Biology subjects

Arab, A.

Publications and source records attributed to Arab, A..

16 recordsLinked to original sources

bioRxiv2026

A Dimeric Rocaglate Promotes Multivalent eIF4A-RNA Assembly

Ligand dimerization represents a powerful strategy to enhance avidity, potency, and selectivity. Leveraging the natural-product molecular glue Rocaglamide (RocA), we identified BisRoc, a dimeric rocaglate ligand that potently and durably suppresses translation and exhibits greater specificity across a cancer cell line panel than the monomeric RocA. CRISPRi screening revealed that BisRoc activity is influenced by cellular context, including IFITM-mediated uptake, ABC-type efflux transporters, and the translation initiation factor eIF4A2. Mechanistic studies showed that the paralogs eIF4A1 and eIF4A2 are differentially sensitive to BisRoc-induced dimerization. Owing to the presence of multiple binding sites on RNAs, BisRoc-bridged eIF4A-RNA motifs assemble into higher-order complexes that promote stress-granule formation more efficiently than monomeric RocA. Given the widespread multivalency of RNA-RBP interactions, this ligand dimerization strategy may be extended to modulate the higher-order assembly of other RNA-binding proteins. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/710667v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1f0ce69org.highwire.dtl.DTLVardef@7f7fadorg.highwire.dtl.DTLVardef@976e81org.highwire.dtl.DTLVardef@1d7eaf2_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Risk-Aware Control for Insulin Delivery via Nonlinear MPC with Safety Barrier Functions and Probabilistic Learning of Uncertainties

Maintaining blood glucose within a physiologically safe range is critical for people with diabetes, as deviations can lead to acute or chronic complications. Hypoglycemia, in particular, represents an immediate threat and requires prioritized mitigation in autonomous insulin delivery systems. This paper introduces a risk-aware hybrid nonlinear model predictive control (NMPC) framework that combines data-driven uncertainty quantification with formal safety assurance through control barrier functions (CBFs). To account for key uncertainties, such as physiological time delays, unannounced meals, and stress-induced glucose variability, Gaussian processes (GPs) are employed as probabilistic estimators. The proposed method dynamically monitors glucose and regulates insulin injection to enforce safe glucose level control by preventing hypoglycemia. The proposed framework is evaluated using validated physiological simulators for various realistic scenarios. The results show a robust performance in maintaining safety under high uncertainty, preparing a foundation for translation into next phase of our research as safe autonomous diabetes management systems.

bioengineering↗

bioRxiv2025

Dietary Resilience of Termite Gut Microbiota and Enzymatic Function Reflects Feeding Strategy

Termites are major decomposers in tropical ecosystems, relying on complex gut microbiomes to digest lignocellulosic substrates. In this study, we compared the gut microbiota composition and enzymatic responses to dietary shifts in two neotropical termite species with contrasting feeding strategies: the polyphagous Silvestritermes euamignathus and the litter-feeding specialist Cornitermes cumulans. High-throughput sequencing and enzymatic assays revealed that S. euamignathus maintained stable microbial communities and enzymatic profiles across diverse diets, including artificial and fiber-rich substrates. In contrast, C. cumulans exhibited significant shifts in bacterial abundance and reduced enzymatic activity under altered diets, particularly those differing from its natural litter-based diet. Functional gene predictions further indicated broader metabolic potential in S. euamignathus, particularly in response to complex substrates, while C. cumulans showed transcriptional suppression of polysaccharide-degrading enzymes. These results suggest that S. euamignathus benefits from a more flexible and functionally resilient gut symbiosis, enabling adaptation to heterogeneous or disturbed environments. In contrast, the narrower metabolic scope of C. cumulans may limit its capacity to respond to dietary change. Our findings highlight how feeding ecology shapes microbiome plasticity and digestive function in termites, with implications for understanding their adaptability under environmental stress and climate-driven shifts in resource availability.

ecology↗

bioRxiv2024

Thermal biology of aphids and implications for agriculture and food security

Climate change poses significant challenges to agriculture and food security, particularly through its effects on insect vector populations and the pathogens they transmit. Aphids are one of the biggest group of ectotherms that transmit viruses to plants; more than 200 species have been identified as pathogen vectors. These aphids are responsible for transmitting over 300 viruses. The life-history traits of aphids such as fecundity and survival respond strongly and non-linearly to temperature and therefore to global warming. In this study, we elaborate the thermal responses for the main life-history traits (i.e, development and mortality rate) for aphid species for which data were available or generated. Also, thermal responses for virus transmission rates were elaborated to describe plant host to vector and vector to plant host dynamics. With these data, we elaborated thermal suitability models which were used to map current and projected scenarios for the transmission of viruses by aphids. Data was only available/generated for 19 aphid species, many of which only have data either at the lower or upper thermal limits. For virus transmission rates, from host plant to vector and from vector to plant data was only available/generated for potato virus Y (PVY), potato virus A (PVA), and potato leaf roll virus (PLRV) transmitted by the aphid Myzus persicae. Projections show that virus transmission by aphids will shift to northern latitudes. Understanding the thermal biology of aphids is crucial for developing effective measures to safeguard agriculture, especially staple crops, and food security in the context of climate change.

plant biology↗

bioRxiv2024

Effects of temperature on the life-history traits of Myzus persicae and its efficiency in transmitting potato virus Y (PVY) in potato crops

Aphids are highly sensitive to temperature changes and play a crucial role in transmitting plant viruses, accounting for the transmission of more than 50% of viruses that cause disease in crops. Among them, Myzus persicae is a major global pest, affecting over 400 plant species and transmitting more than 100 plant viruses, including potato virus Y (PVY), which poses a severe threat to potato crops. This study examines how temperature influences the life-history traits of M. persicae and its efficiency in transmitting PVY. Our research revealed that temperature significantly affects developmental duration, survival, and fecundity of M. persicae. The aphids exhibit the longest lifespan at 10{degrees}C and the shortest at 30{degrees}C. Similarly, fecundity declined from 29.81 offspring per female at 10{degrees}C to 14.25 at 30{degrees}C. PVY transmission efficiency was highest at 20{degrees}C. We also mapped potential PVY transmission regions and identified tropical and subtropical areas as high-risk due to their favourable temperatures and aphids abundance. Understanding these geographical variations is crucial for effective pest/disease management. Our findings emphasize the importance of integrating climatological, ecological, and epidemiological data to develop robust pest/disease management strategies to mitigate the impact of M. persicae and PVY on potato production and enhancing global food security.

plant biology↗

bioRxiv2023

Higher-order combinatorial chromatin perturbations by engineered CRISPR-Cas12a for functional genomics

Multiplexed genetic perturbations are critical for testing functional interactions among coding or non-coding genetic elements. Compared to double-stranded DNA cutting, repressive chromatin formation using CRISPR interference (CRISPRi) avoids genotoxicity and is more effective for perturbing non-coding regulatory elements in pooled assays. However, current CRISPRi pooled screening approaches are limited to targeting 1-3 genomic sites per cell. To develop a tool for higher-order (>3) combinatorial targeting of genomic sites with CRISPRi in functional genomics screens, we engineered an Acidaminococcus Cas12a variant -- referred to as multiplexed transcriptional interference AsCas12a (multiAsCas12a). multiAsCas12a incorporates a key mutation, R1226A, motivated by the hypothesis of nicking-induced stabilization of the ribonucleoprotein:DNA complex for improving CRISPRi activity. multiAsCas12a significantly outperforms prior state-of-the-art Cas12a variants in combinatorial CRISPRi targeting using high-order multiplexed arrays of lentivirally transduced CRISPR RNAs (crRNA), including in high-throughput pooled screens using 6-plex crRNA array libraries. Using multiAsCas12a CRISPRi, we discover new enhancer elements and dissect the combinatorial function of cis-regulatory elements. These results instantiate a group testing framework for efficiently surveying potentially numerous combinations of chromatin perturbations for biological discovery and engineering.

genetics↗

bioRxiv2023

Inhibition of muscarinic receptor signaling protects human enteric inhibitory neurons against platin chemotherapy toxicity

GI toxicity is a common dose-limiting adverse effect of platin chemotherapy treatment. Up to 50% of cancer survivors continue to experience symptoms of chronic constipation or diarrhea induced by their chemotherapy for many years after their treatment. This drug toxicity is largely attributed to damage to enteric neurons that innervate the GI tract and control GI motility. The mechanisms responsible for platin-induced enteric neurotoxicity and potential preventative strategies have remained unknown. Here, we use human pluripotent stem cell derived enteric neurons to establish a new model system capable of uncovering the mechanism of platin-induced enteric neuropathy. Utilizing this scalable system, we performed a high throughput screen and identified drug candidates and pathways involved in the disease. Our analyses revealed that excitotoxicity through muscarinic cholinergic signaling is a key driver of platin-induced enteric neuropathy. Using single nuclei transcriptomics and functional assays, we discovered that this disease mechanism leads to increased susceptibility of specific neuronal subtypes, including inhibitory nitrergic neurons, to platins. Histological assessment of the enteric nervous system in platin-treated patients confirmed the selective loss of nitrergic neurons. Finally, we demonstrated that pharmacological and genetic inhibition of muscarinic cholinergic signaling is sufficient to rescue enteric neurons from platin excitotoxicity in vitro and can prevent platin-induced constipation and degeneration of nitrergic neurons in mice. These studies define the mechanisms of platin-induced enteric neuropathy and serve as a framework for uncovering cell type-specific manifestations of cellular stress underlying numerous intractable peripheral neuropathies.

pharmacology and toxicology↗

bioRxiv2023

Functional microRNA-Targeting Drug Discovery by Graph-Based Deep Learning

MicroRNAs are recognized as key drivers in many cancers, but targeting them with small molecules remains a challenge. We present RiboStrike, a deep learning framework that identifies small molecules against specific microRNAs. To demonstrate its capabilities, we applied it to microRNA-21 (miR-21), a known driver of breast cancer. To ensure the selected molecules only targeted miR-21 and not other microRNAs, we also performed a counter-screen against DICER, an enzyme involved in microRNA biogenesis. Additionally, we used auxiliary models to evaluate toxicity and select the best candidates. Using datasets from various sources, we screened a pool of nine million molecules and identified eight, three of which showed anti-miR-21 activity in both reporter assays and RNA sequencing experiments. One of these was also tested in mouse models of breast cancer, resulting in a significant reduction of lung metastases. These results demonstrate RiboStrikes ability to effectively screen for microRNA-targeting compounds in cancer.

cancer biology↗

bioRxiv2022

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

The search for new approaches in cancer therapy requires a mechanistic understanding of cancer vulnerabilities and anti-cancer drug mechanisms of action. Problematically, some effective therapeutics target cancer vulnerabilities that have poorly defined mechanisms of anti-cancer activity. One such drug is decitabine, a frontline therapeutic approved for the treatment of high-risk acute myeloid leukemia (AML). Decitabine is thought to kill cancer cells selectively via inhibition of DNA methyltransferase enzymes, but the genes and mechanisms involved remain unclear. Here, we apply an integrated multiomics and CRISPR functional genomics approach to identify genes and processes associated with response to decitabine in AML cells. Our integrated multiomics approach reveals RNA dynamics are key regulators of DNA hypomethylation induced cell death. Specifically, regulation of RNA decapping, splicing and RNA methylation emerge as important regulators of cellular response to decitabine.

cancer biology↗

bioRxiv2022

Propagated circulating tumor cells uncovers the rople of NFκB and COP1 in metastasis

Circulating tumor cells (CTCs), a population of cancer cells that represents the seeds of metastatic nodules, are a promising model system for studying metastasis. However, expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here, we report the development of a combined CTC and CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. Propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-kB signaling as a pan-cancer signaling pathway involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective 5-gene signature (BCAR1, COL1A1, IGSF3, RRAD, and TFPI2). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (COP1) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.

cancer biology↗

bioRxiv2022

Detyrosination enrichment on microtubule subsets is established by the interplay between a stochastically-acting enzyme and microtubule stability

Microtubules in cells consist of functionally diverse subpopulations carrying distinct post-translational modifications (PTMs). Akin to the histone code, the tubulin code regulates a myriad of microtubule functions ranging from intracellular transport to chromosome segregation. Yet, how individual PTMs only occur on subsets of microtubules to contribute to microtubule specialization is not well understood. In particular, microtubule detyrosination, which is the removal of the C-terminal tyrosine on -tubulin subunits, marks the stable population of microtubules and modifies how microtubules interact with other microtubule-associated proteins to regulate a wide range of cellular processes. Previously, we found that, in certain cell types, only a small subpopulation of microtubules is highly enriched with the detyrosination mark ([~]30%) and that detyrosination spans most of the length of a microtubule, often adjacent to a completely tyrosinated microtubule. How the activity of a cytosolic detyrosinase, Vasohibin (VASH) leads to only a small subpopulation of highly detyrosinated microtubules is unclear. Here, using quantitative super-resolution microscopy, we visualized nascent microtubule detyrosination events in cells consisting of 1-3 detyrosinated -tubulin subunits after Nocodazole washout. Microtubule detyrosination accumulates slowly and in a disperse pattern across the microtubule length. By visualizing single molecules of VASH in live cells, we found that VASH engages with microtubules stochastically on a short time scale suggesting limited removal of tyrosine per interaction, consistent with the super-resolution results. Combining these quantitative imaging results with simulations incorporating parameters from our experiments, we propose a stochastic model for cells to establish a subset of detyrosinated microtubules via a detyrosination-stabilization feedback mechanism.

cell biology↗

bioRxiv2022

Deriving Schwann Cells from hPSCs Enables Disease Modeling and Drug Discovery for Diabetic Peripheral Neuropathy

Schwann cells (SCs) are the myelinating and non-myelinating glia of the peripheral nervous system (PNS) and are essential for its function. Defects in SCs are associated with many PNS disorders including diabetic peripheral neuropathy (DPN), a condition affecting millions of patients. Here we present a strategy for deriving and purifying SCs from human pluripotent stem cells (hPSCs). The scalable cultures of SCs allow basic and translational applications such as high-resolution molecular and functional characterization, developmental studies, modeling and mechanistic understanding of SC diseases and drug discovery. Our hPSC-derived SCs recapitulate the key molecular features of primary SCs and are capable of engrafting efficiently and producing myelin in injured sciatic nerves in rats. We further established an hPSC-based in vitro model of DPN that revealed the selective vulnerability of human SCs to hyperglycemia-induced cytotoxicity. We established a high-throughput screening system that identified a candidate drug that counteracts glucose-mediated cytotoxicity in SCs and normalizes glucose-induced transcriptional and metabolic abnormalities in SCs. Treatment of hyperglycemic mice with this drug candidate rescues sensory function, prevents SC death, and counteracts myelin damage in sciatic nerves suggesting considerable potential as a novel treatment for DPN.

developmental biology↗

bioRxiv2021

A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy.

Advances in cancer biology are increasingly dependent on integration of heterogeneous datasets. Large scale efforts have systematically mapped many aspects of cancer cell biology; however, it remains challenging for individual scientists to effectively integrate and understand this data. We have developed a new data retrieval and indexing framework that allows us to integrate publicly available data from different sources and to combine publicly available data with new or bespoke datasets. Beyond a database search, our approach empowered testable hypotheses of new synthetic lethal gene pairs, genes associated with sex disparity, and immunotherapy targets in cancer. Our approach is straightforward to implement, well documented and is continuously updated which should enable individual users to take full advantage of efforts to map cancer cell biology.

bioinformatics↗

bioRxiv2020

Tau forms oligomeric complexes on microtubules that are distinct from pathological oligomers in disease

Tau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single molecule localization microscopy (SMLM), we show that, in vivo, tau forms small oligomers on microtubules under physiological conditions. These physiological oligomers are distinct from those found in cells exhibiting tau aggregation and could be pre-cursors of aggregated tau in pathology. Further, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates taus nanoscale composition under physiological and pathological conditions in vivo.

cell biology↗

bioRxiv2018

jouvence, a new small nucleolar RNA required in the gut extends lifespan in Drosophila

Longevity is influenced by various genetic and environmental factors, but the underlying mechanisms remain poorly understood. Here, we functionally characterise a new Drosophila small nucleolar RNA (snoRNA), named jouvence whose loss of function dramatically reduces lifespan. A transgene containing the genomic region of jouvence rescues the longevity in mutant, while its overexpression in wild-type flies increases lifespan. Jouvence is expressed in epithelial cells of the gut. Targeted expression of jouvence specifically in the enterocytes increases lifespan, indicating that its role in the control of longevity takes place in these cells. A transcriptomic analysis performed from the gut reveals that several genes are either up-or down-regulated in mutant indicating that the snoRNA-jouvence might be involved in transcriptional control. Finally, since snoRNAs are structurally and functionally well conserved throughout evolution, we identified putative jouvence orthologue in mammals including humans, suggesting that its function in longevity might be conserved through evolution.

genetics↗

bioRxiv2017

Socio-environmental and measurement factors drive spatial variation in influenza-like illness

The mechanisms hypothesized to drive spatial heterogeneity in reported influenza activity include: environmental factors, contact patterns, population age structure, and socioeconomic factors linked to healthcare access and quality of life. Harnessing the large volume and high specificity of diagnosis codes in medical claims data for influenza seasons from 2002-2009, we estimate the importance of socio-environmental determinants and measurement-related factors on observed variation in influenza-like illness (ILI) across United States counties. We found that South Atlantic states tended to have higher ILI seasonal intensity, and a combination of transmission, environmental, influenza subtype, socioeconomic and measurement factors explained the variation in seasonal intensity across our study period. Moreover, our models suggest that sentinel surveillance systems should have fixed report locations across years for the most robust inference and prediction, and high volumes of data can offset measurement biases in opportunistic data samples.

epidemiology↗