Biology subjects

Kim, S.

Publications and source records attributed to Kim, S..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

BenchHub enables an inclusive and transparent ecosystem for community-focused benchmarking in computational biology

The rapid growth of computational methods for the computational biology field highlights the critical role of benchmarking in guiding method selection. However, there is no standardised data structure that effectively links and stores datasets, performance metrics and available ground truth. Without such a unified and shareable structure, it is difficult for the community to contribute, update and extend existing benchmarking studies to ensure long-term relevancy. To address this challenge, we present BenchHub, a community-oriented ecosystem with a modular R6-based structure that enables "living benchmarking." BenchHub comprises three key components: (i) a Trio database that links datasets, performance metrics, and supporting evidence (e.g. ground truth), (ii) a BenchmarkStudy structure that captures the different benchmark study designs, and (iii) a series of tools together with vignettes and interactive platform that allow users to gain insights from the benchmarking results. Together, these components streamline the benchmarking process for benchmark study developers, methods contributors, and benchmark consumers, promoting reproducibility, comparability, and long-term sustainability in computational biology.

bioinformatics↗

bioRxiv2025

Predictive in vitro profiling of LNP-induced innate immune response using an iPSC-derived monocyte model

Lipid nanoparticles (LNPs) are a powerful drug delivery platform advancing vaccines and gene therapies. While their efficacy and safety has been found to be closely linked to innate immune activation, current in vitro models are unable to predict immune responses reliably. Conventional models, such as PBMCs, are limited by donor variability and inconsistent sensitivity. To address this, we developed a cytokine profiling platform using induced pluripotent stem cell (iPSC)-derived monocytes (iMonocytes), a physiologically relevant innate immune cell type that plays a key role in immune surveillance and inflammation. iPSCs provide a renewable, uniform monocyte source for consistent, high-sensitivity LNP screening. When tested with LNPs of graded immunostimulatory potency, iMonocytes showed improved reproducibility and strong correlation with in vivo cytokine responses. This platform enables evaluation of cargo- and dose-dependent effects, providing a robust and scalable tool for preclinical assessment and rational design of LNP therapeutics.

bioengineering↗

bioRxiv2025

XomicsDB: a database of paired multi-omics datasets for systems biology

Life science research is primarily driven by data integration on the basis of theoretical development. Broad applications of multiomics (xomics) data calls for efficient integration of xomics data to infer cellular operation and regulation. To that end, it is urgently needed good-quality xomics data should be curated and shared for the community. Here we present XomicsDB, a database curating paired xomics datasets at both bulk and single-cell levels in model organisms. It contains 183 datasets from 13 model organisms, with a total of seven xomics data types. Users can download these datasets individually or in a batch from the ftp server provided. Users can also upload their paired xomics datasets for sharing. Incoporation of xomics data intom GSMs are demonstrated in model organisms Escherichia coli and human. Future efforts will be on collecting more single-cell xomics data and curating non-model oragnisms. The XomicsDB can be found at: http://xomicsdb.com.

systems biology↗

bioRxiv2025

Transcriptional profiling of Hutchinson-Gilford Progeria patients identifies primary target pathways of progerin

Hutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder. The disease is caused by a point mutation in the LMNA gene leading to the production of the dominant-negative progerin isoform of the nuclear envelope protein lamin A. Disease severity and progression amongst the population of [~]140 known patients is variable. Most of the mechanistic insights into the disease have come from studies using cellular or mouse models of HGPS. To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, we have performed transcriptomic analysis of a comprehensive set of HGPS patients. We find misexpression of several cellular pathways across the patient population, particularly of multiple signaling pathways as well as the Unfolded Protein Response (UPR) and mesodermal cell fate specification. Variability amongst individual patients was limited, with misregulation of the major pathways observed in most patients. Comparing the transcriptome of patients with an inducible HGPS cell model, we distinguished immediate-early cellular response pathways from secondary adaptive pathways and identified mTORC1, the UPR, UV response, apoptosis and TNF signaling via NF-{kappa}B as primary targets of the disease-causing progerin protein.

cell biology↗

bioRxiv2025

CXCR6⁺ CD127- Tr1 Cells Balance Immunity and Persistence in Plasmodium falciparum Infection

Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells with a capacity for long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical gap in knowledge, we first performed scRNAseq on gated cell populations to validate CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNg during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNg, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

immunology↗

bioRxiv2025

Structural basis for color tuning and passive ion conductance in red-shifted pump-fold channelrhodopsin ChR024

ChR024 is a cation-conducting channelrhodopsin with a red-shifted absorption spectrum, recently discovered from a previously unidentified clade through machine-learning-guided gene mining. Due to its unique position in the phylogenetic tree and distinctive spectral properties, it serves as an important model for elucidating rhodopsin evolution and for engineering optogenetic tools with enhanced performance, but its structure and function remain poorly understood. Here, we present cryo-electron microscopy structures of ChR024 in detergent micelles and lipid nanodiscs at resolutions of 3.22 and 2.45 [A], respectively. The structures reveal an architecture strikingly similar to that of ion-pumping rhodopsins, even more so than other pump-like channelrhodopsins such as ChRmine. Structural, theoretical, and spectroscopic analyses uncover a unique color-tuning mechanism, in which charged residues close and distant from the retinal chromophore cooperatively modulate the pKa of the Schiff base counterion and thereby determine the absorption maximum wavelength. Finally, comparative structural analysis of channel- and pump-type rhodopsins, combined with electrophysiology, provides insights into the molecular boundary between these two functional classes and demonstrates the conversion of an outward proton pump into a light-gated channel. Together, these findings illuminate diverse mechanisms of color tuning and functional specification within the rhodopsin family, paving the way for the rational engineering of next-generation optogenetic tools.

biophysics↗

bioRxiv2025

Streptococcus pneumoniae accessory capsular genes modulate fitness, pathogenicity and immune evasion

Globally, Streptococcus pneumoniae disproportionally affects children in resource-poor settings, older adults and people living with HIV. Frequently found as an asymptomatic colonizer of the nasopharynx, this versatile pathogen is a prominent cause of pneumonia, meningitis, bacteraemia and otitis media. Recently, a serotype 3 capsule variant (GPSC10-ST700) has expanded in Malawi with enhanced vaccine escape potential. Here, using a mutational and complementation approach, we show that loss of accessory capsular genes in GPSC10-ST700 contribute to increased opsonophagocytic resistance in this lineage. Although originally thought to be nonfunctional pseudogenes, we show that these genes modulate fitness and the global phosphoproteome in serotype 3 strains. These findings highlight that vaccine escape may be mediated through variations in the pneumococcal capsular locus that enhance fitness, pathogenicity and immune evasion, without capsule switching. IMPORTANCEPneumococcal polysaccharide-conjugate vaccines (PCV) target the polysaccharide capsule (CPS), which is a dominant virulence factor. However, current PCVs induce suboptimal protection against serotype 3 strains, which produce a thicker capsule that when released from the bacterial surface, interferes with antibody-mediated bacterial killing and protection. We recently described the clonal expansion of a sequence type (ST) 700-GPSC10 serotype 3 lineage in Malawi post-PCV13 introduction. This lineage is characterized by the absence of at least 6 genes in its cps locus and a distinct antimicrobial resistance (AMR) profile compared to other serotype 3 strains. Here we uncovered a functional role for the accessory capsular genes (acl) in serotype 3, previously considered to be pseudogenes, which modulate capsule production, shedding, serum tolerance, and bacterial fitness. By linking genotype to phenotype, our work provides new insights into the molecular basis of serotype 3 immune evasion, informing the design of more effective pneumococcal vaccines.

microbiology↗

bioRxiv2025

A bacterial PrimPol-reverse transcriptase hybrid protein has a proofreading exonuclease activity that can be transferred to other reverse transcriptases

Gene disruption analysis revealed that an E. coli PPRT protein, which has an N-terminal Primase-Polymerase (PrimPol) domain fused to a group II intron-like reverse transcriptase (RT) domain followed by a long C-terminal domain (CTD), contributes to a cellular oxidative DNA damage response in addition to its previously described function in phage defense. Biochemical analysis showed that the PrimPol domain has an error-prone DNA polymerase activity that enables read through of oxidation-induced DNA damage. Surprisingly, we found that the RT-like domain, in addition to synthesizing protein-primed DNAs for phage defense, has a 3 to 5 DNA exonuclease activity that functions in proofreading DNAs synthesized by the PrimPol domain. Extending these findings, we identified structural features that contribute to this proofreading activity, enabling us to associate it with both a group II intron-encoded and retroviral RT and suggesting general methods for incorporating proofreading activity into RTs.

molecular biology↗

bioRxiv2025

Enduring Autism-like Phenotypes and Deregulated Hypothalamic Prosocial Peptides After Early-Life Exposure to Indoor Flame Retardants in Male C57BL/6 Mice

BackgroundPolybrominated diphenyl ethers (PBDEs) are neuroendocrine disrupting chemicals that produce adverse neurodevelopmental effects. PBDEs have been implicated as risk factors for autism spectrum disorder (ASD), which is characterized by abnormal psychosocial functioning and is commonly accompanied by co-morbidities such as cognitive and attentional deficits. Here, we used a mouse model with translationally relevant exposure to establish direct causal evidence that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in male offspring. MethodsC57Bl6/N mouse dams were exposed to a commercial PBDE mixture, DE-71, via oral administration of 0 (vehicle control, VEH/CON), 0.1 (L-DE-71), or 0.4 (H-DE-71) mg/kg bw/d for 10 weeks, spanning three weeks prior to gestation through the end of lactation at postnatal day (PND) 21. ResultsMass spectrometric analysis indicated dose-dependent transfer of PBDEs (in ppb) to brains of F1 male offspring at PND 30, with reduction in levels by PND 110. Adult F1 male offspring displayed ASD-relevant neurobehavioral phenotypes, including impaired short- and long-term social recognition memory (SRM), despite intact general sociability, and exaggerated repetitive behavior. Exposed mice also displayed altered olfactory discrimination of social odors, impaired novel object recognition memory, and reduced open field habituation. However, no changes were observed in anxiety-like, sensorimotor, or depressive-like behaviors relative to VEH/CON. At the molecular level, DE-71 exposed males displayed deregulated gene markers of prosocial neuropeptides. Oxt was upregulated in the paraventricular nucleus (PVN); Avp was upregulated in the PVN and bed nucleus of the stria terminalis (BNST) but downregulated in the lateral septum (LS); Avp1ar and Adcyap1 were upregulated in the BNST; and Adcyap1r1 was upregulated in the PVN, supraoptic nucleus (SON), and BNST. ConclusionsThese findings demonstrate that developmental PBDE exposure produces enduring behavioral and neurochemical phenotypes that resemble core domains of ASD, which may result from early neurodevelopmental reprogramming within central social and memory networks.

neuroscience↗

bioRxiv2025

De novo and scaffold-based design of GDF15 binders for cancer cachexia diagnostics and therapeutics

Growth differentiation factor 15 (GDF15), a stress-responsive cytokine of the TGF-{beta} superfamily, is elevated in cancer cachexia, chemotherapy-induced nausea, and hyperemesis gravidarum, making it both a biomarker and a therapeutic target. Here, we developed high-affinity GDF15 binders using an AI-driven protein design framework. To achieve this, we systematically explored three complementary scaffold-generation strategies: scaffold grafting (SG), diffusion-based de novo design, and scaffold-search and grafting (SSG), identifying distinct advantages - SG rapidly optimized receptor-derived motifs to subnanomolar affinity; de novo diffusion produced topologically novel binders; and SSG enabled access to GDF15s concave site B by repurposing evolutionary structural analogs from natural complexes. The designed GDF15 binders were translated into two functional modalities. First, a one-step, wash-free luminescent biosensor was created by coupling a de novo binder to split-luciferase fragments, enabling the rapid and sensitive quantification of GDF15. Second, the highest-affinity binder was engineered as an Fc-fusion decoy receptor, thereby effectively neutralizing GDF15 signaling in cell-based assays (IC50 = 7.2 nM), demonstrating comparable in vitro potency to ponsegromab, a monoclonal antibody currently undergoing Phase II clinical trials. Together, this work establishes a versatile AI-driven binder design pipeline with broad potential for next-generation diagnostics and therapeutics in cancer cachexia and other GDF15-mediated diseases.

bioengineering↗

bioRxiv2025

High-fidelity CRISPR genome editing of single-nucleotide mutation with near-complementary guide RNA via enhanced target binding kinetics

The CRISPR-Cas9 system is a powerful genome editing tool capable of precisely recognizing and cleaving specific DNA sequences, and has been extensively investigated as a strategy for correcting mutations associated with genetic diseases and cancer. However, conventional CRISPR genome engineering often fail to discriminate single-nucleotide mutations from wild-type alleles when the mutation is located outside the protospacer adjacent motif (PAM) sequence. To address this limitation, we developed a RNA engineering approach for designing near-complementary single guide RNA (sgRNA) that contain intentional mismatches within the seed region of the sgRNA. Single molecule kinetic analyses showed that the near-complementary sgRNA selectively reduces the binding affinity of CRISPR ribonucleoprotein complex by via differentiated increment in the dissociation rates to the wild-type target DNA compared to the mutant allele. The engineered kinetic characteristics of near-complementary sgRNAs enable highly specific genome editing of single-base mutations without reliance on PAM proximity. We demonstrate the application of the strategy to the a cancer-specific single-nucleotide G228A (-124C > T) mutation in the TERT promoter, frequently found in glioblastomas and other tumors, that does not generate a canonical PAM sequence. Our near-complementary sgRNA successfully induced selective editing of the mutant allele while sparing the wild-type sequence. Furthermore, single-molecule fluorescence resonance energy transfer (smFRET) analyss revealed distinct differences in binding kinetics between mutant and wild-type DNA, providing kinetic insight into the discrimination process. We conclude that the near-complementary sgRNA CRISPR editing strategy facilitates precise PAM-independent targeting of single-nucleotide mutations without protein engineering and offers a molecular framework for expanding the specificity and applicability of CRISPR-based genome and epigenome editing technologies.

biochemistry↗

bioRxiv2025

Therapeutic Salmonella induces long-term protective trained immunity in NK cells against cancer metastasis

Trained immunity, a form of innate immune memory initially recognized in pathogen defense, has recently been reported to aid in combating cancer. Although trained immunity has been well-characterized in myeloid lineage cells, its presence in innate lymphoid cells, particularly natural killer (NK) cells, remains largely unexplored. Here, we report that a single dose of Salmonella YB1, an attenuated candidate anticancer vaccine strain, provides long-lasting protection against cancer metastasis in mice by inducing trained natural killer (NK) cells. Functional assays coupled with multiomics analysis revealed that Salmonella-trained NK (stNK) cells establish an enduring reprogrammed epigenome characterized by enhanced pro-survival signaling and immune effector functions, resulting in more potent IFN-{gamma} release and cytotoxicity upon secondary stimulation. We further revealed that IL-12 and IL-18 are essential but insufficient for this NK cell training effect. Crucially, stNK cells far outperform the common immune checkpoint therapies, including PD-1 and TIGIT blockade, in suppressing metastasis, underscoring the unique immunological mechanisms in combating metastasis. These findings uncover a novel long-term anti-metastatic function of trained immunity in NK cells, highlighting its potential as an effective antitumor strategy.

immunology↗

bioRxiv2025

Decoding human B cell ontogeny in prenatal and adult bone marrow and in vitro models via single-cell multiomics

In humans, the bone marrow becomes the primary site for B lymphopoiesis during the second trimester of pregnancy and continues throughout life. Prenatal and adult B cell progenitors play distinct roles in the aetiology and pathology of paediatric and adult hematopoietic malignancies, though the molecular drivers of these differences remain unclear. Here, we created a comprehensive multiomics atlas of over 500k cells covering immune and stromal compartment from prenatal and adult bone marrow, enabling high-resolution analysis of the cell-intrinsic and cell-extrinsic processes that modulate prenatal and adult B lymphopoiesis. Even though B cells follow broadly similar developmental trajectories, we identify a novel postnatal lateCLP subset equivalent to prenatal preProB cells, and uncover prenatal cells carry several signatures characteristic of leukemias, including enhanced proliferation, higher RAG1/RAG2 activity, extrinsic B cell signals such as IL7, and lower retention signals in the bone marrow. We also developed and characterised, at both cellular and molecular levels, a new experimental framework for generating B cell precursors from human induced pluripotent stem cells (hiPSCs), and show that it faithfully recapitulates key stages of B cell differentiation. Together, our single-cell multiomics atlas of B lymphopoiesis in vivo and in vitro offers detailed insights into the unique molecular features of prenatal and adult B cell lymphopoiesis, and serves as a powerful resource for investigating the early events that contribute to haematological disorders.

immunology↗

bioRxiv2025

Field evaluation of non-invasive sampling for monitoring nine swine pathogens in the Republic of Korea

BackgroundNon-invasive sampling methods, such as swine oral fluid (OF) and fecal boot (FB) sampling, have gained attention due to their animal welfare considerations, ease of collection, and cost effectiveness. However, comparative data regarding non-invasive and standard sampling methods remain limited, particularly in the Republic of Korea, where research on OF and FB sampling is sparse. Therefore, we investigated representative pig pathogens, including six porcine respiratory pathogens and three gastrointestinal pathogens, using OF and FB samples for pathogen surveillance across commercial farms in the Republic of Korea. MethodsThe results from targeted polymerase chain reaction (PCR) assays for major respiratory and gastrointestinal pathogens obtained using OF and FB samples were compared with those obtained from standard samples. Non-invasive samples included 30 OF ropes and 30 FBs collected from nine farms, and 360 standard samples (blood, fecal, oral, and nasal swabs) were also collected. PCR assays for the nine pathogens were conducted, and the results from OF, FB, and combined OF+FB were compared with those from standard samples at the pen level. ResultsOF sampling showed superior test concordance with respiratory pathogens than gastrointestinal pathogens, and FB sampling demonstrated superior detection of gastrointestinal pathogens compared with OF sampling. Additionally, the combination of OF+FB sampling improved the detection concordance for all nine target pathogens investigated. ConclusionsWe demonstrated the feasibility and potential applicability of OF and FB sampling under field conditions in Korean pig farms. Therefore, this study supports OF and FB sampling as useful tools for swine pathogen monitoring in both research and practical field applications.

microbiology↗

bioRxiv2025

DeepDiff-SHAP: Interpretable deep learning for subgroup-specific causal inference using conditional SHAP

Precision medicine aims to tailor healthcare strategies to individual differences in genetic, clinical, and environmental factors. However, identifying subgroup-specific causal relationships in complex biomedical data remains a major challenge, especially when standard causal inference methods average over population heterogeneity. We introduce DeepDiff-SHAP, a novel framework that combines regression-based and deep learning-based differential causal inference to detect changes in causal relationships across patient subgroups. DeepDiff-SHAP integrates SHapley Additive exPlanations (SHAP) to estimate conditional dependencies and perform nonlinear differential causal inference in a principled, interpretable manner. Applying DeepDiff-SHAP to two population-scale datasets, the CDC Diabetes Health Indicators Dataset and a UK Biobank sepsis cohort stratified by hypertension, we identified clinically meaningful and subgroup-specific causal changes in relationships between features such as age, general health, alkaline phosphatase, and cholesterol. Our results demonstrate that deep learning enhances sensitivity to complex interaction patterns overlooked by linear models, providing new biological insights into disease progression and comorbidity-specific risk mechanisms. DeepDiff-SHAP offers a scalable and interpretable solution to uncover individualized causal pathways, advancing the goal of truly personalized medicine.

bioinformatics↗

bioRxiv2025

Lysine lactylation regulates ATF4-mediated stress responses under glucose starvation in canine hemangiosarcoma

Hemangiosarcoma (HSA) is a malignant endothelial tumor that occurs frequently in dogs but is rare in other species including humans. Due to its aggressive behavior and limited therapeutic options, patient prognosis is generally poor. Tumor cells produce excess lactate via anerobic glycolysis, and it regulate gene expressions through histone lactylation in response to cellular metabolic conditions. However, how histone lactylation affects biological behavior under glucose-limited conditions in HSA remains unknown. Here, we established canine HSA cell lines and patient-derived xenograft models and investigated the role of histone lactylation during glucose deprivation. HSA cells exhibited higher global histone lactylation levels than normal endothelial cells. Although glucose restriction reduced global histone lactylation levels, Cleavage Under Targets and Tagmentation (CUT&Tag) analysis revealed enrichment of lactylation peaks at transcription-start sites (TSSs) of ATF4-regulated stress-response, asparagine biosynthesis and immune-related genes. TSSs of stress-response genes were co-occupied with RNA polymerase II phosphorylated at serine 5 and showed increased gene expressions, suggesting that lactylation at TSSs activated transcription under glucose-deprived conditions. [U-13C]glutamine tracing indicated that HSA cells synthesized asparagine from glutamine when glucose was scarce. Asparagine supplementation modestly activated cell proliferation. In HSA patient tissues, H3K18la levels were heterogeneous, and M2-like macrophages preferentially infiltrated tumor regions showing low histone lactylation levels. Consistently, glucose-starved HSA cells attracted macrophages and induced M2-like polarization in vitro. These findings demonstrate that lysine lactylation, possibly histone lactylation, persists even under glucose-deprived conditions and regulate transcription that supports tumor cell survival and fosters a pro-tumor microenvironment. One Sentence SummaryLysine lactylation is enriched at TSSs of stress-response genes under glucose starvation and associated with their transcription in canine hemangiosarcoma.

cancer biology↗

bioRxiv2025

Mechanism for oil-phase separation by the lipid droplet assembly complex

Cells store metabolic energy as triglyceride (TG) oils in lipid droplets (LDs). LDs form de novo from the endoplasmic reticulum. How the lipid droplet assembly complex (LDAC), composed of seipin and LDAF11,2, catalyzes the organized formation of an oil phase in a membrane bilayer before spontaneous phase separation is triggered is unknown. Here, we reconstitute LD formation in vitro using purified LDAC and membranes containing physiologic levels of TG, demonstrating that the LDAC is both necessary and sufficient to catalyze oil-phase formation below the threshold of spontaneous phase separation. Structural studies of the LDAC reveal that LDAF1 forms a central ring within a seipin cage, creating a toroidal, membrane-spanning structure. Molecular dynamics simulations and biochemical assays show that this structure forms a selective chamber within the ER bilayer that limits phospholipids but allows TG to access a reaction compartment between the inner and outer rings of the LDAC. Within this compartment, TG interacts with LDAF1 and each other to form an oil phase to initiate LD formation. Thus, the LDAC acts as a protein catalyst for oil-phase separation in cells, revealing a fundamental mechanism for how cells resolve the biophysical challenge of storing oils within a hydrophilic environment in an organized manner.

cell biology↗

bioRxiv2025

δ-catenin haploinsufficiency is sufficient to alter behaviors and glutamatergic synapses in mice

{delta}-catenin (also known as CTNND2) functions as an anchor for the glutamatergic AMPA receptor (AMPARs) to regulate synaptic activity in excitatory synapses. Alteration in the gene coding {delta}-catenin has been implicated in many neurological disorders. Some of these genetic alterations exhibit a profound loss of {delta}-catenin functions in excitatory synapses. We have shown that {delta}-catenin deficiency induced by the homozygous {delta}-catenin knockout (KO) and autism-associated missense glycine 34 to serine (G34S) mutation significantly alters AMPAR-mediated synaptic activity in cortical neurons and disrupts social behavior in mice. Importantly, many genetic disorders are caused by haploinsufficiency. Indeed, {delta}-catenin haploinsufficiency contributes to severe autism and learning disabilities in humans. However, previous studies have used only homozygous {delta}-catenin deficiency models. Therefore, it is important to examine the effects of {delta}-catenin haploinsufficiency on animals behaviors and excitatory synapses. Here, we use heterozygous {delta}-catenin KO and G34S mice as a {delta}-catenin haploinsufficiency model to examine this idea. Multiple behavioral assays, a social behavior test, contextual fear conditioning, and an open field test, reveal that both {delta}-catenin KO and G34S haploinsufficiency significantly disrupt animals social behavior and fear learning and memory. Interestingly, only KO haploinsufficiency mice show anxiety-like behavior. A biochemical assay using brain extracts demonstrates that {delta}-catenin haploinsufficiency significantly affects the levels of synaptic {delta}-catenin and AMPARs. Our findings thus suggest that {delta}-catenin haploinsufficiency affects animals behaviors via altering glutamatergic synaptic activity.

neuroscience↗