Biology subjects

Park, J.

Publications and source records attributed to Park, J..

At least 253 records · Page 14Linked to original sources

bioRxiv2024

Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS

Microglia have been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Dectin-1, encoded by the Clec7a gene, is highly upregulated in a specific microglial response state called disease-associated microglia (DAM) in various neurodegenerative conditions. However, the role of Dectin-1 in ALS is undetermined. Here, we show that Clec7a mRNA upregulation occurs in central nervous system (CNS) regions that exhibit neurodegeneration in a MATR3 S85C knock-in mouse model (Matr3S85C/S85C) of ALS. Furthermore, a significant increase in the number of Dectin-1+ microglia coincides with the onset of motor deficits, and this number increases with disease severity. We demonstrate that the knockout of Dectin-1 does not affect survival, motor function, neurodegeneration, or microglial responses in Matr3S85C/S85Cmice. These findings suggest that Dectin-1 does not play a role in modifying ALS onset or progression but could potentially serve as a valuable biomarker for ALS severity. Subject areasPhysiology; Molecular biology; Neuroscience; Immunology HighlightsO_LIClec7a upregulation is confined to central nervous system regions that exhibit overt neurodegeneration in a MATR3 S85C knock-in mouse model of ALS C_LIO_LIThe appearance of Dectin-1+ microglia coincides with the onset of motor deficits, and its number increases with disease progression C_LIO_LIKnockout of Dectin-1 does not modify survival, motor deficits, neurodegeneration, or microglial responses in MATR3 S85C knock-in mice C_LI

neuroscience↗

bioRxiv2024

Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties

Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2-knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested Hepatocyte nuclear factor 4-alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.

cancer biology↗

bioRxiv2024

A framework for quality control in quantitative proteomics

A thorough evaluation of the quality, reproducibility, and variability of bottom-up proteomics data is necessary at every stage of a workflow from planning to analysis. We share vignettes applying adaptable quality control (QC) measures to assess sample preparation, system function, and quantitative analysis. System suitability samples are repeatedly measured longitudinally with targeted methods, and we share examples where they are used on three instrument platforms to identify severe system failures and track function over months to years. Internal QCs incorporated at protein and peptide-level allow our team to assess sample preparation issues and to differentiate system failures from sample-specific issues. External QC samples prepared alongside our experimental samples are used to verify the consistency and quantitative potential of our results during batch correction and normalization before assessing biological phenotypes. We combine these controls with rapid analysis (Skyline), longitudinal QC metrics (AutoQC), and server-based data deposition (PanoramaWeb). We propose that this integrated approach to QC is a useful starting point for groups to facilitate rapid quality control assessment to ensure that valuable instrument time is used to collect the best quality data possible. Data are available on Panorama Public and on ProteomeXchange under the identifier PXD051318.

biochemistry↗

bioRxiv2024

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types. SIGNIFICANCE STATEMENTTreatment of prostate cancer is rapidly evolving with several promising new drugs targeting different cell surface antigens. Selection of patients most likely to benefit from these therapies requires an understanding of how expression of these cell surface antigens varies across patients and how they change during disease progression, particularly in tumors that undergo lineage plasticity. Using immunohistochemistry and single cell mRNA sequencing, we reveal heterogeneity of cell states across a cohort of advanced disease prostate cancer patients; this heterogeneity is not captured by conventional histology-based designations of adenocarcinoma and neuroendocrine prostate cancer. We show these cell states can be identified by gene regulatory networks that could provide additional diagnostic precision based on their correlation with clinically relevant cell surface antigen expression.

cancer biology↗

bioRxiv2024

An integrative single-cell atlas to explore the cellular and temporal specificity of neurological disorder genes during human brain development

Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to the developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expressions under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of developing human brains, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder genes. Lineages of non-neuronal cells determined by molecular profiles also showed temporal-specific expressions, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types for neuronal disorders, indicative of the prenatal stages influence on disease determination. Our findings facilitate unbiased comparisons of cell type-disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders.

neuroscience↗

bioRxiv2024

Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

genetics↗

bioRxiv2024

Landscape profiling of PET depolymerases using a natural sequence cluster framework

Since the demonstration that rapid polyethylene terephthalate (PET) decomposition using enzymes is feasible, a number of efficient depolymerases have been reported with the aim of resolving the plastic pollution issues. However, sporadic studies on enzymes with PET hydrolysis activity hinder the understanding of the distribution of potential PETases hidden in natures repertoire, and subsequently, the identification of potent enzymes. Here, we present the clustering of 1,894 PETase candidates, which include the majority of known PETases, and describe their profiling. An archipelago landscape of 170 lineages shows distribution of 289 representative sequences with features associated with PET-degrading capabilities. A birds-eye view of the landscape identifies three highly promising yet unexplored PETase lineages and two potent PETases, Mipa-P and Kubu-P. The engineered Mipa-PM19 and Kubu-PM12 variants exhibit both high PET hydrolysis activity and thermal stability. In particular, Kubu-PM12 outperformed the engineered benchmarks in terms of PET depolymerization in harsh environments, such as with high substrate load and ethylene glycol as the solvent. Our landscape framework and the identified variants assist in the understanding of how biological processes respond to solid-state and non-natural PET plastics.

systems biology↗

bioRxiv2024

Novel extracellular matrix architecture on excitatory neurons revealed by HaloTag-HAPLN1

The brains extracellular matrix (ECM) regulates neuronal plasticity and animal behavior. ECM staining shows an aggregated pattern in a net-like structure around a subset of neurons and diffuse staining in the interstitial matrix. However, understanding the structural features of ECM deposition across various neuronal types and subcellular compartments remains limited. To visualize the organization pattern and assembly process of the hyaluronan-scaffolded ECM in the brain, we fused a HaloTag to HAPLN1, which links hyaluronan and proteoglycans. Expression or application of the probe enables us to identify spatial and temporal regulation of ECM deposition and heterogeneity in ECM aggregation among neuronal populations. Dual-color birthdating shows the ECM assembly process in culture and in vivo. Sparse expression in vivo reveals novel forms of ECM architecture around excitatory neurons and developmentally regulated dendritic ECM. Overall, our study uncovers extensive structural features of the brain ECM, suggesting diverse roles in regulating neuronal plasticity.

neuroscience↗

bioRxiv2024

Gapless assembly of complete human and plant chromosomes using only nanopore sequencing

The combination of ultra-long Oxford Nanopore (ONT) sequencing reads with long, accurate PacBio HiFi reads has enabled the completion of a human genome and spurred similar efforts to complete the genomes of many other species. However, this approach for complete, "telomere-to-telomere" genome assembly relies on multiple sequencing platforms, limiting its accessibility. ONT "Duplex" sequencing reads, where both strands of the DNA are read to improve quality, promise high per-base accuracy. To evaluate this new data type, we generated ONT Duplex data for three widely-studied genomes: human HG002, Solanum lycopersicum Heinz 1706 (tomato), and Zea mays B73 (maize). For the diploid, heterozygous HG002 genome, we also used "Pore-C chromatin contact mapping to completely phase the haplotypes. We found the accuracy of Duplex data to be similar to HiFi sequencing, but with read lengths tens of kilobases longer, and the Pore-C data to be compatible with existing diploid assembly algorithms. This combination of read length and accuracy enables the construction of a high-quality initial assembly, which can then be further resolved using the ultra-long reads, and finally phased into chromosome-scale haplotypes with Pore-C. The resulting assemblies have a base accuracy exceeding 99.999% (Q50) and near-perfect continuity, with most chromosomes assembled as single contigs. We conclude that ONT sequencing is a viable alternative to HiFi sequencing for de novo genome assembly, and has the potential to provide a single-instrument solution for the reconstruction of complete genomes.

bioinformatics↗

bioRxiv2024

Mutability and hypermutation antagonize immunoglobulin codon optimality

The efficacy of polyclonal antibody responses is inherently linked to paratope diversity, as generated through V(D)J recombination and somatic hypermutation (SHM). These processes arose in early jawed vertebrates; however, little is known about how immunoglobulin diversity, mutability, and hypermutation have evolved in tandem with another more ubiquitous feature of protein-coding DNA - codon optimality. Here, we explore these relationships through analysis of germline IG genes, natural V(D)J repertoires, serum VH usage, and monoclonal antibody (mAb) expression, each through the lens of multiple optimality metrics. Strikingly, proteomic serum IgG sequencing showed that germline IGHV codon optimality positively correlated with VH representation after influenza vaccination, and in vitro, codon deoptimization of mAbs with synonymous amino acid sequences caused consistent expression loss. Germline V genes exhibit a range of codon optimality that is maintained by functionality, and inversely related to mutability. SHM caused a load-dependent deoptimization of IGH VDJ repertoires within human tonsils, bone marrow, and lymph nodes (including SARS-CoV-2-specific clones from mRNA vaccinees), influenza-infected mice, and zebrafish. Comparison of natural mutation profiles to true random suggests the presence of selective pressures that constrain deoptimization. These findings shed light on immunoglobulin evolution, providing unanticipated insights into the antagonistic relationship between variable region diversification, codon optimality, and antibody secretion; ultimately, the need for diversity takes precedence over that for the most efficient expression of the antibody repertoire.

immunology↗

bioRxiv2024

Multiple Isoforms of the Activin-like receptor Baboon differentially regulate proliferation and conversion behaviors of neuroblasts and neuroepithelial cells in the Drosophila larval brain

In Drosophila coordinated proliferation of two neural stem cells, neuroblasts (NB) and neuroepithelial (NE) cells, is pivotal for proper larval brain growth that ultimately determines the final size and performance of an adult brain. The larval brain growth displays two phases based on behaviors of NB and NEs: the first one in early larval stages, influenced by nutritional status and the second one in the last larval stage, promoted by ecdysone signaling after critical weight checkpoint. Mutations of the baboon (babo) gene that produces three isoforms (BaboA-C), all acting as type-I receptors of Activin-type transforming growth factor {beta} (TGF-{beta}) signaling, cause a small brain phenotype due to severely reduced proliferation of the neural stem cells. In this study we show that loss of babo function severely affects proliferation of NBs and NEs as well as conversion of NEs from both phases. By analyzing babo-null and newly generated isoform-specific mutants by CRISPR mutagenesis as well as isoform-specific RNAi knockdowns in a cell- and stage-specific manner, we further demonstrate differential contributions of the isoforms for these cellular events with BaboA playing the major role. Our data show that stage-specific expression of EcR-B1 in the brain is also regulated primarily by BaboA along with function of the other isoforms. Blocking EcR function in both neural stem cells results in a small brain phenotype that is more severe than baboA-knockdown alone. In summary, our study proposes that the Babo-mediated signaling promotes proper behaviors of the neural stem cells in both phases and achieves this by acting upstream of EcR-B1 expression in the second phase. Author SummaryEvolutionarily conserved TGF-{beta} signaling pathway is widely utilized as a regulator of diverse processes of brain development in both vertebrates and invertebrates. A key element in Drosophila Activin type TGF-{beta} signaling pathway is the type-I receptor Babo. The babo gene produces three isoforms, each with a unique ligand preference. Our study uncovers that Babo-mediated signaling promotes proper proliferation of NBs and NEs and conversion of NEs, together responsible for the magnitude of larval brain size growth. Three isoforms act individually or together to regulate these cellular events in coordination with developmental status. Our findings emphasize that Babo-mediated signaling is a crucial regulator of postembryonic neurogenesis that generates 90% of neuronal population for the adult brain.

developmental biology↗

bioRxiv2024

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

cancer biology↗

bioRxiv2024

Dispensable regulation of brain development and myelination by Serpina3n

Serine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory immune-related molecule produced primarily in the liver and brain under homeostatic conditions and upregulated in response to system inflammation. Yet it remains elusive regarding its cellular identity and physiological significance in the development of the postnatal brain. Here, we reported that oligodendroglial lineage cells are the major cell population expressing Serpina3n protein in the postnatal murine CNS. Using loss-of-function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2-expressing cells does not significantly affect cognitive and motor functions in mice. Serpina3n depletion does not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affects the population of other glial cells and neurons in vivo. Together, these data suggest that the immune-related molecule Serpina3n plays a minor role, if any, in regulating neural cell development in the postnatal brain under homeostatic conditions. We found that Serpina3n is significantly upregulated in response to oxidative stress, and it potentiates oxidative injury and cell senescence of oligodendrocytes. Our data raise the interest in pursuing its functional significance in the CNS under disease/injury conditions.

neuroscience↗

bioRxiv2024

High-throughput single-cell, single-mitochondrial DNA assay using hydrogel droplet microfluidics

There is growing interest in understanding the biological implications of single cell heterogeneity and intracellular heteroplasmy of mtDNA, but current methodologies for single-cell mtDNA analysis limit the scale of analysis to small cell populations. Although droplet microfluidics have increased the throughput of single-cell genomic, RNA, and protein analysis, their application to sub-cellular organelle analysis has remained a largely unsolved challenge. Here, we introduce an agarose-based droplet microfluidic approach for single-cell, single-mtDNA analysis, which allows simultaneous processing of hundreds of individual mtDNA molecules within >10,000 individual cells. Our microfluidic chip encapsulates individual cells in agarose beads, designed to have a sufficiently dense hydrogel network to retain mtDNA after lysis and provide a robust scaffold for subsequent multi-step processing and analysis. To mitigate the impact of the high viscosity of agarose required for mtDNA retention on the throughput of microfluidics, we developed a parallelized device, successfully achieving ~95% mtDNA retention from single cells within our microbeads at >700,000 drops/minute. To demonstrate utility, we analyzed specific regions of the single mtDNA using a multiplexed rolling circle amplification (RCA) assay. We demonstrated compatibility with both microscopy, for digital counting of individual RCA products, and flow cytometry for higher throughput analysis.

bioengineering↗

bioRxiv2024

Genome-wide profiling of genetic variation at tandem repeat from long reads

Tandem repeats are frequent across the human genome, and variation in repeat length has been linked to a variety of traits. Recent improvements in long read sequencing technologies have the potential to greatly improve TR analysis, especially for long or complex repeats. Here we introduce LongTR, which accurately genotypes tandem repeats from high fidelity long reads available from both PacBio and Oxford Nanopore Technologies. LongTR is freely available at https://github.com/gymrek-lab/longtr.

bioinformatics↗

bioRxiv2024

Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the of AD-BXD Mouse Population

Alzheimers disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of- onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity of human populations, we utilized the AD-BXD mouse panel. This genetically diverse resource combines AD genotypes with multiple BXD strains to discover new genetic drivers of AD resilience. Comparing AD-BXD carriers to noncarrier littermates, we computed a novel quantitative metric for resilience to cognitive decline in the AD-BXDs. Our quantitative AD resilience trait was heritable and genetic mapping identified a locus on chr8 associated with resilience to AD mutations that resulted in amyloid brain pathology. Using a hippocampus proteomics dataset, we nominated the mitochondrial glutathione S reductase protein (GR or GSHR) as a resilience factor, finding that the DBA/2J genotype was associated with substantially higher GR abundance. By mapping protein QTLs (pQTLs), we identified synaptic organization and mitochondrial proteins coregulated in trans with a cis-pQTL for GR. We found four coexpression modules correlated with the quantitative resilience score in aged 5XFAD mice using paracliques, which were related to cell structure, protein folding, and postsynaptic densities. Finally, we found significant positive associations between human GSR transcript abundance in the brain and better outcomes on AD-related cognitive and pathology traits in the Religious Orders Study/Memory and Aging project (ROSMAP). Taken together, these data support a framework for resilience in which neuronal antioxidant pathway activity provides for stability of synapses within the hippocampus.

neuroscience↗

bioRxiv2024

Microvilli regulate the release modes of alpha-tectorin to organize the domain-specific matrix architecture of the tectorial membrane.

The tectorial membrane (TM) is an apical extracellular matrix (ECM) in the cochlea essential for auditory transduction. The TM exhibits highly ordered domain-specific architecture. Alpha-tectorin/TECTA is a glycosylphosphatidylinositol (GPI)-anchored ECM protein essential for TM organization. Here, we identified that TECTA is released by distinct modes: proteolytic shedding by TMPRSS2 and GPI-anchor-dependent release from the microvillus tip. In the medial/limbal domain, proteolytically shed TECTA forms dense fibers. In the lateral/body domain produced by the supporting cells displaying dense microvilli, the proteolytic shedding restricts TECTA to the microvillus tip and compartmentalizes the collagen-binding site. The tip-localized TECTA, in turn, is released in a GPI-anchor-dependent manner to form collagen-crosslinking fibers, required for maintaining the spacing and parallel organization of collagen fibrils. Overall, we showed that distinct release modes of TECTA determine the domain-specific organization pattern, and the microvillus coordinates the release modes along its membrane to organize the higher-order ECM architecture. O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/574255v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@10479c6org.highwire.dtl.DTLVardef@d6cb33org.highwire.dtl.DTLVardef@1b6b4fdorg.highwire.dtl.DTLVardef@2477f4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

developmental biology↗

bioRxiv2024

Pathogen infection induces sickness behaviors by recruiting neuromodulatory systems linked to stress and satiety in C. elegans

When animals are infected by a pathogen, peripheral sensors of infection signal to the brain to coordinate a set of adaptive behavioral changes known as sickness behaviors. While the pathways that signal from the periphery to the brain have been intensively studied in recent years, how central circuits are reconfigured to elicit sickness behaviors is not well understood. Here we find that neuromodulatory systems linked to stress and satiety are recruited upon infection to drive sickness behaviors in C. elegans. Upon chronic infection by the bacterium Pseudomonas aeruginosa PA14, C. elegans decrease their feeding behavior, then display reversible bouts of quiescence, and eventually die. The ALA neuron and its neuropeptides FLP-7, FLP-24, and NLP-8, which control stress-induced sleep in uninfected animals, promote the PA14-induced feeding reduction. However, the ALA neuropeptide FLP-13 instead acts to delay quiescence and death in infected animals. Cell-specific genetic perturbations show that the neurons that release FLP-13 to delay quiescence in infected animals are distinct from ALA. A brain-wide imaging screen reveals that infection-induced quiescence involves ASI and DAF-7/TGF-beta, which control satiety-induced quiescence in uninfected animals. Our results suggest that a common set of neuromodulators are recruited across different physiological states, acting from distinct neural sources and in distinct combinations to drive state-dependent behaviors.

neuroscience↗