Biology subjects

Karmi, A.

Publications and source records attributed to Karmi, A..

5 recordsLinked to original sources

bioRxiv2026

Dihydropyrimidines sustain aggressive cancer states by stabilizing DPYSL2

Cancer cell states are governed by coordinated signaling and metabolic networks, yet the mechanisms coupling metabolic activity to oncogenic signaling remain poorly understood. Here, we identify dihydropyrimidines (DHPs), metabolites generated during pyrimidine catabolism, as "signaling metabolites" that sustain aggressive cancer cell states. Depletion of DHPs, either by knockout of the pyrimidine catabolic enzyme DPYD or by expression of the DHP-degrading enzyme DPYS, suppressed STAT3 signaling and attenuated mesenchymal and inflammatory transcriptional programs. Mechanistically, DHPs stabilized DPYSL2, a JAK1-interacting adaptor protein required for efficient STAT3 activation. Structural modeling and thermal stability analyses further support a direct interaction between DHPs and DPYSL2. Accordingly, high DPYD expression was associated with EMT, inflammatory signaling, and poor-prognosis breast cancer subtypes across patient cohorts. Ultimately, our findings establish pyrimidine catabolism as a direct regulator of signaling competence and identify DHPs as signaling-active metabolites that couple cellular metabolic state to oncogenic transcriptional programs and mesenchymal identity.

cancer biology↗

bioRxiv2025

It is about time: neural temporal scaling accounts for robust hunting behavior across temperatures

Animals are often required to maintain stable performance in critical behaviors despite environmental fluctuations. Temperature broadly affects neural activity, and even localized shifts in brain temperature can alter behavior. However, whether widespread changes across the brain, such as those experienced by ectotherms, disrupt survival-critical behaviors remains unclear. Here, we show that larval zebrafish maintain robust hunting performance across a 10{degrees}C ecological range. Although behavior accelerates with temperature, spatial parameters, such as bout distance and turn angle, remain stable. This invariance results from coordinated adjustments in tail beat frequency and movement duration. Brain-wide calcium imaging revealed that behavioral temporal scaling is mirrored at the level of single neurons. A simple rate model showed that temperature-dependent changes in neural time constants can account for compensatory tail dynamics, enabling stability without active regulation. These findings suggest that neural temporal scaling can preserve performance under diffuse temperature fluctuations, supporting robust behavior in natural environments.

neuroscience↗

bioRxiv2025

Distinct brain-wide neural dynamics predict social approach behavior

Social behavior is essential for animal survival and adaptation, requiring the integration of sensory cues to guide interactions with conspecifics. A key component of social behavior is approach, where animals actively move to-ward social partners to maintain group cohesion, establish affiliations, and coordinate actions. While a continuous stream of social information is encoded across sensory modalities, it remains unclear whether a distinct neural process underlies social approach. Here, we developed a novel assay in which a head-fixed, tail-free zebrafish interacts with a freely swimming conspecific, enabling precise quantification of social behavior alongside whole-brain functional imaging at cellular resolution. We demonstrate that zebrafish approach behavior is jointly shaped by spatial and temporal information from conspecifics rather than by these features acting independently. Social approach behavior is preceded by distinct brain-wide neural activity patterns emerging seconds before movement onset, characterized by increased activity in a small subset of forebrain neurons and decreased activity in midbrain and hindbrain neuronal populations. These activity patterns reliably predict upcoming approach movements from each of these regions separately. Moreover, the extent to which neural activity distinguishes approach from non-approach movements predicts individual differences in social behavior, directly linking neural dynamics to behavioral variability. Together, our findings reveal a neural mechanism underlying social approach behavior, highlighting how a distributed yet functionally coordinated network facilitates social interaction.

neuroscience↗

bioRxiv2023

The metabolic enzyme EXT1 is sufficient to induce the epithelial-mesenchymal transition program in cancers

Carcinomas often exhibit aggressive characteristics, such as enhanced migration abilities, through the execution of the epithelial-mesenchymal transition (EMT) program. Heparan sulfate (HS) is a polysaccharide expressed on the surface of aggressive cancer cells, which acts as a co-receptor to stimulate EMT-associated signaling pathways. However, despite HS role in cancer aggressiveness, the mechanisms governing its EMT-dependent biosynthesis remains poorly understood. Here, we characterized the HS chain elongation enzyme, exostosin glycosyltransferase 1 (EXT1), as an essential component of the EMT program. We identified an EMT-dependent expression of EXT1 and its selective upregulation in aggressive tumor subtypes and cell lines. Overexpression of EXT1 in epithelial cells is sufficient to induce HS biosynthesis, cell migration, and invasion, form tumors in mice, and activate the STAT3 pathway. Moreover, its knockout in aggressive cells significantly inhibited their EMT-associated characteristics. These findings demonstrate a cellular mechanism by which metabolic processes regulate signaling pathways to govern cell state.

cancer biology↗

bioRxiv2020

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinsons disease (PD), whose hallmark is degeneration of substantia nigra dopaminergic neurons (DNs). We use C. elegans as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model we demonstrate conserved functions of DN-expressed nAChRs. We find that DOP-2, a D3-receptor homolog, MCU-1, a mitochondrial calcium uniporter, and PINK-1, PTEN-induced kinase 1, are required for nicotine-mediated protection of DNs. Together, our results support involvement of calcium-dependent mitochondrial stress activation of PINK-1 in nicotine-dependent neuroprotection. This suggests that nicotines selective protection of substantia nigra DNs is due to the confluence of two factors: first, their unique vulnerability to mitochondrial stress, which is mitigated by increased mitochondrial quality control due to PINK1 activation; and second, to their specific expression of D3 receptors.

neuroscience↗