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Nazir, A.

Publications and source records attributed to Nazir, A..

14 recordsLinked to original sources

GlioVision: A Multi-Modal MRI Framework for Non-Invasive Glioma Molecular Biomarkers Prediction

Gliomas are aggressive primary brain tumors that necessitate critical molecular biomarker predictions for optimal clinical decision-making. Traditional assessment relies on surgical tumor specimens analysis, which carries procedural risks and sampling bias due to tumor heterogeneity. Existing deep learning methods for non-invasive prediction lack real-time applicability, remain resource-intensive, and are frequently trained on narrowly represented datasets. We present GlioVision, a framework built on the MONAI library to process multimodal data, including glioma MRI and molecular labels, to predict and identify, non-invasively, four major glioma molecular biomarkers: IDH mutation, 1p/19q co-deletion, MGMT methylation, and WHO grade. The core architecture comprises Spatially and Channel-wise Recalibrated 3D DenseNet (SCRU-DenseNet), which utilizes a computational attention gate and an Adaptive Contrast-Specific Processing Stream (ACPS) to tackle multi-site, heterogeneous datasets. We introduced the Confidence-Filtered Predictive Manifold (CFPM) to manage uncertainty by excluding predictions with low confidence. GlioVision is trained and validated on the largest multi-cohort datasets, achieving strong biomarker prediction with AUCs of (IDH 0.94, 1p/19q 0.87, MGMT 0.86, WHO grades 0.92), supporting molecularly defined glioma diagnosis under the WHO 2021 classification guidelines. Finally, we provide a Differential Training Integrity Assessment (DTI-A) to analyze routes of MRI data privacy protections through model obfuscation. Our results advance the codebase, model release, and leakage considerations around MRI data analysis literature.

neuroscience↗

Spatiotemporal profiling reveals the role of inflammatory niche in driving prostate cancer

Prostate cancer (PCa) is a lethal malignancy that displays profound resistance to immune checkpoint blockade (ICB), via mechanisms that are poorly understood. Here, we investigate the causes of CD8 T cell exhaustion and mechanisms of tumor progression in a PCa animal model, by single cell and spatial profiling, along a time course, following orthotopic transplantation of RB1/TP53/PTEN-deficient mouse organoids, competent to express neoantigens. The resulting tumors were castration resistant, consisting of largely basal and L2 malignant cells with upregulated inflammatory gene programs, and a specific spatial distribution of macrophages, cancer associated fibroblast (CAF) subtypes, and CD8 T-cells that was not previously reported. Using Zman-seq, we demonstrate that the effector function of tumor-infiltrating CD8 T cells was rapidly impaired as early as 24hrs after their infiltration, likely driven by signals from proinflammatory macrophages, Ccl2-Jak2+ inflammatory CAFs, and malignant basal cells, thus driving resistance to ICB. Interestingly, dual blockade of JAK1/2 and PD1 induced potent anti-tumor effects in tumor epithelial cells, decreased malignant epithelial cells and pro-inflammatory macrophages, and increased the proportion of normal (Pi16+) fibroblasts in the TME. Our results underscore the therapeutic potential of targeting JAK1/2 to enhance the efficacy of ICB, providing a rationale for clinical investigation of this combination in PCa.

cancer biology↗

A Multi-Organ Single-Cell Atlas Maps Allergen and Organ-Specific Cellular Dynamics in the Progression from Food Allergy to Anaphylactic Shock

The transition from food allergic sensitization to life-threatening anaphylactic shock (AS) with complex multi-organ cellular interactions has been poorly understood. We herein conducted a multi-organ single-cell sequencing of heart, lung, and intestinal tissues from mouse models of food allergy, sensitized to bovine serum albumin (BSA) or ovalbumin (OVA), across both sensitization (Phase I) and anaphylactic shock (Phase II). We found that organ-specific pathologies included cardiac vascular dysfunction with pericyte loss and cardiomyocyte adaptation, distinct lung responses (Th2/B-cell predominance with BSA vs. neutrophilia with OVA), and profound intestinal remodeling featuring Paneth cell expansion. We also identified conserved inflammatory pathways (e.g., NOD-like receptor, NF-{kappa}B, JAK-STAT signaling) and unique organ specific signatures. Notably, phase-dependent reprogramming showed NLRP3 inflammasome activation and suppressed anti-inflammatory responses during AS. Cell-cell communication networks shifted from stromal-immune crosstalk in Phase I to dominant myeloid-vascular/neuroimmune interactions in Phase II. We further linked early extracellular matrix remodeling to late-stage neuromodulatory responses in Schwann and smooth muscle cells. This multi-organ atlas elucidates the coordinated, organ-selective immune cascade driving FA to AS progression, providing a foundational resource for developing targeted therapeutic strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/703914v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@19ffd9forg.highwire.dtl.DTLVardef@c3fda3org.highwire.dtl.DTLVardef@141174corg.highwire.dtl.DTLVardef@60ac5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

FOXA1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity

Mutations in the pioneer transcription factor FOXA1, found in 10-40% of human prostate cancers, alter global chromatin accessibility and promote growth in prostate cells. Through analysis of a novel cohort of 874 primary and metastatic prostate tumors with somatic FOXA1 mutations, we confirm the high frequency of missense mutations (n=339) and indels (n=335) in the Wing2 region of the Forkhead domain, as well as frameshift mutations that truncate the C-terminus (n=287). To investigate the transcriptomic consequences of each mutation subgroup as well as elevated levels of wild-type FOXA1 (WT) (a fourth well documented subgroup), we performed single nucleus multiome sequencing in primary mouse organoids following inducible expression of representative alleles. Whereas each mutant induced distinct transcriptomic and DNA accessibility features, a prominent feature of all mutants was perturbed epithelial lineage specification, ranging from basal-like fates in cells expressing indel mutants to secretory (L1-like) luminal fates in cells expressing C-terminal truncation, missense mutations or excess WT. Integrated RNA-seq, ATAC-seq and ChIP-seq analysis of L1-like fate specification revealed enrichment of a composite androgen receptor-FOXA1 hybrid motif and cooperativity with the Oct family transcription factor POU2F1. Importantly, L1-like fate specification is seen in vivo tumorigenicity assays where, in combination with Trp53/Pten loss, expression of these mutants results in a histologic switch from basal-like to secretory luminal histology.

genomics↗

T13F2.2 of C. elegans is Critical for Chromatin Organization, Autophagy, and Longevity

Intricately modulated by a spectrum of proteins, Chromatin structure governs gene expression and cellular homeostasis. In Caenorhabditis elegans, critical components like the TATA-binding protein tbp-1 play pivotal roles in orchestrating chromatin dynamics. While the function of many of the interacting partners of tbp-1 is well-understood, our study brings into focus a lesser-known entity, T13F2.2, an unexplored tbp-1 interacting protein and a putative RNA polymerase II transcriptional coactivator. Employing reverse genetics, we found that RNAi-induced depletion of T13F2.2 resulted in pronounced disruptions to nuclear architecture, evidenced by nuclear staining and transmission electron microscopy. Accompanying these structural anomalies, we observed increased autophagy, pointing to cellular stress and a hyperacetylation of the core histones, suggesting potential chromatin decompaction. Notably, multifaceted functional alterations, upon the partial knockdown of the T13F2.2, culminated in a substantial reduction in the worms lifespan. Intriguingly, interventions such as administering ROS scavengers and autophagy modulators offered a reprieve from this life-shortening effect. Transcriptomic analysis upon T13F2.2 knockdown revealed upregulation of genes related to autophagy and chromatin remodelling, alongside downregulation of genes involved in longevity pathways and oxidative stress response. This study, thus, not only puts forward the functional implication of an uncharacterized gene in C. elegans biology, but also further emphasizes the role of chromatin organization in aging at the organismal level.

genetics↗

SpatialAgent: An Autonomous AI Agent for Spatial Biology

Advances in AI are transforming scientific discovery, yet spatial biology, a field that deciphers the molecular organization within tissues, remains constrained by labor-intensive workflows. Here, we present SpatialAgent, an autonomous AI agent for spatial biology research. SpatialAgent couples large language models with a Plan-Act-Conclude architecture, dynamic tool and skill retrieval, multimodal interpretation, and verification modules that audit generated claims. It supports the full discovery loop, from gene-panel design and multimodal annotation to trajectory inference, cell-cell communication analysis, imputation, and hypothesis generation. Across human and mouse brain, heart, tonsil, colon, and prostate datasets, SpatialAgent outperformed established computational baselines and matched or surpassed expert scientists in key tasks. In open-ended case studies, it recovered known tissue organization and generated spatially grounded hypotheses. In a prospective mouse prostate cancer Xenium study, it designed a compact 100-gene add-on panel that profiled 4.2 million cells across 21 samples, improved cell-type and malignant-state prediction, and captured spatially structured tumor and microenvironment programs. SpatialAgent establishes a framework for autonomous and collaborative discovery in spatial biology.

bioinformatics↗

Local Haplotype Classifiers enable Efficient, Flexible, and Secure Genotype Imputation and Downstream Analyses

The decreasing cost of genotyping technologies led to abundant availability and usage of genetic data. Although it offers many potentials for improving health and curing diseases, genetic data is highly intrusive in many aspects of individual privacy. Secure genotype analysis methods have been developed to perform numerous tasks such as genome-wide association studies, meta-analysis, kinship inference, and genotype imputation outsourcing. Here we present a new approach for using lightweight haplotype classifier models to use predicted haplotype information in a flexible privacy-preserving framework to perform genotype imputation and downstream tasks. Compared to the previous secure methods that rely main on linear models, our approach utilizes efficient models that rely on utilizing haplotypic information, which improves accuracy and increases the throughput of imputation by performing multiple imputations per model evaluation.

bioinformatics↗

Identification and characterization of anti-epileptic compounds from Papaver somniferum using quantification techniques (GC-MS, FTIR), integrated network pharmacology, molecular docking, and molecular dynamics simulations

Epilepsy is a common neurological condition identified by repetitive seizures that affect the overall quality of life. Existing anti-epileptic drugs have undesirable side effects, necessitating safer alternatives. This study develops an integrated computational framework to discover potential anti-epileptic leads from Papaver somniferum (opium poppy). Literature and databases were mined to compile all chemicals from Papaver somniferum. PubChem provided structural data, and compounds satisfying drug-likeness and bioavailability criteria were selected. GeneCards, DisGeNET and SwissTargetPrediction identified 344 target genes of the compounds and common targets with epilepsy. Network pharmacology analyses were performed. Cytoscape constructed a compound-target network comprising 5 active constituents and 22 shared targets. Degree distributions revealed molecular interactions. STRING elucidated target connectivity. Hub targets were identified using CytoHubba. GO and KEGG enrichment on 123 targets recognized biological roles and pathways. DAVID and Hiplot characterized functional annotations. Cytoscape visualized a compound-target-pathway association network involving targets, pathways, and compounds related to epilepsy. GC-MS identified 25 compounds in the Papaver somniferum extract. FTIR characterized functional groups. Molecular docking scored compound affinities for 10 targets. Autodock Vina docked 15 constituents into binding pockets. Interactions were validated using Desmond MD simulations of IL6 with scoulerine over 100 ns, assessing RMSD, RMSF, interactions. RMSD/RMSF plots and histograms characterized protein/ligand stability and flexibility. This integrative Insilico and Invitro framework facilitates prioritizing Papaver somniferum constituents for epilepsy. Network analyses provided systems-level understanding of multi-target mechanisms. Molecular modeling established structure-activity relationships, validating predicted interactions. Compounds with good ADMET profiles, network centrality, docking scores, and stable simulations emerge as candidates warranting further examination for safer anti-epileptic therapy.

bioinformatics↗

Oral administration of a specific p300/CBP Lysine acetyltransferase activator induces synaptic plasticity and repairing spinal cord injury

TTK21 is a small molecule activator of p300/CBP acetyltransferase activity, which upon conjugation with glucose-derived carbon nanosphere (CSP) can efficiently cross the blood-brain barrier and activate histone acetylation in the brain. Its role in adult neurogenesis and retention of long-term spatial memory upon intraperitoneal (IP) administration is well established. In this study, we have successfully demonstrated that CSP-TTK21 can be effectively administered via oral gavage. Using a combination of molecular biology, microscopy, and electrophysiological techniques, we systematically investigated the comparative efficacy of oral administration of CSP and CSP-TTK21 in wild-type mice, evaluating their functional effects in comparison to intraperitoneal (IP) administration. Our findings indicate that CSP-TTK21, when administered orally, induces long-term potentiation in the hippocampus without significantly altering basal synaptic transmission, a response comparable to that achieved through IP injection. Remarkably, in a spinal cord injury model, oral administration of CSP-TTK21 exhibits equivalent efficacy to IP administration. Furthermore, our research demonstrates that oral delivery of CSP-TTK21 leads to improvements in motor functions, histone acetylation dynamics, and increased expression of regeneration associated genes (RAGs) in a spinal injury rat model, mirroring the effectiveness of IP administration. Collectively, these results underscore the potential utility of CSP as an oral drug delivery system, particularly for targeting the neural system.

neuroscience↗

Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinsons disease

Parkinsons disease (PD) is the second most common neurodegenerative disease. The presence of lewy bodies, primarily consisting of -synuclein (-syn) aggregates is one of the common features seen in the substantia nigra region of the brain in PD patients. The disease remains incurable and only symptomatic relief is available. We screened various cell-penetrating peptides and reveal that penetratin is a potent inhibitor of -syn aggregation in-vitro, and significantly improved locomotor coordination in mice models of PD in-vivo. The peptide inhibits -syn aggregation in vitro as well as in yeast, and C.elegans models. We further made a cyclic derivative of penetratin by disulfide coupling of N- and C-terminal cysteine residues. Both penetratin and its cyclized derivative interact with -syn. NMR studies show that both linear as well as cyclic derivative interact at the acidic C-terminal tail of the protein. Similar to penetratin, its cyclic derivative inhibited -syn aggregation in the C.elegans model of Parkinsons disease, and also improved worm motility. Molecular Dynamics studies show that penetratin interacts with -synuclein and prevents its conformational transition from disordered into {beta}-sheet rich structure. The therapeutic efficacy of penetratin was further confirmed in a transgenic mice model of the disease, wherein penetratin treatment over a period of 90 days improved locomotor coordination, and halted disease progression. Overall, the present work provides a potent therapeutic agent that could be further explored in the management of PD.

neuroscience↗

Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms

Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation.1 Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele.2 While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients.3, 4 This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles;5 however we hypothesize this is due to the inability of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617Fabrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet26, 7 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.

cancer biology↗

Biosorption potential and molecular characterization of metal resistant autochthonous microbes from tannery solid waste

This study encompasses isolation and screening of heavy metal-resistant fungal and bacterial strains from tannery solid waste (TSW). Twelve fungal strains and twenty-five bacterial strains were isolated from TSW. The growth of fungal strains was observed against different heavy metals ranging from 10 mg L-1 to 1050 mg L-1 and the growth of bacteria was observed in metal concentrations ranging from 10 mg L-1 to 1200 mg L-1. Five multi-metal resistant fungal isolates belonging to the genus Trichoderma and ten bacterial isolates belonging to the genus Bacillus showed good metal resistance and biosorption potential. They were identified through molecular techniques, fungi based on ITS region ribotyping, and bacteria based on 16S rRNA ribotyping. The fungal strains were characterized as T. hamatum (TSWF-06), T. harzianum (TSWF-11), T. lixii (TSWF-02) and T. pseudokoningii (TSWF-03, TSWF-10). The bacterial strains were characterized as Bacillus xiamenensis (TSW-02), B. velezensis (TSW-05), B. piscis (TSW-06), B. safensis (TSW-10), B. subtilis (TSW-14, TSW-15, TSW-17) B. licheniformis (TSW-19), B. cereus (TSW-20) and B. thuringiensis (TSW-22). The fungal strains namely, T. pseudokoningii (TSWF-03) and T. harzianum proved to be two multi-metal resistant strains with good biosorption efficiency. Unlike fungi, bacterial strains showed metal specific resistance. The strains Bacillus xiamenensis, B. subtilis (TSW-14) and B. subtilis (TSW-15) showed good biosorption efficiency against Cr, B. safensis against Cu, B. piscis and B. subtilis (TSW-17) against Pb and B. licheniformis and B. thuringiensis against Zn. The autochthonous fungal and bacterial strains can therefore be employed to clean metal contaminated environments.

microbiology↗

Studies on C. elegans probed with estradiol, elucidate the critical role of Na+/H+ exchanger, nhx-2 in reproductive senescence and neuronal health

Setting in of reproductive senescence (RS) gives rise to several changes, making aged individuals susceptible to multiple disorders including neurodegenerative diseases, cardiovascular ailments and bone disorders amongst others. The present study, employing transgenic C. elegans that expresses human alpha synuclein, endeavors to decipher the association of reproductive senescence with age-associated neurodegenerative diseases and behavioral ageing, under normal conditions and after being probed with estradiol. We carried out RNAi induced silencing of a subset of 22 genes that are known to delay RS, followed by studies on alpha-Synuclein aggregation and associated effects. These studies led us to functional characterization of the Na+/H+ exchanger; nhx-2, expressed exclusively in gut. We found that RNAi of nhx-2 not only ameliorates the effects associated with alpha-Synuclein aggregation, but it also attunes effects related to behavioral aging including that of reproductive health-span and neuroprotection via mimicking dietary restriction, as it alters food absorption from the gut. We further elucidated that these effects are Sir-2.1 driven as nhx-2 knock out did not delay reproductive senescence in knock down condition of sir-2.1. To substantiate our findings, we performed whole transcriptome analysis in nhx-2 mutant strain. Our data revealed differential expression of 61 out of 62 hallmark genes of CR described by GenDR, in knock out condition of nhx-2. As estradiol plays a central role in both reproductive health as well as neuronal health, we subjected worms to exogenous estradiol treatment and observed that it led to elevated levels of nhx-2. Studies on structural binding analysis demonstrated significant binding potential of estradiol receptor NHR-14 with nhx-2 gene and ChIP analysis revealed that estradiol treatment gives rise to enhanced NHX-2 levels through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3). These studies identify nhx-2 as an important modulator that extends reproductive longevity and ameliorates effects associated with alpha synuclein aggregation in C elegans. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/229344v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@917377org.highwire.dtl.DTLVardef@133a07dorg.highwire.dtl.DTLVardef@6d6f28org.highwire.dtl.DTLVardef@9cde9a_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISilencing of sodium proton antiporter nhx-2 affords neuroprotection and ameliorates effects associated with alpha-Synuclein aggregation via mimicking dietary restriction in C. elegans. C_LIO_LIExogenous 17-{beta}-Estradiol treatment induces the expression of nhx-2, through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3). C_LIO_LIEffects associated with nhx-2, including prolonged reproductive span and neuroprotective effects, are SIR-2.1 driven. C_LIO_LInhx-2 silencing decreases alpha-Synuclein aggregation, however; estradiol mediated overexpression above the endogenous levels, does not amend the aggregation any further. C_LI

neuroscience↗