Biology subjects

Hussain, Z.

Publications and source records attributed to Hussain, Z..

9 recordsLinked to original sources

bioRxiv2026

Invasion status stratifies the composition of the human pancreatic cancer perineural niche

The peripheral nervous system innervates the pancreatic ductal adenocarcinoma (PDAC) microenvironment, and perineural invasion (PNI), the invasion of cancer cells in and around nerves, correlates with metastatic burden and poor outcomes. Though PDAC innervation is near universal and the majority of PDAC patients harbor PNI, the cellular and molecular composition of the heterocellular perineural niche is largely unknown, obscuring functional significance. Here we provide a deeply phenotyped spatial and single-cell atlas of the human PDAC perineural niche, enabling a high-resolution comparison of invaded versus non-invaded nerve neighborhoods. This atlas leverages a novel vision-centric artificial intelligence model for imaging-based spatial transcriptomics, coupled with pathology-guided single-nucleus RNA-seq. These analyses revealed that invaded nerve neighborhoods harbor cancer cells of the classical subtype, together with myofibroblastic cancer-associated fibroblasts (CAFs) and lipid-associated macrophages. Non-invaded nerve neighborhoods, in contrast, harbor inflammatory CAFs and infiltration of B and T lymphocytes. These findings raise the possibility that PNI and not innervation itself is immune-suppressive in this setting, motivating functional studies. Statement of SignificanceHuman PDAC is innervated and almost invariably harbors PNI, but the composition and functions of perineural niches remain unclear. Here we provide a spatial and single-cell atlas of the human PDAC perineural niche, defining cancer and stromal cell states in the context of PNI and nominating this process as potentially immune-suppressive.

cancer biology↗

bioRxiv2026

Surface-stabilized sub-micron condensates for compartmentalizing synthetic cells and enhanced enzyme kinetics

Living cells harbor numerous membraneless organelles (MOs), which are dynamic protein/nucleic acid assemblies responding to specific physicochemical triggers. Liquid-liquid phase separation (LLPS) plays a crucial role in their formation and activity. Inspired by the natural MOs that maintain their individual identities, this work presents a bioengineering strategy to generate LLPS-driven, isochemical MO populations using surfactant-like peptides that stabilize the MO interface. The result is highly stable, monodispersed, sub-{micro}m-sized MO populations, which are not only capable of compartmentalizing synthetic cells but also provide superior environments for enzymatic reactions. This is achieved using pH-responsive elastin-like polypeptides (PREs) as MOs and formulating an amphiphilic PRE-based peptide to stabilize the MO interface. Relative abundance of the surface-active peptide, as well as the rate of pH change, allows direct control over the MO size. Encapsulating these components within synthetic vesicles using a microfluidic platform leads to on-demand multi-compartmentalization via an external pH trigger. Lastly, a functional consequence of the acute size control is shown through a phosphatase reaction, where the highest reaction rate is observed in size-controlled MOs when compared to dilute environments and surfactant-free MOs. The presented strategy provides a new avenue for designing programmable MOs and thus achieve functional compartmentalization within synthetic cells.

bioengineering↗

bioRxiv2026

In silico analysis reveals the structural basis of TomEP specificity, a tomato extensin peroxidase

BackgroundExtensin peroxidases (EPs) are class III plant peroxidases and are responsible for intermolecular covalent crosslinking of extensin (EXT) monomers to create scaffolds within plant cell walls. The formation of these scaffolds impacts plant development, mechanical wounding, and response to pathogen attacks. Therefore, elucidating the molecular mechanism controlling covalent crosslinking of EXT monomers is crucial for understanding cell wall deposition and potentially improving plant growth and adaptation. The focus of this work is to use in silico analysis to determine the structural characteristics of an EP from tomato (TomEP) to elucidate its specificity for crosslinking of EXT monomers. ResultsIn this study the two-dimensional (2D) and three-dimensional (3D) structures of TomEP were determined using several advanced bioinformatics tools and compared to two other peroxidases: GvEP1 (a known EP) and HRP-C (having a low affinity for EXT substrates). The results revealed that TomEP is a stable and hydrophilic protein with high thermal stability. The heme binding pockets of TomEP and GvEP1 have more hydrophobic residues and larger volume and pocket area compared to HRP-C. Molecular docking at the active site, which includes a heme heteroatom, showed that the ligands consisting of the hydrophobic Tyrosine-X-Tyrosine [-Y-X-Y-] motifs (i.e., [-Y-K-Y-], [-Y-V-Y-], and [-Y-Y-Y-] found in EXTs, and their derivatives, Isodityrosine (IDT), Pulcherosine (Pul), Di-Isodytirosine (diIDT), bind perfectly to the active site of TomEP with dominant interactions of Val54, Ser94, Ala96 and Phe196 residues. Pulcherosine had the highest binding affinity, while [-Y-K-Y-] showed the lowest binding affinity. Molecular dynamics simulations showed that [-Y-X-Y-] motifs (and the derivative substrate ligands) remain bound to the active site of TomEP throughout the 100 ns long simulation. Furthermore, the binding of these substrates stabilized the protein structure. ConclusionThese results may explain why TomEP is particularly well-suited for EXT crosslinking and will have significant implications on biochemistry, biotechnology, and the potential use of these EPs in crops improvement.

plant biology↗

bioRxiv2026

Gaze and perception covary with reading direction

Human observers prioritise the left visual field in perceptual judgements, a phenomenon widely attributed to cerebral asymmetries in vision. How stable are these mechanisms across differences in reading direction? We show that the classic left-side bias for faces is correlated with reading direction and tightly linked to gaze. Observers with varying proficiency in reading English (left-to-right) and Arabic (right-to-left) performed a chimeric face matching task (N = 271), with eye movements recorded in a subset (N = 115). The left-side bias scaled linearly with reading direction: strongest in English readers, reduced in bidirectional readers, and absent in Arabic readers. Reading direction also shifted gaze: English readers fixated further left on target faces and preferentially inspected faces in the left hemifield, and these gaze patterns predicted trial-by-trial perceptual judgements. These results suggest that cerebral asymmetries in face perception are flexible, coupled to gaze, and modified by reading direction.

neuroscience↗

bioRxiv2025

Integrative metagenomics and structural bioinformatics identify explainable gut microbial variants associated with Crohns disease

Metagenomics has revealed disease-associated shifts in microbial taxa and functions in inflammatory bowel disease (IBD) patients. However, the role of genomic variation in gut commensals remains poorly understood. Here, we integrated metagenomic profiling, variant calling, and structural bioinformatics to identify disease-associated variants in the gut microbes. Crohns disease (CD) and ulcerative colitis (UC) showed significant negative associations with Bacteroides uniformis, Bacteroides vulgatus, and Eubacterium rectale. These bacteria exhibited 190,712 single-nucleotide polymorphisms, including 479 CD-specific and 235 UC-specific variants. Variant prioritization identified a CD-specific Val170Leu substitution in the conserved starch-binding domain of the Starch Utilization System D (SusD) protein in B. uniformis. Structural modeling and cyclodextrin docking indicated reduced binding affinity in the mutant, while 200-ns molecular dynamics simulations showed stable ligand retention only in the wild type. These findings suggest that impaired starch metabolism driven by SusD variation may contribute to B. uniformis depletion in CD and demonstrate the value of integrating metagenomics with structural analyses to identify functionally relevant microbial variants.

bioinformatics↗

bioRxiv2025

On the stabilization of plant lipid droplets: Dynamic interplay between oleosins and phospholipids

As the central organelles of lipid and energy homeostasis in plant seeds, lipid droplets (LDs) consist of a neutral lipid core, decorated by phospholipids (prominently phosphatidylcholines, PCs) and surfactant-like proteins (mostly oleosins, OLs). So far, the dynamic interplay between PCs and OLs at the LD interface remains unclear. The presented work addresses this knowledge gap by reconstituting oil-in-water emulsions stabilized by OLs and PCs using microfluidic systems. Our results show that the resistance to droplet coalescence is primarily provided by OLs. We further reveal that the addition of PCs alters the assembly of OLs at the interface, reducing the OL network density and interfacial elasticity, thereby rendering a weaker interface. In conclusion, our study suggests complementary roles, with OLs acting as the primary stabilizers while PCs playing a destabilizing role. This contrast likely contributes to the observed metastability of LDs and can be exploited to design stimuli-responsive emulsions. HIGHLIGHTSO_LIOleosins form an interfacial network that stabilizes the oil-water interface. C_LIO_LIPhosphatidylcholines globally weaken the oleosin network and promote droplet coalescence. C_LIO_LIMicrofluidics enables controlled reconstitution and real-time analysis of lipid droplets. C_LIO_LIOleosin-phospholipid interplay explains lipid droplet metastability and can guide the design of bio-inspired emulsions. C_LI

biophysics↗

bioRxiv2025

The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage.

The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, dramatic tumor progression and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we use in-vitro-generated ECM bio-scaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multi-omics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes Impdh and Gmps, the expression of which correlated with that of matrisomal and DNA repair genes in PDAC patient samples. We propose that targeting ECM-driven metabolic processes, like the enhanced Impdh activity, may be an effective therapeutic approach for PDAC patients that bypasses the negative side effects of direct targeting of the ECM itself.

cancer biology↗

bioRxiv2022

Vasoactive Endothelial Growth Factor and Heat Shock Protein Gene Expression Response in Kawasaki Disease Associated Coronary Arteritis

Kawasaki Disease (KD) is a childhood vasculitis primarily affecting medium-sized arteries, which can lead to severe complications, particularly with respect to coronary artery disease (CAD). The impact of thermal stress on KD coronary artery pathogenesis, in association with prolonged fever and inflammation, remains unclear. In this study, we hypothesized that altered gene expression (GE) of angiogenesis-inducing Heat Shock Proteins (HSPs) is associated with KD-CAD through pro-inflammation. Transcriptomic analysis was performed using the three largest KD peripheral blood studies in the clinical literature (KD1-KD3), and one study direct from coronary artery tissue (KD4). The analysis revealed a significant increase in TNF and NFKB1 GE, indicating the presence of inflammation based on gene expression profiles. Gene set enrichment analysis (GSEA) of KD1-KD3 datasets identified inflammatory pathways, including TNFA signaling via NFKB, IL6 JAK STAT 3 Signalling, and p53 (Heat Shock Protein 90). The study also focused on specific HSPs known to be associated with angiogenesis, namely HSPB1, HSPA1A, and HSP90AB1. The temporal transcript model (TTM) consistently showed up-regulation of pro-inflammatory genes VEGF-A, TNF, and NFKB1, as well as up-regulation of HSPA1A. GSEA revealed gene ontology pathways associated with VEGF production. These findings suggest that the binding of VEGF-A or VEGF-B to their receptors could potentially impact the coronary artery in KD. Additionally, the up-regulation of the gene HSPAB1 in KD has not been described previously. In contrast, KD4 showed no differential GE for the studied genes potentially related to end-stage KD. This study provides valuable insights into VEGF and HSPs in KD-associated inflammation. Future research should focus on developing a VEGF-HSP CAD model to explore implications for KD biomarking as well as developing precision management strategies.

genomics↗

bioRxiv2021

In silico evidence of superantigenic features in ORF8 protein from COVID-19

Very early on COVID-19 pandemic outbreak, it was noted that the some of the virus-induced clinical conditions resembled features of toxaemia caused by the toxic shock syndrome toxin type 1, which is a soluble superantigen produced by Staphylococcus aureus. Among all SARS proteins, the ORF8 protein from SARS-2 virus is significantly different from other known SARS-like coronaviruses, and therefore could exhibit unique pathogenic properties. We assess if ORF8 protein bears super antigenic features using in silico tools. We show that ORF8 has properties of an extracellular soluble protein and shares a significant degree of amino acid sequence identity with toxic shock syndrome toxin. Besides, docking and binding affinity analyses between monomeric and homodimeric ORF-8 with V{beta} 2.1 and TRBV11-2 reveal strong interaction and high binding affinity. ORF8-TRBV11-2 strong interaction can contribute to the observed clonal expansion of that chain during COVID-19-associated multisystem inflammatory syndrome. Taken together, the evidence presented here supports the hypothesis that ORF8 protein from SARS-2 bears super antigenic properties.

microbiology↗