Biology subjects

Arey, R. N.

Publications and source records attributed to Arey, R. N..

8 recordsLinked to original sources

bioRxiv2026

Single-cell foundation models transfer across deep evolutionary distances

Single-cell foundation models are trained mostly on human and other vertebrate cells, yet are proposed as general-purpose models. Whether they transfer far beyond their training species is unknown. We evaluated zero-shot embeddings from Geneformer, scGPT and UCE against PCA and scVI in developmental atlases of Dictyostelium discoideum and Caenorhabditis elegans, separated from humans by 1.2 billion and 600 million years. Without retraining, the models recovered developmental order and preserved organism-specific cell identities. UCE encodes genes by protein sequence and could use 97% of measured genes, whereas Geneformer and scGPT, after ortholog mapping, used under one-fifth. UCE performed most consistently, often exceeding species-native baselines. Restricted to ortholog-mappable genes, it still scored above vocabulary-based models on five of six annotation tasks, some narrowly. Foundation models can thus yield informative cell embeddings across more than a billion years of evolution, and protein-sequence gene representations make these embeddings more complete and often more accurate.

bioinformatics↗

bioRxiv2026

Lipoproteins modulate the uptake and biological functionof cationic cell-penetrating peptides across the animal lineage.

Cationic cell-penetrating peptides (+CPPs) are pervasive killer peptides produced by all animals and found in innate immune systems, venoms and neurodegenerative diseases. Despite their ubiquity, the mechanisms underlying their uptake remain opaque and intensely debated. Here, we interrogate +CPPs spanning 600 million years of animal evolution and identify endocytosis as a conserved/convergent uptake mechanism across cell types and organisms, at physiological concentrations. By combining multiplex imaging, genetic screening, cryo-electron tomography, and biophysical methods, we uncover that +CPPs seemingly universally enter eukaryote cells via 'hitchhiking' on lipoproteins. We further show that the interaction of +CPPs with lipoproteins modulates their antimicrobial function. Combined, our findings establish a unified molecular framework describing a pan-eukaryote cell penetrance mechanism. As hyperlipidemia is a common comorbidity, our findings have direct implications for human health. Lastly, the insights gleaned from this work highlight design principles that may inform the future engineering of peptide-based therapeutics and delivery vehicles.

cell biology↗

bioRxiv2025

INS-17, an insulin-receptor ligand, confers specificity in adult IIS-regulated phenotypes in C. elegans

Insulin/IGF growth factor (IGF) signaling (IIS) is a pleiotropic signaling pathway that functions across tissues to coordinate phenotypic changes in response to nutrient status. Thus, the ubiquity of the IIS pathway hinders efforts to elucidate the mechanisms driving specific IIS-related phenotypes, Previous research in the nematode worm C. elegans has demonstrated that loss of function of the IGF transmembrane receptor (IR) ortholog, DAF-2, results in a doubled lifespan and enhanced learning and memory behaviors in young and aged animals. However, these findings are the result of reducing DAF-2 receptor function rather than modulating ligand-receptor interactions. In the current study, we aimed to dissect ligand-receptor interactions that may regulate associative behaviors apart from canonical IIS lifespan phenotypes in C. elegans. To this end, we performed targeted genetic screening of Insulin-like Peptides (ILPs) previously identified as DAF-2 antagonists to test their role in learning and memory phenotypes. We discovered that only a single uncharacterized ILP, INS-17, is required for learning and memory. We also demonstrate that INS-17 is sufficient to confer extended memory ability and can promote the maintenance of learning and memory with age. Additionally, we observe that ins-17 regulates learning and memory ability independent of lifespan, uncoupling IIS-mutant phenotypes. We find that regulation of the ins-17 genetic locus explains its unique requirement among ILP for learning and memory behaviors. Finally, we found that INS-17 may act to signal a state of nutrient deprivation that is required to properly process stimulus valence to promote advantageous behaviors. Our findings deepen the understanding of how IIS can regulate specific phenotypic outputs in response to changes in internal metabolic states.

genetics↗

bioRxiv2025

Altered glr-1 expression is linked to EtOH cessation-mediated behavior deficits in C. elegans.

Chronic ethanol (EtOH) exposure and withdrawal are linked to worsened memory and cognitive outcomes. One target of EtOH is the glutamatergic -amino-3-hydroxy-5methyl-4-isoxazoleproprionic acid receptor (AMPAR). Both EtOH exposure and cessation influences AMPAR expression, function, and broad glutamate signaling. Studies of EtOHrelated AMPAR regulation suggest that EtOH regulation of AMPARs drives behaviors related to dependence and memory phenotypes. However, due to the complexity of the mammalian brain, it is difficult to unravel the precise mechanism by which EtOH regulates AMPARs in mammals to modify specific memory behaviors. In C. elegans, GLR-1, an AMPAR ortholog, has tightly defined expression in relatively few neurons, has conserved regulatory mechanisms, and is linked to molecularly conserved associative behaviors including those disrupted by EtOH. Using an established paradigm that exposes worms to chronic EtOH and cessation ("withdrawal"), we examined the relationship between cessation from chronic EtOH exposure, associative memory, and GLR-1/AMPAR regulation. We found that cessation from chronic EtOH disrupts intermediate-term associative memory (ITM) in wild-type worms, phenocopying loss of GLR-1 function. Next, we found that loss of GLR-1 occludes the ITM deficit and EtOH-ceased wild-types phenocopy glr-1 loss-of-function in other glutamate-dependent behaviors. We demonstrate that cessation downregulates glr-1, and increases CREB-mediated transcriptional activity in neurons, whereas losing CREB protects against cessationinduced glr-1 downregulation and associated behavior deficits. Overall, CREB-mediated repression of glr-1 may regulate behavior deficits in cessation. Significance statementAnimals must navigate and remember their environments to survive. The neuronal processes underlying these behaviors can be disrupted by chronic EtOH. EtOH interacts with many processes and pathways in the complex mammalian nervous system. Here, we established a paradigm combining chronic EtOH exposure with associative memory conditioning in C. elegans to study the consequences of EtOH exposure and cessation on memory behaviors and their underlying molecular pathways. We found cessation leads to memory deficits that depend on functional excitatory transmission and master transcriptional regulator, CREB.

animal behavior and cognition↗

bioRxiv2024

Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition

RNA-binding proteins (RBPs) regulate translation and plasticity which are required for memory. RBP dysfunction has been linked to a range of neurological disorders where cognitive impairments are a key symptom. However, of the 2,000 RBPs in the human genome, many are uncharacterized with regards to neurological phenotypes. To address this, we used the model organism C. elegans to assess the role of 20 conserved RBPs in memory. We identified eight previously uncharacterized memory regulators, three of which are in the C. elegans Y-Box (CEY) RBP family. Of these, we determined that cey-1 is the closest ortholog to the mammalian Y-Box (YBX) RBPs. We found that CEY-1 is both necessary in the nervous system for memory ability and sufficient to increase memory. Leveraging human datasets, we found both copy number variation losses and single nucleotide variants in YBX1 and YBX3 in individuals with neurological symptoms. We identified one predicted deleterious YBX3 variant of unknown significance, p.Asn127Tyr, in two individuals with neurological symptoms. Introducing this variant into endogenous cey-1 locus caused memory deficits in the worm. We further generated two humanized worm lines expressing human YBX3 or YBX1 at the cey-1 locus to test evolutionary conservation of YBXs in memory and the potential functional significance of the p.Asn127Tyr variant. Both YBX1/3 can functionally replace cey-1, and introduction of p.Asn127Tyr into the humanized YBX3 locus caused memory deficits. Our study highlights the worm as a model to reveal memory regulators and identifies YBX dysfunction as a potential new source of rare neurological disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/574402v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@c1e04forg.highwire.dtl.DTLVardef@6d82b9org.highwire.dtl.DTLVardef@1a15571org.highwire.dtl.DTLVardef@f0ad20_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

A systems biology-based identification and in vivo functional screening of Alzheimer's disease risk genes reveals modulators of memory function

Genome-wide association studies (GWAS) have uncovered over 40 genomic loci associated with risk for late-onset Alzheimers Disease (LOAD), but identification of the underlying causal genes remains challenging. While the role of glial biology in the mediation of LOAD genetic risk has been increasingly recognized, recent studies of induced pluripotent stem cell (iPSC)-derived neurons from LOAD patients have demonstrated the existence of neuronal cell-intrinsic functional defects, absent interactions with other brain cell types or exposure to neurotoxic insults. Here, we searched for genetic contributions to neuronal dysfunction in LOAD pathobiology, using an integrative systems approach that incorporated multi-evidence-based gene-mapping and network analysis-based prioritization. We found widespread dysfunction in neuronal gene co-expression networks in the LOAD brain and identified synaptic and endolysosomal function as being specifically impacted by LOAD-associated genetic variation. A systematic perturbation screening of candidate risk genes in C. elegans revealed that neuronal knockdown of the LOAD risk gene orthologs vha-10 (ATP6V1G2), cmd-1 (CALM3), amph-1 (BIN1), ephx-1 (NGEF), and pho-5 (ACP2) significantly alters short/intermediate-term memory function, the cognitive domain affected earliest during LOAD progression. These results highlight the impact of LOAD risk genes on evolutionarily conserved memory function, as mediated through neuronal endosomal dysfunction, and identify new targets for further mechanistic interrogation.

genetics↗

bioRxiv2022

A lysosomal surveillance response (LySR) that reduces proteotoxicity and extends healthspan

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the Lysosomal Surveillance Response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimers and Huntingtons disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan. The GATA transcription factor, ELT-2, regulates the LySR program as well as its associated beneficial effects. In mammalian cells, overexpression of GATA4/GATA6, the mammalian orthologs of ELT-2, is sufficient to induce the expression of multiple lysosome-specific proteases and alleviate proteotoxicity. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan. HighlightsO_LIRNAi of specific v-ATPase subunits extends C. elegans lifespan and activates LySR C_LIO_LIGATA transcription factor ELT-2 regulates LySR and LySR-associated lifespan extension C_LIO_LILySR activation reduces protein aggregates and extends worm healthspan C_LIO_LIOverexpression of GATA4/GATA6 alleviates amyloid-{beta} proteotoxicity in mammalian cells C_LI

cell biology↗

bioRxiv2019

Profiling of presynaptic mRNAs reveals a role for axonal PUMILIOs in associative memory formation

Presynaptic protein synthesis is important in the adult central nervous system; however, the set of mRNAs localized to presynaptic areas has yet to be identified in any organism. We differentially labeled somatic and synaptic compartments nervous system-wide in adult C. elegans and isolated synaptic regions for deep sequencing. Analysis of the synaptic transcriptome reveals that synaptic transcripts are predicted to have specialized functions in neurons. Differential expression analysis identified 543 genes enriched in synaptic regions relative to somatic regions, with synaptic functions conserved in higher organisms. We find that mRNAs for pumilio RNA-binding proteins are abundant in synaptic regions, which we confirmed through high-sensitivity in situ hybridization. We identified a new role for the PUM2 orthologs puf-7/8 as repressors of memory formation through regulation of the mitochondrial dynamics regulator, mff-1. Identification of presynaptic mRNAs provides insight into mechanisms that regulate synaptic function and behavior.

neuroscience↗