Biology subjects

Kim, J. S.

Publications and source records attributed to Kim, J. S..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Self-extinguishing relay waves enable homeostaticcontrol of human neutrophil swarming

Neutrophils exhibit self-amplified swarming to sites of injury and infection. How swarming is controlled to ensure the proper level of neutrophil recruitment is unknown. Using an ex vivo model of infection, we find that human neutrophils use active relay to generate multiple pulsatile waves of swarming signals. Unlike classic active relay systems such as action potentials, neutrophil swarming relay waves are self-extinguishing, limiting the spatial range of cell recruitment. We identify an NADPH-oxidase-based negative feedback loop that is needed for this self-extinguishing behavior. Through this circuit, neutrophils adjust the number and size of swarming waves for homeostatic levels of cell recruitment over a wide range of initial cell densities. We link a broken homeostat to neutrophil over-recruitment in the context of human chronic granulomatous disease.

cell biology↗

bioRxiv2023

A leaky integrate-and-fire computational model based on the connectome of the entire adult Drosophila brain reveals insights into sensorimotor processing

The forthcoming assembly of the adult Drosophila melanogaster central brain connectome, containing over 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain. Here, we create a leaky integrate-and-fire computational model of the entire Drosophila brain, based on neural connectivity and neurotransmitter identity, to study circuit properties of feeding and grooming behaviors. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation. Computational activation of neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing, a testable hypothesis that we validate by optogenetic activation and behavioral studies. Moreover, computational activation of different classes of gustatory neurons makes accurate predictions of how multiple taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Our computational model predicts that the sugar and water pathways form a partially shared appetitive feeding initiation pathway, which our calcium imaging and behavioral experiments confirm. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit that do not overlap with gustatory circuits, and accurately describes the circuit response upon activation of different mechanosensory subtypes. Our results demonstrate that modeling brain circuits purely from connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can accurately describe complete sensorimotor transformations.

neuroscience↗

bioRxiv2023

Mind of a dauer: Comparative connectomics reveals developmental plasticity

A fundamental question in neurodevelopmental biology is how flexibly the nervous system changes during development. To address this, we reconstructed the complete connectome of dauer, an alternative developmental stage of nematodes with distinct behavioral characteristics, by volumetric reconstruction and automated synapse detection using deep learning. With the basic architecture of the nervous system preserved, structural changes in neurons, large or small, were closely associated with connectivity changes, which in turn evoked dauer-specific behaviors such as nictation. Graph theoretical analyses revealed significant dauer-specific rewiring of sensory neuron connectivity and increased clustering within motor neurons in the dauer connectome. We suggest that the nervous system in the nematode, probably animals in general, has evolved to respond to harsh environments by reversibly developing a quantitatively and qualitatively differentiated connectome.

neuroscience↗

bioRxiv2023

The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode for active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a mitochondrial-encoded host defense peptide (HDP) that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted E. coli and methicillin-resistant S. aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In monocytes, IFN{gamma}, LPS, and differentiation signals each induced the expression of endogenous MOTS-c. Notably, MOTS-c translocated to the nucleus to regulate gene expression during monocyte differentiation and programmed them into macrophages with unique transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicates that our immune system is not only encoded by the nuclear genome, but also by the co-evolved mitochondrial genome.

immunology↗

bioRxiv2023

Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

genomics↗

bioRxiv2022

BLEND: A Fast, Memory-Efficient, and Accurate Mechanism to Find Fuzzy Seed Matches in Genome Analysis

Generating the hash values of short subsequences, called seeds, enables quickly identifying similarities between genomic sequences by matching seeds with a single lookup of their hash values. However, these hash values can be used only for finding exact-matching seeds as the conventional hashing methods assign distinct hash values for different seeds, including highly similar seeds. Finding only exact-matching seeds causes either 1) increasing the use of the costly sequence alignment or 2) limited sensitivity. We introduce BLEND, the first efficient and accurate mechanism that can identify both exact-matching and highly similar seeds with a single lookup of their hash values, called fuzzy seed matches. BLEND 1) utilizes a technique called SimHash, that can generate the same hash value for similar sets, and 2) provides the proper mechanisms for using seeds as sets with the SimHash technique to find fuzzy seed matches efficiently. We show the benefits of BLEND when used in read overlapping and read mapping. For read overlapping, BLEND is faster by 2.4x-83.9x (on average 19.3x), has a lower memory footprint by 0.9x-14.1 x (on average 3.8x), and finds higher quality overlaps leading to accurate de novo assemblies than the state-of-the-art tool, minimap2. For read mapping, BLEND is fasterby 0.8x-4.1x (on average 1.7x) than minimap2. Source code is available at https://github.com/CMU-SAFARI/BLEND.

bioinformatics↗

bioRxiv2022

Best Practices for Interpretable Machine Learning in Computational Biology

Advances in machine learning (ML) have enabled the development of next-generation prediction models for complex computational biology problems. These developments have spurred the use of interpretable machine learning (IML) to unveil fundamental biological insights through data-driven knowledge discovery. However, in general, standards and guidelines for IML usage in computational biology have not been well-characterized, representing a major gap toward fully realizing the potential of IML. Here, we introduce a workflow on the best practices for using IML methods to perform knowledge discovery which covers verification strategies that bridge data, prediction model, and explanation. We outline a workflow incorporating these verification strategies to increase an IML methods accountability, reliability, and generalizability. We contextualize our proposed workflow in a series of widely applicable computational biology problems. Together, we provide an extensive workflow with important principles for the appropriate use of IML in computational biology, paving the way for a better mechanistic understanding of ML models and advancing the ability to discover novel biological phenomena.

bioinformatics↗

bioRxiv2022

USP11 promotes endothelial apoptosis-resistance in pulmonary hypertension by deubiquitinating HINT3

IntroductionPulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. Evolving evidence indicates that the ubiquitin-specific proteases (USPs), play an important role in the pathogenesis of PAH by deubiquitinating key proteins involved in cell proliferation, migration, and apoptosis. Our genome-wide association study (GWAS) analysis-paired with transcriptomic profiling indicated that deubiquitinase USP11 and histidine triad nucleotide binding protein 3 (HINT3) are positively correlated and that their expression increased in lungs of PAH patients compared to control (fail donor) group, and inversely correlated with survival. However, mechanisms and function of the USP11/HNT3 axis have not been explored in PAH. Therefore, we aimed to investigate that HINT3 stabilized by USP11 activation links to endothelial apoptosis-resistance in PAH. Methods and ResultsExpression of USP11 and HINT3 was increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice using qRT-PCR and Western blot analyses. USP11 and HINT3 interacted physically as shown by co-immunoprecipitation (co-IP) assay in human pulmonary artery endothelial cells (HPAECs). HINT3 levels were decreased upon transfection of HA-tagged Ubi plasmid into HPAECs. Pretreatment with the potent proteasome inhibitor MG132 prolonged the half-life of HINT3 protein, indicating that HINT3 is degraded by polyubiquitination. HINT3 was stabilized and destabilized by forced overexpression or siRNA knockdown of USP11 respectively. Similarly, treatment with mitoxantrone, a USP11 antagonist, reduced HPAEC HINT3 expression. HINT3 interacted with the antiapoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, knockdown of HINT3 function led to depletion of BCL2. ConclusionsThe HINT3-USP11 axis contributes to apoptosis-resistance in pulmonary artery endothelial cells, as is potentially a novel and attractive therapeutic target for ubiquitination modulators.

physiology↗

bioRxiv2022

Comparative genomic and crystal structure analyses identify a collagen glucosyltransferase from Acanthamoeba Polyphaga Mimivirus

Humans and Acanthamoeba Polyphaga Mimivirus share numerous homologous genes, including collagens and collagen-modifying enzymes. To explore the homology, we performed a genome-wide comparison between human and mimivirus using DELTA-BLAST (Domain Enhanced Lookup Time Accelerated BLAST) and identified 52 new mimiviral proteins that are homologous with human proteins. To gain functional insights into mimiviral proteins, their human protein homologs were organized into Gene Ontology (GO) and REACTOME pathways to build a functional network. Collagen and collagen-modifying enzymes form the largest subnetwork with most nodes. Further analysis of this subnetwork identified a putative collagen glycosyltransferase R699. Protein expression test suggested that R699 is highly expressed in E coli, unlike the human collagen-modifying enzymes. Enzymatic activity assays showed that R699 catalyzes the conversion of unique galactosylhydroxylysine within the GXXXUG motif (U=galactosylhydroxylysine) to glucosylgalactosylhydroxylysine on collagen using uridine diphosphate glucose (UDP-Glc) as a sugar donor, suggesting R699 is a mimiviral collagen galactosylhydroxylysyl glucosyltransferase (GGT) with defined substrate specificity. Structural study of R699 produced the first crystal structure of a collagen GGT with a visible UDP-Glc. Sugar moiety of the UDP-Glc resides in a previously unrecognized pocket. Mn2+ coordination and nucleoside-diphosphate binding site are conserved among GGT family members and critical for R699s collagen GGT activity. To facilitate further analysis of human and mimiviral homologous proteins, we presented an interactive and searchable genome-wide comparison website for quickly browsing human and Acanthamoeba Polyphaga Mimivirus homologs, which is available at RRID Resource ID: SCR_022140 or https://guolab.shinyapps.io/app-mimivirus-publication/.

biochemistry↗

bioRxiv2021

PEDOT:PSS-Modified Cotton Conductive Thread for Mass Manufacturing of Textile-Based Electrical Wearable Sensors by Computerized Embroidery

The textile industry has advanced processes that allow computerized manufacturing of garments at large volumes with precise visual patterns. The industry, however, is not able to mass fabricate clothes with seamlessly integrated wearable sensors, using its precise methods of fabrication (such as computerized embroidery). This is due to the lack of conductive threads compatible with standard manufacturing methods used in industry. In this work, we report a low-cost poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS)-modified cotton conductive thread (PECOTEX) that is compatible with computerized embroidery. The PECOTEX was produced using a crosslinking reaction between PEDOT:PSS and cotton thread using divinyl sulfone as the crosslinker. We extensively characterized and optimized our formulations to create a mechanically robust conductive thread that can be produced in large quantities in a roll-to-roll fashion. Using PECOTEX and a domestic computerized embroidery machine, we produced a series of wearable electrical sensors including a facemask for monitoring breathing, a t-shirt for monitoring heart activity and textile-based gas sensors for monitoring ammonia as technology demonstrators. PECOTEX has the potential to enable mass manufacturing of new classes of low-cost wearable sensors integrated into everyday clothes.

bioengineering↗

bioRxiv2021

Temporal changes in resting state networks induced by propofol anesthesia.

The cerebral cortical changes associated with propofol-induced unconsciousness remain unknown. While the anesthetic agent affects the entire cerebral cortices, there might be spatiotemporal differences in cortical changes. In particular, we hypothesized that there might be spatiotemporal differences in cortical changes with propofol-anesthesia. To address this hypothesis, we investigated power spectrum changes in electrocorticography (ECoG) signals obtained during the induction phase from awake state to unconsciousness. We found that, 1) the power increased in the range of frequencies < 46 Hz (delta to low gamma), and decreased in the range (62-150) Hz (high gamma), in global channels during the induction phase. 2) The power in the frontoparietal network (FPN), specifically the superior parietal lobule and prefrontal cortex, started to change early, but took a long time to completely change. However, the power in the default mode network (DMN) started to change late, but took a short time to completely change. 3) The power change ({Delta}Power) in the DMN was more conspicuous than that of the dorsal attention network (DAN) in high gamma frequency. Considering that the FPN is involved in communication with the external world and that DMN is involved in communication with self, loss of consciousness induced by general anesthesia results from first, disrupted communication between self and external world, and is then followed by disrupted communication within self, with decreased activity of the FPN, and later, attenuated activity of the DMN. Significance StatementWe investigated the spatiotemporal changes of power spectrum in human electrocorticography (ECoG) during the induction phase from awake state to unconsciousness. We found that from delta to low gamma frequency, the power increased, while in high gamma frequency, the power decreased over all channels. The power in the frontoparietal network (FPN) preferentially changed, then the power in the DMN changed later. The power in DMN decreased more than those in other RSNs in high gamma frequency. Loss of consciousness induced by general anesthesia results from first, disrupted communication between self and external world, followed by disrupted communication within self, with decreased activity of the FPN, and later, attenuated activity of the DMN.

neuroscience↗

bioRxiv2021

Reading Modality Modifies Reading Network: Insights from Neural basis of Braille in Proficient Blind Readers

The neural basis of reading is highly consistent across many languages and scripts. Are there alternative neural routes to reading? How does the sensory modality of symbols (tactile vs. visual) influence their neural representations? We examined these questions by comparing reading of visual print (sighted group, n=19) and tactile Braille (congenitally blind group, n=19). Blind and sighted readers were presented with written (words, consonant strings, non-letter shapes) and spoken stimuli (words, backward speech) that varied in word-likeness. Consistent with prior work, the ventral occipitotemporal cortex (vOTC) was active during Braille and visual reading. A posterior/anterior vOTC word-form gradient was observed only in sighted readers with more anterior regions preferring larger orthographic units (words). No such gradient was observed in blind readers. Consistent with connectivity predictions, in blind compared to sighted readers, posterior parietal cortices were recruited to a greater degree and contained word-preferring patches. Lateralization of Braille in blind readers was predicted by laterality of spoken language and reading hand. The effect of spoken language increased along a cortical hierarchy, whereas effect of reading-hand waned. These results suggested that the neural basis of reading is influenced by symbol modality and spoken language and support connectivity-based views of cortical function.

neuroscience↗

bioRxiv2021

AirLift: A Fast and Comprehensive Technique for Remapping Alignments between Reference Genomes

AirLift is the first read remapping tool that enables users to quickly and comprehensively map a read set, that had been previously mapped to one reference genome, to another similar reference. Users can then quickly run downstream analysis of read sets for each latest reference release. Compared to the state-of-the-art method for remapping reads (i.e., full mapping), AirLift reduces the overall execution time to remap read sets between two reference genome versions by up to 27.4x. We validate our remapping results with GATK and find that AirLift provides high accuracy in identifying ground truth SNP/INDEL variants. Code AvailabilityAirLift source code and readme describing how to reproduce our results are available at https://github.com/CMU-SAFARI/AirLift.

bioinformatics↗

bioRxiv2020

Synapses from the high-order thalamic nucleus and motor cortex are co-clustered spatially in the distal tuft dendrites of the somatosensory cortex

The posterior medial nucleus of the thalamus (POm) and vibrissal primary motor cortex (vM1) convey essential information to the barrel cortex (S1BF) regarding whisker position and movement. Therefore, understanding the relative spatial relationships of these two inputs is critical prerequisites to acquire insight into how S1 synthesizes information to interpret the location of an object. Using array tomography, we identified the locations of synapses from vM1 and POm on distal tuft dendrites of L5 pyramidal neurons. We found that synapses from vM1 and POm are spatially clustered on the same set of dendrites with unusually high density. Furthermore, the clusters of vM1 and POm synapses colocalize each other. These findings suggest that synaptic clusters, but not dendritic branches, act as functional units and cooperatively contribute to nonlinear dendritic responses.

neuroscience↗

bioRxiv2020

Unrestrained Gαi2 Signaling Disrupts Normal Neutrophil Trafficking, Aging, and Clearance

Neutrophil trafficking, homeostatic and pathogen elicited, depends upon chemoattractant receptor triggered heterotrimeric G-protein Gi{beta}{gamma} signaling, whose magnitude and kinetics are governed by RGS protein/Gi interactions. Yet how in totality RGS proteins shape neutrophil chemoattractant receptor activated responses remains unclear. Here, we show that C57Bl/6 neutrophils with genomic knock-in of a mutation that disables all RGS protein-Gi2 interactions (G184S) cannot properly balance chemoattractant receptor signaling, nor appropriately respond to inflammatory insults. Mutant neutrophils accumulate in bone marrow, spleen, lung, and liver; despite neutropenia and an intrinsic inability to properly mobilize from bone marrow. In vitro they rapidly adhere to ICAM-1 coated plates, but poorly adhere to blood vessel endotheliums in vivo. Those few neutrophils that cross endotheliums migrate haphazardly. Following Concanavalin-A administration fragmented G184S neutrophils accumulate in liver sinusoids leading to thrombo-inflammation and perivasculitis. Thus, neutrophil Gi2/RGS protein interactions limit and facilitate Gi2 signaling allowing normal neutrophil trafficking, aging, and clearance.

immunology↗

bioRxiv2020

Phenome-wide association study of a comprehensive health check-up database in a Korea population: Clinical application & trans-ethnic comparison

AbstractsO_ST_ABSBackgroundC_ST_ABSThe expanding use of the phenome-wide association study (PheWAS) faces challenges in the context of using International Classification of Diseases billing codes for phenotype definition, imbalanced study population ethnicity, and constrained application of the results to clinical practice or research. MethodsWe performed a PheWAS utilizing deep phenotypes corroborated by comprehensive health check-ups in a Korean population, along with trans-ethnic comparisons through the UK Biobank and Biobank Japan Project. Network analysis, visualization of cross-phenotype mapping, and causal inference mapping with Mendelian randomization were conducted in order to make robust, clinically applicable interpretations. ResultsOf the 136 phenotypes extracted from the health check-up database, the PheWAS associated 65 phenotypes with 14,101 significant variants (P < 4.92x10-10). In the association study for body mass index, our population showed 583 exclusive loci relative to the Japanese population and 669 exclusive loci relative to the European population. In the meta-analysis with Korean and Japanese populations, 72.5% of phenotypes had uniquely significant variants. Tumor markers and hematologic phenotypes had a high degree of phenotype-phenotype pairs. By Mendelian randomization, one skeletal muscle mass phenotype was causal and two were outcomes. Among phenotype pairs from the genotype-driven cross-phenotype associations, 71.65% also demonstrated penetrance in correlation analysis using a clinical database. ConclusionsThis comprehensive analysis of PheWAS results based on a health check-up database will provide researchers and clinicians with a panoramic overview of the networks among multiple phenotypes and genetic variants, laying groundwork for the practical application of precision medicine.

genetics↗

bioRxiv2020

Genome-Enabled Discovery of Anthraquinone Biosynthesis in Senna tora

Senna tora is a widely used medicinal plant. Its health benefits have been attributed to the large quantity of anthraquinones, but how they are made in plants remains a mystery. To identify the genes responsible for plant anthraquinone biosynthesis, we sequenced and annotated the genome of S. tora at the chromosome level with contig N50 and super-scaffold N50 of 4.03 Mb and 41.7 Mb. Comparison among related plant species showed that a chalcone synthase-like (CHS-L) gene family has lineage-specifically and rapidly expanded in S. tora. Combining genomics, transcriptomics, metabolomics, and biochemistry, we identified a CHS-L responsible for biosynthesis of anthraquinones, the first example in plants. The S. tora reference genome will accelerate the discovery of biologically active anthraquinone biosynthesis pathways in medicinal plants. One Sentence SummaryThe chromosome-scale reference genome of a medicinal plant Senna tora, transcriptomics, metabolomics, and biochemical analysis provide new insights into anthraquinone biosynthesis in plants.

plant biology↗

bioRxiv2020

Dissociation of connectivity for syntactic irregularity and perceptual ambiguity in musical chord stimuli

Previously syntactic irregularity has been most studied with chord sequences. However, the same chord may be interpreted as having different harmonic functions, implying perceptual ambiguity. Hence, syntactic irregularity and perceptual ambiguity may be processed simultaneously. We devised 3 different 5-chord sequences in which the ending chord differed with the tonic (T), submediant (SM), and supertonic (ST). In terms of syntactic regularity, T is most regular, ST is most irregular. However, in terms of perceptual ambiguity, the most irregular ST had the salient highest voice. Therefore, the SM was the most ambiguous condition. We investigated how the human brain separates syntactic irregularity and perceptual ambiguity in terms of effective connectivity in bilateral inferior frontal gyri (IFGs) and superior temporal gyri (STGs) with magnetoencephalography in 19 subjects. Correct rate was lower for the most ambiguous chord (SM) (P = 0.020) as expected. Connectivity from the right to the left IFG was enhanced for the most irregular chord (ST) (P = 0.024, false discovery rate (FDR) corrected), whereas connectivity from the right to the left STG was enhanced for the most ambiguous chord (SM) (P < 0.001, FDR corrected). The correct rate was negatively correlated with connectivity in the STG, further reflecting perceptual ambiguity (P = 0.026). We found that syntactic irregularity and perceptual ambiguity in music are dissociated in connectivity between bilateral IFGs and STGs, respectively. Significance StatementWe provide the first neurophysiological evidence of the processing of perceptual ambiguity, other than syntactic irregularity, implied in musical chords. We found that the notion of "perceptually ambiguity" is applicable to musical chord stimuli different in syntactic irregularity, and that perceptual ambiguity is separate from syntactic irregularity. Our data demonstrate that the brain interprets the three conditions of musical chords as both "from regular to irregular" and "from ambiguous to unambiguous" conditions simultaneously. This study is the first to unveil dissociation of connectivity by syntactic irregularity and perceptual ambiguity involved in musical chord stimuli.

neuroscience↗