Biology subjects

Lidsky, P. V.

Publications and source records attributed to Lidsky, P. V..

8 recordsLinked to original sources

bioRxiv2026

Social immunity as a driver of life-history evolution in eusocial species

Eusociality is accompanied by puzzling lifespan phenotypes that challenge classic theories of aging. In eusocial species, breeders age more slowly than non-breeders while sharing the same genomes. A notable exception is the naked mole-rat, in which all castes show negligible actuarial senescence. We show that both patterns can be explained with a single epidemiological model. Chronic parasites that reduce worker productivity can drive the evolution of shorter lifespan in workers, but not in queens. A genetic program that triggers the death of infected workers can evolve as an efficient alternative strategy for controlling pathogens, thereby reducing selection for shorter lifespan. However, in the presence of benign pathogens, this program results in excessive deaths and becomes too costly. Therefore, the composition of the pathogen mixture defines optimal life histories in eusocial communities: species exposed to a broad pathogen repertoire evolve caste differences in lifespan, whereas species occupying pathogen-poor environments are predicted to die rapidly upon infection and experience negligible aging. This framework links social immunity to life-history evolution and yields testable predictions for the pathogen control hypothesis of aging.

evolutionary biology↗

bioRxiv2025

Avoidance Of Rejuvenation: A Stress Test For Evolutionary Theories Of Aging

The biological feasibility of human rejuvenation remains a subject of intense debate, yet answering this question is critical for guiding research strategies. Should aging research focus on reversing aging in older individuals, or on pausing its progression at earlier ages? We address this question with evolutionary biology. Classic evolutionary theories of aging-- damage accumulation, antagonistic pleiotropy, and the disposable soma--consider aging as a detrimental byproduct of evolution. From this perspective, rejuvenation should confer strong fitness advantages and therefore be expected to evolve in species experiencing substantial aging in the wild. Its rarity in nature should thus be interpreted as evidence of its mechanistic implausibility. Yet, rejuvenation does occur in a few species, and, paradoxically, it is typically induced by stress but not used under optimal conditions. Using mathematical modeling of lifespan plasticity in eusocial insects, we show that this pattern cannot be reconciled with classic theories of aging, revealing an internal contradiction between these theories and the observed avoidance of rejuvenation. By contrast, the pathogen control hypothesis--which interprets aging as an adaptive, programmed process--offers a consistent evolutionary framework for understanding and potentially achieving rejuvenation.

evolutionary biology↗

bioRxiv2023

Introduction of Dicistrovirus IRESs into UAS/SV40-polyA constructs results in premature polyadenylation and strong overexpression of the upstream ORF in Drosophila animals.

To evaluate the properties of insect virus internal ribosomal entry sites (IRESs) for protein expression in Drosophila, we have introduced Cricket Paralysis virus (CrPV) and Drosophila C virus (DCV) IRESs into UAS/SV40-polyA vector. We found that introduction of IRESs induce premature polyadenylation, resulting in both truncation of the mRNA, and an increase in mRNA levels of approximately 40-fold. The increase in mRNA levels was accompanied by increased resistance to nonsense-mediated mRNA decay (NMD)-mediated degradation. Our results suggest that premature polyadenylation increases mRNA stability in the SV40 polyadenylation site-containing constructs, suggesting a novel method for robust overexpression of transgenes in Drosophila.

genetics↗

bioRxiv2023

Monitoring integrated stress response in live Drosophila

Cells exhibit stress responses to various environmental changes. Among these responses, the integrated stress response (ISR) plays a pivotal role as a crucial stress signaling pathway. While extensive ISR research has been conducted on cultured cells, our understanding of its implications in multicellular organisms remains limited, largely due to the constraints of current techniques that hinder our ability to track and manipulate the ISR in vivo. To overcome these limitations, we have successfully developed an internal ribosome entry site (IRES)-based fluorescent reporter system. This innovative reporter enables us to label Drosophila cells, within the context of a living organism, that exhibit eIF2 phosphorylation-dependent translational shutoff - a characteristic feature of the ISR and viral infections. Through this methodology, we have unveiled tissue- and cell-specific regulation of stress response in Drosophila flies and have even been able to detect stressed tissues in vivo during virus and bacterial infections. To further validate the specificity of our reporter, we have engineered ISR-null eIF2S50A mutant flies for stress response analysis. Our results shed light on the tremendous potential of this technique for investigating a broad range of developmental, stress, and infection-related experimental conditions. Combining the reporter tool with ISR-null mutants establishes Drosophila as an exceptionally powerful model for studying the ISR in the context of multicellular organisms.

developmental biology↗

bioRxiv2023

SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection

A better mechanistic understanding of virus-host interactions can help reveal vulnerabilities and identify opportunities for therapeutic interventions. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in polysome composition and protein synthesis during SARS-CoV-2 (CoV2) infection. We identify specific translation factors and molecular chaperones whose inhibition impairs infectious particle production without major toxicity to the host. We find that CoV2 non-structural protein Nsp1 selectively enhances virus translation through functional interactions with initiation factor EIF1A. When EIF1A is depleted, more ribosomes initiate translation from an upstream CUG start codon, inhibiting translation of non-structural genes and reducing viral titers. Together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and identifies druggable targets for potential antiviral development.

microbiology↗

bioRxiv2022

Robust expression of transgenes in Drosophila melanogaster

Drosophila is a classic experimental system used in fundamental and biopharmaceutical research. Manipulating gene expression in the larvae and adult flies can facilitate basic and translational studies. Here we report a method for robust transgene overexpression in Drosophila melanogaster. This approach is compatible with the UAS/Gal4 gene expression system. The improved expression involves a gene expression cassette that prevents transgenic mRNA transcript degradation by the nonsense-mediated RNA decay pathway. The protection is mediated by CrPV and DCV IRES sequences that apparently encode cryptic polyadenylation sites and NMD inhibitors. Stabilization of the transgene mRNA results in a >40-fold increase in its levels.

genetics↗

bioRxiv2021

A type I interferon response defines a conserved microglial state required for effective phagocytosis

Microglia are brain resident phagocytes that can engulf synaptic components and extracellular matrix as well as whole neurons. However, whether there are unique molecular mechanisms that regulate these distinct phagocytic states is unknown. Here we define a molecularly distinct microglial subset whose function is to engulf neurons in the developing brain. We transcriptomically identified a cluster of Type I interferon (IFN-I) responsive microglia that expanded 20-fold in the postnatal day 5 somatosensory cortex after partial whisker deprivation, a stressor that accelerates neural circuit remodeling. In situ, IFN-I responsive microglia were highly phagocytic and actively engulfed whole neurons. Conditional deletion of IFN-I signaling (Ifnar1fl/fl) in microglia but not neurons resulted in dysmorphic microglia with stalled phagocytosis and an accumulation of neurons with double strand DNA breaks, a marker of cell stress. Conversely, exogenous IFN-I was sufficient to drive neuronal engulfment by microglia and restrict the accumulation of damaged neurons. IFN-I deficient mice had excess excitatory neurons in the developing somatosensory cortex as well as tactile hypersensitivity to whisker stimulation. These data define a molecular mechanism through which microglia engulf neurons during a critical window of brain development. More broadly, they reveal key homeostatic roles of a canonical antiviral signaling pathway in brain development.

neuroscience↗

bioRxiv2017

Protection from epidemics is a driving force for evolution of lifespan setpoints

Most living organisms age, as determined by species-specific limits to lifespan1-6. The biological driving force for a genetically-defined limit on the lifespan of a given species (herein called \"lifespan setpoint\") remains poorly understood. Here we present mathematical models suggesting that an upper limit of individual lifespans protects their cohort population from infection-associated penalties. A shorter lifespan setpoint helps control pathogen spread within a population, prevents the establishment and progression of infections, and accelerates pathogen clearance from the population when compared to populations with long-lived individuals. Strikingly, shorter-living variants efficiently displace longer-living individuals in populations that are exposed to pathogens and exist in spatially structured niches. The beneficial effects of shorter lifespan setpoints are even more evident in the context of zoonotic transmissions, where pathogens undergo adaptation to a new host. We submit that the selective pressure of infectious disease provides an evolutionary driving force to limit individual lifespan setpoints after reproductive maturity to secure its kins fitness. Our findings have important public health implications for efforts to extend humans lifespan.

evolutionary biology↗