Biology subjects

Aydin, B.

Publications and source records attributed to Aydin, B..

9 recordsLinked to original sources

bioRxiv2025

Microgravity Remodels Longevity Networks in Astronaut PBMCs: Integrated Findings of Telomere Elongation, DNA Repair Responses, and miRNA Suppression

Microgravity provides a unique environment for elucidating the fundamental mechanisms of human aging. In the Microgravity Associated Genetics (MESSAGE) Science Mission--Turkiyes first human space biology experiment--we performed an integrative analysis of telomere dynamics, transcriptomic remodeling, and microRNA regulation in peripheral blood mononuclear cells (PBMCs) collected before launch (L-7day), after suborbital ascent (L+3hrs), and during days 4-10 aboard the International Space Station (ISS). Spaceflight induced a striking early elongation of telomeres, accompanied by transcriptional activation of DNA repair, oxidative stress mitigation, mitochondrial homeostasis, and immune regulatory pathways. Concurrently, microgravity triggered robust suppression of longevity-associated microRNAs, including members of the miR-17-92, miR29, and miR34 families, suggesting coordinated epigenetic reprogramming of genome stability and stress responses. Notably, the adaptor protein gene AP2A1, recently implicated in cellular rejuvenation and mechanotransductive aging processes, emerged as a consistently microgravity-responsive hub, linking cytoskeletal signaling to telomere maintenance and DNA repair networks. Together, these findings reveal that short-duration spaceflight initiates a multi-layered molecular longevity program in human immune cells, characterized by telomere extension, stabilization of genome maintenance pathways, and suppression of aging-associated miRNA regulators. This systems-level view provides foundational insight into how human biology adapts to short-term microgravity exposure and identifies AP2A1-centered networks as promising targets for enhancing astronaut health and performance and ultimately understanding terrestrial aging.

molecular biology↗

bioRxiv2025

Inhibitory potential of autologous neutralizing antibodies sets quantitative limits on the rebound-competent HIV-1 reservoir

HIV-1 cure requires preventing viral rebound after treatment interruption, but quantitative criteria defining the rebound-competent reservoir are lacking. We studied individuals undergoing observational treatment interruption without confounding interventions to identify virologic and immunologic determinants of rebound. In 9 of 13 participants, rebound viruses were genetically identical or similar to proviruses in circulating resting CD4+ T-cells. We found no evidence of recombination among rebound sequences. Instead, resistance to autologous neutralizing antibodies (aNAbs) was a critical determinant of viral rebound. Increased suppression of viral outgrowth by contemporaneous IgG isolated from plasma was correlated with longer time to rebound. Using inhibitory potential (IP), the log reduction in single-round infection at physiologic IgG concentrations, we defined quantitative limits governing rebound-competency with respect to contemporaneous aNAbs. Contemporaneous IgG antibodies inhibited different reservoir variants with a wide range of IP values (0.4-8.2 logs), whereas rebound viruses were minimally inhibited (0.5-2.8 logs), indicating that inhibition by even up to 2.8 logs (631-fold) cannot prevent rebound. Longitudinal analyses revealed that waning aNAb potency over time on ART allows previously neutralized variants to gain rebound potential, consistent with the finding that rebound can come from variants deposited in the reservoir at different pre-ART time points. Thus, rebound competency is a dynamic, immune-governed property defined by quantitative immunologic constraints, including those exerted by aNAbs. SIGNIFICANCE STATEMENTPreventing viral rebound after treatment interruption is the goal of HIV-1 cure research, but the latent proviruses responsible remain undefined. Although rebound is initiated in lymphoid tissues, we found rebound viruses are genetically similar to proviruses in circulating resting CD4+ T-cells. Rebound is not explained by recombination and is not solely from proviruses seeded at treatment initiation. Instead, rebound potential is governed by autologous neutralizing antibodies (aNAbs). We define a quantitative threshold of aNAb-mediated inhibition identifying reservoir variants with rebound potential. During treatment, waning aNAb levels allow previously neutralized variants to become rebound-competent. Thus rebound-competency is not a static property, but a dynamic immune-governed feature. Durable aNAb responses against all rebound-competent reservoir variants may be required for functional HIV-1 cure.

immunology↗

bioRxiv2025

Hypothetical LOC Genes as Biomarkers of Spaceflight Adaptation: A Comparative Study from ISS, Suborbital, and Earth-Based Experiments

Microgravity constitutes one of the most profound environmental stressors encountered by humans during spaceflight, capable of altering fundamental cellular processes and gene regulatory networks. While the effects of spaceflight on well-characterized protein-coding genes have been widely documented, little is known about the behavior of uncharacterized or poorly annotated genomic regions under these conditions. LOC (Locus) genes, often classified as long non-coding RNAs and excluded from conventional analyses, represent a largely unexplored component of the human transcriptome. In this study, we systematically investigated the transcriptional responses of LOC genes as part of the MESSAGE (Microgravity Associated Genetics) Science Mission, Turkiyes first human space biology initiative. Peripheral blood samples were collected from astronauts across five mission phases: pre-launch baseline, post-suborbital flight ([~]100 km), and on International Space Station (ISS) Days 4, 7, and 10 ([~]400 km). RNA-Seq analyses revealed six LOC genes with statistically significant expression changes (p < 0.05, Kruskal-Wallis test), alongside additional transcripts that, while not statistically significant, exhibited biologically meaningful temporal fluctuations. These dynamic profiles included continuous upregulation, transient activation with subsequent return to baseline, and delayed induction at later ISS stages, highlighting the functional diversity of LOC responses. To assess their translational potential, Open Reading Frame (ORF) analyses were performed on significant transcripts, revealing conserved ORF structures--most notably identical ORF33 sequences in LOC124905103 and LOC124900480-- suggesting coding capacity. Phylogenetic analyses further supported evolutionary clustering consistent with expression and ORF similarities. Collectively, these findings challenge the notion of LOC genes as transcriptional noise, instead positioning them as candidate biomarkers and functional elements of microgravity adaptation. By extending space biology research into the "dark genome," this study provides novel insights with potential implications for astronaut health monitoring and therapeutic development in long-duration missions.

molecular biology↗

bioRxiv2024

Gut bacteria-derived succinate induces enteric nervous system regeneration

Enteric neurons control gut physiology by regulating peristalsis, nutrient absorption, and secretion1. Disruptions in microbial communities caused by antibiotics or enteric infections result in the loss of enteric neurons and long-term motility disorders2-5. However, the signals and underlying mechanisms of this microbiota-neuron communication are unknown. We studied the effects of microbiota on the recovery of the enteric nervous system after microbial dysbiosis caused by antibiotics. We found that both enteric neurons and glia are lost after antibiotic exposure, but recover when the pre-treatment microbiota is restored. Using murine gnotobiotic models and fecal metabolomics, we identified neurogenic bacterial species and their derived metabolite succinate as sufficient to rescue enteric neurons and glia. Unbiased single-nuclei RNA-seq analysis uncovered a novel neural precursor-like population marked by the expression of the neuronal gene Nav2. Genetic fate-mapping showed that Plp1+ enteric glia differentiate into neurons following antibiotic exposure. In contrast, Nav2+ neurons expand upon succinate treatment and indicate an alternative mode of neuronal regeneration under recovery conditions. Our findings highlight specific microbial species, metabolites, and the underlying cellular mechanisms involved in neuronal regeneration, with potential therapeutic implications for peripheral neuropathies.

neuroscience↗

bioRxiv2023

Suppression of epithelial proliferation and tumorigenesis by immunoglobulin A

Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis1. Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function2,3 with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities4-8. Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.

immunology↗

bioRxiv2023

Biological motion perception in the theoretical framework of perceptual decision-making: An event-related potential study

Biological motion perception plays a critical role in various decisions in daily life for humans. Failure to decide accordingly in such a perceptual task could have life-threatening consequences. Neurophysiological studies on non-human primates and computational modeling studies suggest two processes that mediate perceptual decision-making. One of these signals is associated with the accumulation of sensory evidence and the other with response selection. Recent EEG studies with human participants have introduced an event-related potential called Centroparietal Positive Potential (CPP) as a neural marker aligned with the sensory evidence accumulation while effectively distinguishing it from motor-related event-related potential, namely lateralized readiness potential (LRP). The present study aims to investigate the neural mechanisms of biological motion perception in the theoretical framework of perceptual decision-making, which has been overlooked before. More specifically, we examine whether CPP would track the coherence of the biological motion stimuli and could be distinguished from the LRP signal. We recorded EEG from human participants while they were engaged in a direction discrimination task of a point-light walker whose coherence was manipulated by embedding it in various levels of noise. Our behavioral findings revealed shorter reaction times and reduced miss rates as the coherence of the target stimuli increased. In addition, CPP tracked the coherence of the biological motion stimuli with a tendency to reach a common level during the response, albeit with a later onset than the previously reported results in random-dot motion paradigms. Furthermore, CPP was distinguished from the LRP signal based on its temporal profile. Overall, our results suggest that the mechanisms underlying perceptual decision-making generalize to more complex and socially significant stimuli like biological motion. We discuss the implications of these findings for advancing computational models of biological motion perception and perceptual decision-making.

neuroscience↗

bioRxiv2021

Enteric pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections

The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss and dysmotility during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via {beta}2-adrenergic receptors ({beta}2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on T cells and systemic production of interleukin (IL)-4 and -13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease- or tissue tolerance that preserves ENS number and functionality.

immunology↗

bioRxiv2020

The BTB transcription factors ZBTB11 and ZFP131 maintain pluripotency by pausing POL II atpro-differentiation genes

In pluripotent cells, a delicate activation-repression balance maintains pro-differentiation genes ready for rapid activation. The identity of transcription factors (TFs) that specifically repress pro-differentiation genes remains obscure. By targeting ~1,700 TFs with CRISPR loss-of-function screen, we found that ZBTB11 and ZFP131 are required for embryonic stem cell (ESC) pluripotency. ZBTB11 and ZFP131 maintain promoter-proximally paused Polymerase II at pro-differentiation genes in ESCs. ZBTB11 or ZFP131 loss leads to NELF pausing factor release, an increase in H3K4me3, and transcriptional upregulation of genes associated with all three germ layers. Together, our results suggest that ZBTB11 and ZFP131 maintain pluripotency by preventing premature expression of pro-differentiation genes and present a generalizable framework to maintain cellular potency. One-sentence summaryA Transcription Factor-wide CRISPR screen identifies ZBTB11 and ZFP131 maintaining pluripotency by pausing POL II at pro-differentiation genes

developmental biology↗

bioRxiv2019

Characterizing the sequence and prior chromatin determinants of induced TF binding with bimodal neural networks

Transcription factor (TF) binding specificity is determined via a complex interplay between the TFs DNA binding preference and cell type-specific chromatin environments. The chromatin features that correlate with TF binding in a given cell type have been well characterized. For instance, the binding sites for a majority of TFs display concurrent chromatin accessibility. However, concurrent chromatin features reflect the binding activities of the TF itself, and thus provide limited insight into how genome-wide TF-DNA binding patterns became established in the first place. To understand the determinants of TF binding specificity, we therefore need to examine how newly activated TFs interact with sequence and preexisting chromatin landscapes. Here, we investigate the sequence and preexisting chromatin predictors of TF-DNA binding by examining the genome-wide occupancy of TFs that have been induced in well-characterized chromatin environments. We develop Bichrom, a bimodal neural network that jointly models sequence and preexisting chromatin data to interpret the genome-wide binding patterns of induced TFs. We find that the preexisting chromatin landscape is a differential global predictor of TF-DNA binding; incorporating preexisting chromatin features improves our ability to explain the binding specificity of some TFs substantially, but not others. Furthermore, by analyzing site-level predictors, we show that TF binding in previously inaccessible chromatin tends to correspond to the presence of more favorable cognate DNA sequences. Bichrom thus provides a framework for modeling, interpreting, and visualizing the joint sequence and chromatin landscapes that determine TF-DNA binding dynamics.

bioinformatics↗