furthermore, genetic silencing of Nha1 dramatically increases excretory water loss and reduces organismal survival during desiccation stress, implying that NHA1 activity is essential for maintaining systemic water balance. Finally, we show that Tiptop, a conserved transcription factor, regulates NHA1 expression in leptophragmata and controls leptophragmata maturation, illuminating the developmental mechanism that establishes the novel functions of this cell. Together, our work provides the first insights into the molecular architecture underpinning the function of one most powerful water-conserving mechanisms in nature, the beetle rectal complex. Significance StatementBeetles are the largest group of insects, inhabiting a wide range of habitats on earth. Unique adaptations in overcoming water stress is critical to their success, yet the mechanisms underpinning this ability are unknown. Using genetics, electrophysiology, imaging and behavioral studies we show that a cation/H+ (NHA1) transporter is exclusively localized to specialized cell type, the leptophragmata, in the Malpighian tubules associated with the rectal complex. Ion transport functions of NHA1 in leptophragmata underpin the movement of water from the rectum, from where it would be destined for excretion, to the Malpighian tubule and then recycled back to the body. This water recovery capability of rectal complex is essential for maintaining systemic water balance in beetles. This work provides the first insight into to the molecular architecture of one of most powerful water-conservation mechanisms in biology, and provides an important clue to the ecological and evolutionary success of the beetles.

systems biology↗

bioRxiv2022

GWAS and functional studies implicate a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis

The emergence of drug resistance in Mycobacterium tuberculosis (Mtb) is alarming and demands in-depth knowledge for timely diagnosis. We performed genome-wide association analysis (GWAS) using 2237 clinical strains of Mtb to identify novel genetic factors that evoke drug resistance. In addition to the known direct targets, for the first time, we identified a strong association between the mutations in the DNA repair genes and the multidrug-resistant phenotype. To evaluate the impact of variants identified in the clinical samples in the evolution of drug resistance, we utilized knockouts and complemented strains in Mycobacterium smegmatis (Msm) and Mtb. Results show that variant mutations abrogated the function of MutY and UvrB. MutY variant showed enhanced survival compared with wild-type (Rv) when the Mtb strains were subjected to multiple rounds of ex vivo antibiotic stress. Notably, in an in vivo Guinea pig infection model, the MutY variant outcompeted the wild-type strain. Collectively, we show that novel variant mutations in the DNA repair genes abrogate their function and contribute to better survival under antibiotic/host stress conditions.

microbiology↗