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Kim, K. M.

Publications and source records attributed to Kim, K. M..

12 recordsLinked to original sources
bioRxiv2026

Avidity-controlled biotherapeutic delivery systems for the treatment of ischemia-reperfusion acute kidney injury

Regulatory T cells (Tregs) are key mediators of immune resolution and tissue repair following acute kidney injury (AKI), yet strategies to selectively enrich Tregs within the renal microenvironment remain limited. Interleukin-2 (IL-2) is essential for Treg survival and function, but systemic IL-2 delivery is constrained by a short half-life, narrow therapeutic window, and risk of off-target activation of cytotoxic T cells. Effective Treg-based immunomodulation may therefore require both localized cytokine signaling and targeted recruitment of precursor immune populations. Here, we present a sequential, biomaterial-based immunomodulatory strategy that integrates immune cell recruitment with sustained cytokine delivery. An injectable granular hydrogel physically encapsulating the chemokine CCL21 was used to initially recruit CD4+ T cells to the injured kidney. Subsequently, supramolecular guest-host interactions were leveraged to deliver IL-2 modified with the hydrophobic "guest" moiety adamantane, enabling prolonged local cytokine release over 28 days. In healthy mice, we observed early CD4+ T cell recruitment, followed by a pronounced increase in Treg frequency, consistent with immune reprogramming driven by our sequential delivery system. In a murine model of bilateral ischemia-reperfusion (BiAKI), this injectable biomaterial induced a local increase in the proportion of FOXP3-expressing Tregs and a concomitant decrease in the levels of AKI markers. This two-step immunomodulatory approach minimizes acute immune activation while promoting long-term enrichment of Tregs within the renal microenvironment. Together, these findings demonstrate that granular hydrogels with supramolecular host capability can orchestrate immune recruitment and differentiation in a spatiotemporally controlled manner, providing a versatile immunomodulatory platform for applicability in kidney disease.

bioengineering↗
bioRxiv2026

Morphological characterization of moulting in the Atlantic horseshoecrab Limulus polyphemus: phylogenetic conservation amongchelicerates and evolutionary convergence of ecdysis linked to headshield patterns

Arthropods must periodically moult their exoskeleton to permit growth, a conserved developmental process whose morphological and behavioural execution varies widely among lineages. Horseshoe crabs (Limulidae) are members of Xiphosura, a chelicerate lineage with a fossil record extending as far back as the Ordovician and provide a valuable comparative framework for studying the evolution of moulting strategies in Arthropoda. Despite their importance, detailed morphological characterization of moulting in horseshoe crabs remains scarce, limiting developmental studies and broader comparative analyses. Here, we provide a detailed morphological characterization of the moulting process in the Atlantic horseshoe crab Limulus polyphemus. Morphological changes in specific anatomical structures, including the anterior margin of the prosoma, lateral spines and dorsal spinous process of the opisthosoma, were observed during the moulting process. By tracking these morphological markers, such as retraction of the epidermis from the cuticle and degree of corrugation of the epidermis, we were able to identify individuals in the early and late pre-moult stage, predict the onset of ecdysis, and distinguish post-moult and intermoult stages. We compare ecdysis patterns in L. polyphemus with other arthropod taxa, both extant and fossil. We find that, despite differences in behavioural execution, ecdysis in L. polyphemus shares features with other chelicerates, and that both phylogenetic signal and convergent patterns are evident across Arthropoda. This study offers a robust, non-invasive method for determining moult stages in juvenile horseshoe crabs and provides insights into the diversity and constraints of ecdysis in Arthropoda.

evolutionary biology↗
bioRxiv2026

Lung cancer-enriched p53 mutants occupy canonical p53 target genes without activating transcription, revealing a distinct loss-of-function behavior

Lung cancer is the most common cause of cancer-related death in the U.S. and globally. Cigarette smoking remains the leading risk factor for lung cancer, in part by inducing loss-of-function mutations in tumor suppressor genes, including TP53. While most cancers share a set of common "hotspot" mutations in p53, lung cancer exhibits an additional, distinct cluster of hotspot mutations. This cluster is typified by the missense mutations TP53:p.V157F and TP53:p.R158L. While canonical hotspot mutations cause broad misfolding of p53 or eliminate specific DNA contact residues, mechanistic studies of the lung cancer mutants reported here demonstrate that they retain the ability to bind the same genomic sites as wild-type p53. Despite actively binding to traditional p53 target genes, the lung cancer mutants are defective in activating transcription. To our knowledge, this represents the first demonstration of functional inactivation of the p53 tumor suppressor at a point after DNA binding, but prior to target gene activation. Relevant to the sequential inactivation of each p53 allele during cancer progression, the lung cancer mutants block the activity of a wild-type p53 allele when co-expressed in a dominant negative manner. Identification of this loss-of-function mechanism has key implications for therapeutic strategies aimed at restoring p53 function in lung cancer.

cancer biology↗
bioRxiv2026

Moulting in Pancrustacea is characterised by both deeplyconserved and recently evolved gene modules

Arthropods such as insects and crustaceans, which together form the monophyletic group Pancrustacea, possess a rigid chitinous exoskeleton that must be periodically shed through moulting to allow growth and morphological change. Although moulting is a deeply conserved developmental process across Arthropoda, our understanding of its molecular mechanisms is still largely derived from insect model species. Lineage-specific innovations and losses of moulting related genes raise fundamental questions on the extent of its conservation outside non-insect arthropods. Here, we investigate the evolutionary conservation of moulting gene expression across five representative pancrustacean species using publicly available transcriptomic datasets. Changes in gene expression during moulting are characterized by both deeply conserved and lineage-specific gene modules. Temporal gene expression analyses reveal that these lineage-specific signatures are not uniformly distributed across the moulting process: the middle transitional phase is more lineage-specific, thereby exhibiting an inverse hourglass pattern. This is likely due to life-history specific processes, development of the cuticle and specialized structures of the exoskeleton. Overall, this study provides evidence for both the evolutionary conservation and divergence of this key post-embryonic developmental process and highlights the modular architecture of the moulting programme.

evolutionary biology↗
bioRxiv2025

Targeting the ITGA3B1 Complex with A Novel Antibody-Drug Conjugate for Metastatic Bladder Cancer

Advances in antibody (Ab) phage display technologies have enabled the development of targeted therapies with enhanced precision and clinical efficacy. Here, we report a phenotypic screening strategy combining target-unbiased live-cell biopanning with in situ chemical crosslinking and mass spectrometry to identify internalizing antibodies and their cognate antigens--key features for effective antibody-drug conjugate (ADC) development. Using this approach, we identified the 2E7 antibody, which exhibits rapid internalization and high specificity for the integrin 3{beta}1 (ITGA3B1) heterodimer, a complex overexpressed in multiple solid tumors, including bladder cancer. We generated an ITGA3B1-targeted ADC by conjugating monomethyl auristatin E (MMAE) to the 2E7 antibody, enabling selective delivery of cytotoxic payloads to ITGA3B1-positive cells. In preclinical bladder cancer models, this ADC demonstrated potent and dose-dependent antitumor efficacy, with significant tumor regression and improved survival. Our findings establish a framework for target discovery using live-cell phenotypic screening and position ITGA3B1 as a promising therapeutic target for ADC-based treatment of advanced bladder cancer. TeaserLive-cell biopanning uncovers ITGA3B1 as a target for ADC development in metastatic bladder cancer.

synthetic biology↗
bioRxiv2024

Genomic divergence of sympatric lineages within Stichopus cf. horrens (Echinodermata: Stichopodidae): Insights on reproductive isolation inferred from SNP markers

How reproductive barriers arise in early stages of divergence among broadcast spawning organisms that exist in sympatry remains poorly understood. Reproductively isolated lineages (Clade A and B) of Stichopus cf. horrens were previously reported across the western Pacific, with an additional putative cryptic species detected within Clade B lineage warranting further examination. The present study further examines the hypothesis that the two mitochondrial lineages (Clade A and Clade B) of Stichopus cf. horrens represent putative cryptic species and whether another cryptic species within the Clade B lineage exists using a reduced representation genomic approach. Using double-digest RAD (ddRAD) sequencing, a total of 9,788 single nucleotide polymorphism (SNP) markers were used to examine divergence among Stichopus cf. horrens lineages (n = 82). Individuals grouped into three SNP genotype clusters, broadly concordant with their mitochondrial lineages and microsatellite genotype clusters, with limited gene flow inferred among clusters. Outlier analysis recovered highly divergent SNP loci with significant homology to proteins related to rhodopsin and tachykinin receptor signaling, sperm motility, transmembrane transport and hormone response. This study confirms the existence of three reproductively isolated genotype clusters within Stichopus cf. horrens and highlights gene regions related to reproduction that may contribute to establishing reproductive barriers between broadcast spawning species at an early stage of divergence.

evolutionary biology↗
bioRxiv2024

Receptors Determine Lytic Phage Host Range in Pseudomonas aeruginosa

Limited phage host range remains one of the obstacles to the widespread use of phage therapy against bacterial infections. Here, we perform a genome-wide association study (GWAS) using Pseudomonas aeruginosa clinical isolates collected from people with cystic fibrosis (pwCF) to identify bacterial genes associated with resistance or susceptibility to two lytic phages, OMKO1 and LPS-5, recently used in a clinical trial in pwCF. Results were validated with transposon mutagenesis experiments and functional assays. Genes associated with flagellum assembly and lipopolysaccharide biosynthesis are essential for infection by OMKO1 and LPS-5, respectively, consistent with functional studies implicating these molecules as receptors for these phages. Notably, the presence of bacterial genes encoding phage defense mechanisms is not predictive of phage susceptibility. Instead, the relative abundance of defense elements is associated with the number of temperate phages within bacterial genomes. Together, our findings highlight the central role of receptors in determining phage host range.

microbiology↗
bioRxiv2024

A Blueprint for Broadly Effective Bacteriophage Therapy Against Bacterial Infections

Bacteriophage therapy is a tantalizing therapeutic option for anti-microbial resistant bacterial infections but is currently limited to personalized therapy due to the narrow host range of individual phages. Theoretically, cocktails incorporating numerous phages targeting all possible bacterial receptor specificities could confer broad host range. Practically, however, extensive bacterial diversity and the complexity of phage-phage interactions precludes this approach. Here, using screening protocols for identifying "complementarity groups" of phages using non-redundant receptors, we generate effective, broad-range phage cocktails that prevent emergence of bacterial resistance. Further, phage complementarity groups have characteristic interactions with particular antibiotic classes, making it possible to predict phage-antibiotic as well as phage-phage interactions. Using this strategy, we generate three phage-antibiotic cocktails, each effective against >96% of 153 Pseudomonas aeruginosa clinical isolates, including when used in biofilm cultures and wound infections in vivo. We similarly develop effective Staphylococcus aureus phage-antibiotic cocktails and demonstrate the utility of combined cocktails against polymicrobial (mixed P. aeruginosa/S. aureus) cultures, highlighting the broad applicability of this approach. These studies establish a blueprint for effective, broad-spectrum phage therapy cocktails and enable off-the-shelf phage-based therapeutics for antimicrobial-resistant bacterial infections.

microbiology↗
bioRxiv2023

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.

biochemistry↗
bioRxiv2020

Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations

Advances in technology have allowed for the study of metabolomics in the context of disease, enabling the discovery of new potential risk factors, diagnostic markers, and drug targets. For neurological and psychiatric phenotypes, the cerebrospinal fluid (CSF) is of particular biomedical importance as it is in direct contact with the brain and spinal cord. However, the CSF metabolome is difficult to study on a large scale due to the relative complexity of the procedure needed to collect the fluid compared to blood or urine studies. Here, we present a metabolome-wide association study (MWAS), an analysis using individual-level genetic and metabolomic data from two cohorts to impute metabolites into large samples with genome-wide association summary statistics. We conducted a metabolome-wide genome-wide association analysis with 338 CSF metabolites, identifying 16 genotype-metabolite associations, 6 of which were novel. Using these results, we then built prediction models for all available CSF metabolites and tested for associations with 27 neurological and psychiatric phenotypes in large cohorts, identifying 19 significant CSF metabolite-phenotype associations. Our results demonstrate the potential of MWAS to overcome the logistic challenges inherent in cerebrospinal fluid research to study the role of metabolomics in brain-related phenotypes and the feasibility of this framework for similar studies of omic data in scarce sample types.

genomics↗
bioRxiv2018

Meteorin-like (Metrnl) adipomyokine improves glucose tolerance in type 2 diabetes via AMPK pathway

Meteorin-like (metrnl) is a recently identified adipomyokine that has beneficial effects on glucose metabolism. However, its underlying mechanism of action is not completely understood. In this study, we have shown that a level of metrnl increase in vitro under electrical-pulse-stimulation (EPS) and in vivo in exercise mice, suggesting that metrnl is an exercise-induced myokine. In addition, metrnl increases glucose uptake through the calcium-dependent AMPK pathway. Metrnl also increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPK-dependent manner. Phosphorylated HDAC5 interacts with 14-3-3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. The intraperitoneal injection of recombinant metrnl improves glucose tolerance in mice with high fat-induced obesity or type 2 diabetes (db/db), but this is not seen in AMPK {beta}1{beta}2 muscle-specific null mice (AMPK {beta}1{beta}2 MKO). In conclusion, we have demonstrated that metrnl induces beneficial effects on glucose metabolism via AMPK and is a promising therapeutic candidate for glucose-related diseases such as type 2 diabetes.

biochemistry↗