Biology subjects

Shalev, O.

Publications and source records attributed to Shalev, O..

7 recordsLinked to original sources

bioRxiv2026

Preclinical Comparison of DMT and 5-MeO-DMT Reveals Behavioral Dissociation, Distinct TrkB Activation and Differential Plasticity Profiles

N, N-dimethyltryptamine (DMT) and 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) are structurally related tryptamine psychedelics with emerging therapeutic potential, yet their comparative acute pharmacology and longer-term neuroplastic effects remain incompletely defined. Here we show that DMT produces a bell-shaped dose-response curve in the mouse head-twitch response (HTR) assay, whereas 5-MeO-DMT elicits a monotonic increase. Selective antagonism at 5-HT2A or 5-HT1D receptors, or agonism at 5-HT1A, robustly attenuates HTR for both compounds without abolishing their ability to reduce marble burying, a screening assay for OCD-like behavior. Acutely, both agents elevate TrkB phosphorylation in a region-specific manner, with broader engagement by DMT across default-mode-network and hippocampal territories. Twelve days after a single dose, both compounds increase synaptic proteins (PSD-95, synaptophysin; SV2A for DMT), while DMT uniquely lowers hippocampal BDNF and reprograms frontal-cortex glutathione and energy metabolism. These findings demonstrate that acute hallucinogenic-like activity and selected therapeutic-like behavioral and plasticity outcomes can be pharmacologically dissociated, informing the rational design of more tolerable, scalable psychedelic-based treatments.

neuroscience↗

bioRxiv2025

Emergent loss of microbial biodiversity with increasing resource diversity

The origin of biodiversity is arguably the most fundamental question in ecology -- especially how countless microbial species coexist within a single community. A prevailing hypothesis holds that microbial species coexist by specializing on different resources, thereby reducing competition. Accordingly, increasing resource diversity is expected to promote species coexistence and boost biodiversity. Surprisingly, we observe the opposite: microbial biodiversity often declines as resource diversity increases. This unexpected result emerges from a widespread physiological response across diverse microbial taxa, in which more complex environments trigger higher overall resource uptake. This intensifies competition and drives biodiversity loss. Updating a central ecological model to include this physiological trait accurately reproduces the observed decline. Our findings demonstrate that physiological changes at the individual level can overturn classical ecological principles and scale up to restructure entire ecosystems.

microbiology↗

bioRxiv2025

Nucleotide insufficiency induced by p53 deficiency leads to replication stress driving genomic instability

P53 prevents DNA damage by inducing repair processes, cell cycle arrest or apoptosis. P53 loss leads to replication stress and genomic instability, yet the mechanisms underlying these effects and their contribution to catastrophic genomic events such as chromothripsis remain poorly understood. Using patient-derived fibroblasts with germline p53 variants, that spontaneously undergo chromothripsis, and p53-downregulated fibroblasts, we discovered that p53 loss leads to aberrant transcriptional upregulation, increasing nucleotide consumption while simultaneously decreasing nucleotide biosynthesis. This imbalance in production and consumption results in insufficient nucleotide pools, leading to replication stress and genomic instability, which are rescued by nucleoside supplementation or transcription normalization. The replication stress triggers telomere dysfunction, micronuclei formation, and ultimately chromothripsis. Emerging dominant chromothriptic clones exhibit normal DNA replication, telomere stabilization, and ecDNA, highlighting critical features for clonal selection. Hence, p53 coordinates transcription and nucleotide pools, crucial for maintaining genomic stability and preventing early cancer development.

cancer biology↗

bioRxiv2025

α-Synuclein Activates the PI3K/AKT Pathway to Drive Lipid Droplets Accumulation: Implications for Parkinson's Disease

Growing evidence supports a metabolic component in Parkinsons disease (PD). - Synuclein (-Syn), a protein central to the onset and progression of PD, facilitates the accumulation of neuronal lipid droplets, which are implicated in disease pathology. We report that AKT is hyper-phosphorylated in PD brains and show that -Syn enhances p110 activity by facilitating palmitoylated Ras localization to the plasma membrane, driving lipid droplet accumulation through PI3K/AKT/mTOR and PPAR{gamma} activation. Phosphorylation of -Syn at Ser129 correlates positively with the localization of Ras to the membrane fraction and with accumulation of lipid droplets. In-vivo treatment of young, asymptomatic -SynA53T transgenic mice with GDC-0084 (paxalisib), a blood- brain barrier-permeable PI3K inhibitor, restored healthy AKT activity levels, reduced levels of PSer129 and -Syn oligomers, decreased neuronal lipid droplet accumulation, and promoted lysosomal clustering. These findings establish a role for -Syn in p110 activation during early, asymptomatic stages of the disease and highlight the therapeutic potential of PI3K inhibition as a disease-modifying strategy. Highlight-Syn activates PI3K/AKT by promoting the localization of palmitoylated Ras to membranes, linking metabolic dysfunction to PD.

neuroscience↗

bioRxiv2024

Biotic resistance predictably shifts microbial invasion regimes

Invading new territory is a central aspect of the microbial lifestyle, allowing microbes to expand to remote locations and pathogens to spread and infect their hosts. However, invading microbes rarely find novel territories uninhabited. In such a scenario, resident microbes can interact with the newcomers and, in many cases, impede their invasion - an effect known as biotic resistance. Accordingly, invasions are shaped by the interplay between dispersal and resistance. However, these two factors are difficult to disentangle or manipulate in natural systems, making their interplay difficult to understand. To address this challenge, we tracked microbial invasions in the lab over space and time - first in a model system of two interacting microbes, then in a multi-strain system involving a pathogen invading resident communities. In the presence of biotic resistance, we observed three qualitatively different invasion regimes: consistent, pulsed, and pinned, where, in the third regime, strong biotic resistance stalled the invasion entirely despite ongoing invader dispersal. Surprisingly, these rich invasion dynamics could be qualitatively predicted with a simple, parameter-free framework that ignores individual species interactions, even for rather complex communities. Moreover, we showed that this simple framework could accurately predict simulated invasions from different mechanistic models, indicating its broad applicability. Our work offers a thorough understanding of how biotic resistance impacts invasions and introduces a predictive tool to identify invasion-resistant communities.

systems biology↗

bioRxiv2022

Spatially resolved host-bacteria-fungi interactomes via spatial metatranscriptomics

All multicellular organisms are closely associated with microbes, which have a major impact on the health of their host. The interactions of microbes among themselves and with the host take place at the microscale, forming complex networks and spatial patterns that are rarely well understood due to the lack of suitable analytical methods. The importance of high-resolution spatial molecular information has become widely appreciated with the recent advent of spatially resolved transcriptomics. Here, we present Spatial metaTranscriptomics (SmT), a sequencing-based approach that leverages 16S/18S/ITS/poly-d(T) multimodal arrays for simultaneous host transcriptome- and microbiome-wide characterization of tissues at 55-{micro}m resolution. We showcase SmT in outdoor-grown Arabidopsis thaliana leaves as a model system, and found tissue-scale bacterial and fungal hotspots. By network analysis, we study inter- and intra-kingdom spatial interactions among microbes, as well as the host response to microbial hotspots. SmT is a powerful new strategy that will be pivotal to answering fundamental questions on host-microbiome interplay.

genomics↗

bioRxiv2018

Divergent Behavior Amid Convergent Evolution: A Case of Four Desert Rodents Learning to Respond to Known and Novel Vipers

Desert communities word-wide are used as natural laboratories for the study of convergent evolution, yet inferences drawn from such studies are necessarily indirect. Here, we brought desert organisms together (rodents and vipers) from two deserts (Mojave and Negev). Both predators and prey in the Mojave have adaptations that give them competitive advantage compared to their middle-eastern counterparts. Heteromyid rodents, kangaroo rats and pocket mice, have fur-lined cheek pouches that allow the rodents to carry larger loads under predation risk compared to gerbilline rodents. Sidewinder rattlesnakes have heat-sensing pits, allowing them to hunt better on moonless nights when their Negev sidewinding counterpart, the Saharan horned vipers, are visually impaired. In behavioral-assays, we used giving-up density (GUD) to gage how each species of rodent perceived risk posed by known and novel snakes. We repeated this for the same set of rodents at first encounter and again two months later following intensive \"natural\" exposure to both snake species. Pre-exposure, all rodents identified their evolutionarily familiar snake as a greater risk than the novel one. However, post-exposure all identified the heat-sensing sidewinder rattlesnake as a greater risk. The heteromyids were more likely to avoid encounters with, and discern the behavioral difference among, snakes than their gerbilline counterparts.

ecology↗