Biology subjects

Arshad, M.

Publications and source records attributed to Arshad, M..

6 recordsLinked to original sources

bioRxiv2025

Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms

RNA splicing shapes neuronal identity and disease risk, yet current maps lack the developmental resolution and depth to resolve this complexity. Here, we integrate deep long-read RNA sequencing and proteomics in iPSC-derived cortical neurons to generate a high-resolution proteogenomic atlas of human neuron development. We identify 182,371 mRNA isoforms (over half previously unknown) and provide direct peptide evidence for the translation of hundreds of novel protein-coding sequences. Population genetics demonstrates that variants affecting novel exons and splice sites are under negative selection, underscoring the potential significance of these isoforms. During neuronal maturation, we observe that ASD risk genes undergo dynamic isoform switching, including microexon inclusion and intron retention, that remodel key protein domains and regulatory regions. Furthermore, we uncover widespread, long-range coordination between splicing and polyadenylation. Finally, our atlas enables variant reinterpretation in ASD, highlighting the value of an isoform-centric view for interpreting pathogenic variation in neurodevelopment.

bioinformatics↗

bioRxiv2025

Mapping the Inter- and Intra-genic Codon Usage Landscape in Homo sapiens

Although the genetic code is degenerate, codon selection is non-random and reflects significant functional constraints. Codon usage bias (CUB) acts as a layer of post-transcriptional regulation, influencing mRNA stability, translation kinetics, and co-translational protein folding. While CUB is well-characterized in unicellular organisms, its regulatory scope and functional consequences in humans remain complex and less defined. Our study offers a comprehensive evaluation of human codon usage. We report that genes exhibiting the strongest codon bias are enriched in high-stoichiometry biological processes, such as skin development and oxygen/carbon dioxide transport, and harbor significantly fewer synonymous variants than expected ({rho} = -0.24, p < 2.2 x 10-16). Furthermore, we find that codon optimization is spatially regulated: it is significantly more pronounced in structured protein domains compared to intrinsically disordered regions (IDRs) (Cliffs {Delta}= 0.26, p < 2.2 x 10-16). Consistent with translational selection, the most frequently used codons are supported by higher tRNA gene copy numbers ({rho} = 0.49, p < 6.4 x 10-4). Finally, by correcting for GC3 content, we reveal that the apparent correlation between ENC and adaptation indices (CAI/tAI) vanishes, allowing us to disentangle mutational pressure from translational selection. Collectively, our findings position codon usage bias as a central, evolutionarily conserved regulator of translation and protein folding in humans. Our results provide a comprehensive and integrated view of intergenic and intragenic codon usage bias in humans, reinforcing the biological relevance of synonymous codon choice in shaping translational dynamics and protein biogenesis. This provides a refined framework for interpreting synonymous variation and guiding functional genomics.

genomics↗

bioRxiv2025

Integrative multi-omic analysis reveals oral microbiome-metabolome signatures of obesity

Obesity is a major global health challenge and a leading risk factor for cardiometabolic disorders. The global surge in obesity, driven by industrialization and the widespread consumption of low-fiber, ultra-processed food, highlights an urgent need for deeper biological insights. While the gut microbiome has been studied in the context of obesity, the contribution of the oral microbiome--the second largest microbial ecosystem in the human body-remains largely underexplored. Here, we report findings from a deeply-phenotyped prospective-cohort of 628 Emirati adults, leveraging amplicon sequencing of mouthwash samples and multi-omics profiling and functional and metabolic activity analysis of 97 obese individuals and 95 matched controls, making this the most comprehensive multi-omics analysis of the oral microbiome. We identified significant differences in oral microbial diversity, composition, functional pathways, and metabolic profiles between obese and non-obese groups. Integrated multi-omics analysis of the 192 matched metagenomes and metabolome samples uncovered significant metabolic reprogramming and altered energy regulation in obesity. Specifically, the oral microbiome of obese participants were enriched for the proinflammatory Streptococcus parasanguinis and Actinomyces oris, and the lactate-producing Oribacterium sinus. Many microbial pathways involved in dietary carbohydrate metabolism, histidine degradation, as well as the production of obesogenic biomolecules were also enriched in obese participants; however, B-vitamin and heme production pathways were depleted. Consequently, metabolites resulting from these pathways such as lactate, histidine derivatives, choline, uridine, and uracil were elevated in obesity. These consistent microbiome-metabolite shifts were strongly associated with prominent obesity-associated cardiometabolic markers, including serum triglycerides and alkaline phosphatases, establishing a robust link between oral microbiome and obesity. These findings provide the most comprehensive insights into how disrupted microbial-metabolic cross-talk in the oral cavity may contribute to obesity and related cardiometabolic disease risk, underscoring the potential of targeting of oral microbiome-host interactions as a novel avenue for obesity prevention and intervention.

microbiology↗

bioRxiv2023

Atypical Cell Cycle Regulation over Neural Stem Cell Expansion

Populations of adult neural stem cells (NSCs) that reside in the mammalian brain aid in neurogenesis throughout life and can be identified by a type VI intermediate filament protein, Nestin. Cell cycle regulation plays an important role in maintaining a balance between self-renewal and differentiation and determining the fate of NSCs. Data from our group and others support that the atypical cyclin-like protein Spy1 (also called RingoA; gene SPDYA) plays a critical role in activating NSCs from a quiescent state. Elevated levels of Spy1 are found in aggressive human brain cancers, including glioblastoma. Using a conditional mouse model, we demonstrate that driving the expression of Spy1, in the Nestin-enriched NSC population of the brain, increases stemness characteristics, decreases differentiation, and increases susceptibility to oncogenic transformation. This study contributes to better understanding of intricate cell cycle mechanisms which lead to deviation from the homeostatic state, promoting aberrant changes in adult NSCs.

molecular biology↗

bioRxiv2019

Comparison of in vitro and in planta toxicity of Vip3A for lepidopteran herbivores

Agricultural pest infestation is as old as domestication of food crops and contributes a major share to the cost of crop production. Transgenic production of Vip3A, an insecticidal protein from Bacillus thuringiensis, effectively controls lepidopteran pests. A synthetic vip3A gene was evaluated its efficacy against Spodoptera litura (cotton leafworm), Spodoptera exigua (beet armyworm), Spodoptera frugiperda (fall armyworm), Helicoverpa armigera (cotton bollworm), Helicoverpa zea (corn earworm), Heliothis virescens (tobacco budworm), and Manduca sexta (tobacco hornworm). In artificial diet assays, the Vip3A concentration causing 50% mortality was H. zea > H. virescens > S. exigua > H. armigera > M. sexta > S. frugiperda > S. litura. In contrast, on vip3A transgenic tobacco the order of resistance (time until 50% lethality) was M. sexta > H. virescens > S. litura > H. zea > H. armigera > S. exigua > S. frugiperda. There was no significant correlation between the artificial diet and transgenic tobacco effects. Notably, the two insect species that are best-adapted for growth on tobacco, M. sexta and H. virescens, showed the greatest tolerance of vip3A-transgenic tobacco. This may indicate synergistic effects of Vip3A and endogenous plant defense mechanisms, e.g. nicotine, to which M. sexta and H. virescens would have greater resistance. Together, our results show that artificial diet assays are a poor predictor of Vip3A efficacy in transgenic plants, lepidopteran species vary in their sensitivity to Vip3A in diet-dependent manner, and that host plant adaptation of the targeted herbivores should be considered when designing transgenic plants for pest control.

molecular biology↗

bioRxiv2018

Polymerization Kinetics Stability, Volumetric Changes, Apatite Precipitation, Strontium Release and Fatigue of Novel Bone Composites for Vertebroplasty

PurposeThe aim was to determine effects of diluent monomer and monocalcium phosphate monohydrate (MCPM) on polymerization kinetics and volumetric stability, apatite precipitation, strontium release and fatigue of novel dual-paste composites for vertebroplasty.\n\nMaterials and methodsPolypropylene (PPGDMA) or triethylene (TEGDMA) glycol dimethacrylates (25 wt%) diluents were combined with urethane dimethacrylate (70 wt%) and hydroxyethyl methacrylate (5 wt%). 70 wt% filler containing glass particles, glass fibers (20 wt%) and polylysine (5 wt%) was added. Benzoyl peroxide and MCPM (10 or 20 wt%) or N-tolyglycine glycidyl methacrylate and tristrontium phosphate (15 wt%) were included to give initiator or activator pastes. Commercial PMMA (Simplex) and bone composite (Cortoss) were used for comparison.\n\nATR-FTIR was used to determine thermal activated polymerization kinetics of initiator pastes at 50-80 {degrees}C. Paste stability, following storage at 4-37 {degrees}C, was assessed visually or through mixed paste polymerization kinetics at 25 {degrees}C. Polymerization shrinkage and heat generation were calculated from final monomer conversions. Subsequent expansion and surface apatite precipitation in simulated body fluid (SBF) were assessed gravimetrically and via SEM. Strontium release into water was assessed using ICP-MS. Biaxial flexural strength (BFS) and fatigue properties were determined at 37 {degrees}C after 4 weeks in SBF.\n\nResultsPolymerization profiles all exhibited an inhibition time before polymerization as predicted by free radical polymerization mechanisms. Initiator paste inhibition times and maximum reaction rates were described well by Arrhenius plots. Plot extrapolation, however, underestimated lower temperature paste stability. Replacement of TEGDMA by PPGDMA, enhanced paste stability, final monomer conversion, water-sorption induced expansion and strontium release but reduced polymerisation shrinkage and heat generation. Increasing MCPM level enhanced volume expansion, surface apatite precipitation and strontium release. Although the experimental composite flexural strengths were lower compared to those of commercially available Simplex, the extrapolated low load fatigue lives of all materials were comparable.\n\nConclusionsIncreased inhibition times at high temperature give longer predicted shelf-life whilst stability of mixed paste inhibition times is important for consistent clinical application. Increased volumetric stability, strontium release and apatite formation should encourage bone integration. Replacing TEGDMA by PPGDMA and increasing MCPM could therefore increase suitability of the above novel bone composites for vertebroplasty. Long fatigue lives of the composites may also ensure long-term durability of the materials.

bioengineering↗