Biology subjects

Syed, Z.

Publications and source records attributed to Syed, Z..

7 recordsLinked to original sources

bioRxiv2026

Cell autonomous inflammation in VEXAS is mediated by cGAS-STING

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a severe adult-onset inflammatory disease caused by somatic mutations that reduce cytoplasmic activity of UBA1, the primary initiating enzyme for ubiquitylation. How this hypomorphic state drives cell-intrinsic immune activation in mature myeloid cells is unknown. Using unbiased multi-omic, biochemical, and cell biological analyses of model systems and patient-derived cells, we show that loss of cytoplasmic UBA1 activity convergently disrupts endoplasmic reticulum- associated degradation (ERAD) and mitochondrial homeostasis. ERAD failure arises from preferential under-charging of ERAD E2 enzymes, explaining hallmark VEXAS features, including ER-derived vacuoles and unfolded protein response activation, and promotes accumulation of the ERAD substrate STING. Simultaneously, mitochondrial dysfunction drives cytosolic leakage of mitochondrial DNA, inducing cGAS-dependent STING signaling and inflammatory cytokine production. STING inhibition or reversal of mitochondrial DNA leakage resolves multi-cytokine inflammation in VEXAS models and patient myeloid cells, establishing the cGAS-STING pathway as a therapeutically actionable vulnerability.

genetics↗

bioRxiv2025

Signatures of adaptive self-organization detected in swidden societies worldwide

Quantitative signatures of adaptive self-organization and the spatial scale of human management can be detected in anthropogenic landscapes. Yet, while abundant evidence for self-organization in physical and natural systems exists, there are few adaptive self-organization models that can explain coupled dynamics of human subsistence systems that have also been rigorously validated. Here, we analyze over 18,000 forest patches extracted from 18 remotely-sensed swidden mosaics from tropical and subtropical regions across the planet. We discover a power law signature of adaptive self-organization in the size of the patches and correlation distances that indicate the spatial scale of socioecological adaptation. To explain this pattern, we propose a mathematical model of swidden labor reciprocity, normative reasoning, field placement, forest disturbance and regrowth dynamics that explains the emergent spatial structure of swidden mosaics. Social self-organization can promote sustainable levels of forest disturbance when ecological dynamics such as facilitation, seed-dispersal and competition are conditioned by social dynamics, giving rise to power-law land-use patterns. We use simulations to explore the emergent properties of the model and identify two regimes: deforestation and sustainable swidden. When we analyze the relationship between the simulation results in the remote sensing data, we find that 16/18 of the study areas exhibit power-law distributions and spatial correlation patterns that match the sustainable swidden regime in the model. These findings support the hypothesis that adaptive self-organization may be a general characteristic of coupled human and natural systems.

ecology↗

bioRxiv2025

The Landscape Ecology of Swidden: A Global Comparison Indicates Swidden Landscape Mosaics Contribute to Vegetation Diversity at Intermediate Levels of Disturbance

Swidden agriculture is a widespread anthropogenic disturbance regime in tropical forests. Swidden research often posits that aggregate levels of forest disturbance correlate with increased land degradation, however a landscape configuration approach may distinguish when swidden degrades landscapes and when it diversifies them. Here we analyze how the configuration of swidden mosaics relates to vegetation diversity. Using satellite imagery from 18 swidden societies across the African, Southeast Asian, and American tropics, we quantify patch geometry using landscape metrics and estimate vegetation diversity from spectral variation and develop a nonlinear hierarchical Bayesian model that links the structure of swidden mosaics with vegetation diversity. Our analyses reveal three dominant gradients of swidden mosaic patterns: (1) aggregation versus interspersion of land-cover types; (2) spatial dispersion versus synchronization of disturbed patches; and (3) alternative modes of landscape connectivity. Across sites, vegetation diversity exhibits a consistent nonlinear response, peaking at intermediate levels of disturbance intensity. These results demonstrate that swidden agriculture does not produce a singular, degradative outcome. Instead, its effects on vegetation diversity depend on how disturbance is spatially configured. By shifting attention from area-based measures of deforestation to landscape configuration, this study reframes swidden as a spatial process with the potential for diversity-enhancing outcomes.

ecology↗

bioRxiv2024

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafish vps4a mutants

Mutations in human VPS4A are associated with neurodevelopmental defects, including motor delays and defective muscle tone. VPS4A encodes a AAA-ATPase required for membrane scission, but how mutations in VPS4A lead to impaired control of motor function is not known. Here we identified a mutation in zebrafish vps4a, T248I, that affects sensorimotor transformation. In biochemical experiments we show the T248I mutation reduces the ATPase activity of Vps4a and disassembly of its substrate, ESCRT filaments, which mediate membrane scission. Consistent with the established role for Vps4a in the endocytic pathway and exosome biogenesis, vps4aT248I mutants have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes. Resembling the central form of hypotonia in human VPS4A patients, motor neurons and muscle cells are unaffected in mutant zebrafish as touch sensitivity is intact. Unlike somatosensory function, optomotor responses, vestibulospinal (VS), and acoustic startle reflexes are severely impaired in vps4aT248I mutants, indicating a greater sensitivity of these circuits to the T248I mutation. ERG recordings indicate that visual ability is largely reduced in the mutants, however, in vivo imaging of tone-evoked responses in the inner ear and ascending auditory pathway show comparable activity. Further investigation of central pathways in vps4aT248I mutants revealed that sensory cues failed to fully activate neurons in the VS and medial longitudinal fasciculus (MLF) nuclei that directly innervate motor neurons. Our results suggest that a defect in sensorimotor transformation underlies the profound yet selective effects on motor reflexes resulting from the loss of membrane scission mediated by Vps4a. Significance StatementHere we present a T248I mutation in vps4a, which causes sensorimotor defects in zebrafish larvae. Spanning biochemical to systems level analyses, our study indicates that a reduction in Vps4a enzymatic activity leads to endosomal defects and reduced exosome biogenesis, resulting in pronounced deficits in vision and sensorimotor transformation of auditory and vestibular cues. We suggest that the mechanisms underlying this type of dysfunction in zebrafish may also contribute to the condition seen in human patients with de novo mutations in the human VPS4A orthologue.

neuroscience↗

bioRxiv2021

Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation

The SARS-CoV-2 coronavirus responsible for the global pandemic contains a unique furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation. Here, we show that O-glycosylation near the furin cleavage site is mediated by specific members of the GALNT enzyme family and is dependent on the novel proline at position 681 (P681). We further demonstrate that O-glycosylation of S decreases furin cleavage. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the potential role of P681 mutations in the recently identified, highly transmissible B.1.1.7 variant.

biochemistry↗

bioRxiv2020

Molecular signatures of sexual communication in the phlebotomine sand flies

Phlebotomine sand flies employ an elaborate system of pheromone communication wherein males produce pheromones that attracts other males to leks (thus acting as aggregation pheromone) and females to the lekking males (sex pheromone). In addition, the type of pheromone produced varies among populations. Despite the numerous studies on sand fly chemical communication, little is known of their chemosensory genome. Chemoreceptors interact with chemicals in an organisms environment to elicit essential behaviors such as the identification of suitable mates and food sources, thus, they play important roles during adaptation and speciation. Major chemoreceptor gene families, odorant receptors (ORs), gustatory receptors (GRs) and ionotropic receptors (IRs) together detect and discriminate the chemical landscape. Here, we annotated the chemoreceptor repertoire in the genomes of Lutzomyia longipalpis and Phlebotomus papatasi, major phlebotomine vectors in the New World and Old World, respectively. Comparison with other sequenced Diptera revealed a large and unique expansion where over 80% of the ~140 ORs belong to a single, taxonomically restricted clade. We next conducted comprehensive analysis of the chemoreceptors in 63 Lu. longipalpis individuals from four different locations in Brazil representing allopatric and sympatric populations and three aggregation-sex pheromone types (chemotypes). Population structure based on single nucleotide polymorphisms (SNPs) and gene copy number in the chemoreceptors corresponded with their putative chemotypes, and corroborate previous studies that identified multiple populations. Our work provides genomic insights into the underlying behavioral evolution of sexual communication in the L. longipalpis species complex in Brazil, and highlights the importance of accounting for the ongoing speciation in central and South American Lutzomyia that could have important implications for vectorial capacity.

evolutionary biology↗

bioRxiv2020

Neurophysiological and Behavioral Responses of Ixodes scapularis to host odors

The black-legged tick, Ixodes scapularis (Ixodida, Ixodidae), is one of the major disease vectors in the United States and due to multiple human impact factors, such as decreasing forest size for land development and climate change, it has expanded its range and established across the United States. Throughout the life cycle, ticks locate hosts for their blood-meal and although the ecologies of this tick and their hosts have been studied in depth, the sensory physiology behind host location largely remains unexplored. Here we report establishing a robust paradigm to isolate and identify odors from the natural milieu for I. scapularis. We performed single sensillum recordings (SSR) from the olfactory sensilla on the tick tarsi, and used the SSR system as biological detector to isolate natural compounds that elicited biological activity. The SSR setup was further tested in tandem with gas chromatography (GC) wherein the ticks olfactory sensillum activity served as a biological detector. The GC-SSR recordings from the wall pore sensilla in the Hallers organ, and further identification of the biologically active deer glad constituents by GC-mass spectrometry (GC-MS) revealed methyl substituted phenols as strong chemostimuli, as compared to ethyl or propyl substitutions. Strongest electrophysiological activity was elicited by meta-cresol followed by para-cresol. Ethyl- and propylphenols with any of the three, ortho, meta or para substitutions, did not induce any neurophysiological activity. Finally, a behavioral analysis in a dual-choice olfactometer of all these phenols at three different doses revealed no significant behavioral response, except for p-cresol at -3 dilution Overall, this study contributes to our understanding of I. scapularis ticks neurophysiology and provides a robust platform to isolate and identify natural attractants and repellents.

zoology↗