Biology subjects

Kwak, Y.

Publications and source records attributed to Kwak, Y..

12 recordsLinked to original sources

bioRxiv2026

Microfluidic Mechanical Reactivation of Aged Stem Cells

Stem cell aging significantly impairs therapeutic efficacy, requiring innovative strategies to restore potency. We present a microfluidic cell-compressing platform for reactivation (-CPR) designed to apply controlled hydrodynamic deformation to late-passage stem cells. This mechanical stimulation facilitates functional reactivation without external chemical cues. Within a defined window, -CPR effectively reduces oxidative stress, SA-{beta}-Gal activity, and {gamma}H2AX foci, while simultaneously restoring proliferation and canonical stemness markers (OCT4, SOX2, and KLF4). Mechanical stimulation via -CPR induces coordinated structural remodeling: nuclei become more compact, actin cortex organization is restored, -actinin redistributes to focal adhesions, and microtubule networks are restructured, suggesting a rebalanced intracellular tension. Transcriptomic and proteomic analyses reveal that this process reprograms extracellular matrix remodeling and DNA repair pathways while attenuating pro-fibrotic and senescence-associated secretory phenotype (SASP)-associated pathways. Crucially, this reactivation occurs without compromising fundamental MSC hallmarks, preserving intrinsic immunophenotypes and multilineage differentiation potential. Functionally, -CPR-processed stem cells demonstrate restored in vitro wound closure and enhanced tissue repair in vivo, with efficacy appearing dependent on mechanical dosage. This platform establishes a non-genetic, mechanobiological approach to restoring stem cell function, offering a scalable strategy for functional reactivation and potentially paving the way toward comprehensive cellular rejuvenation.

bioengineering↗

bioRxiv2026

Intrahost mutational dynamics parallel long-term genome evolution in endosymbionts

Obligate endosymbionts of insects undergo extreme genome evolution, marked by accelerated molecular evolution, severe base-pair compositional bias, and massive gene loss. However, the microevolutionary processes driving these patterns remain poorly understood, as they occur at intrahost population scales that are rarely captured. To address this gap, we measured intrahost genetic diversity of two endosymbionts, Karelsulcia and Nasuia, from the aster leafhopper, Macrosteles quadrilineatus (Hemiptera: Cicadellidae). Contrary to the theoretical expectation of strict clonality, we found that both endosymbionts harbor measurable intrahost genetic variation, with lineage-specific mutational dynamics that parallels long-term evolutionary trends. Karelsulcia showed sparse intrahost variation dominated by repeat-associated indels, while Nasuia exhibited more abundant single-nucleotide mutations that appear to shape genome-wide A+T bias. Mitochondrial heteroplasmy did not covary with endosymbiont nucleotide diversity, indicating that these patterns are not driven by host-level dynamics. Notably, recurrent nonsynonymous variants in Nasuia affect essential genes for amino acid biosynthesis and translation. The intrahost mutational patterns we observed in endosymbionts are consistent with long-term sequence changes between our population founder genome and contemporary endosymbiont populations after [~]11 years of maintenance. Taken together, our results demonstrate how distinct mutational processes operating at the intrahost populations scale drive macroevolutionary patterns in endosymbiont genomes. Moreover, our study establishes that laboratory endosymbiont systems provide a powerful framework for dissecting and understanding these fundamental evolutionary processes.

evolutionary biology↗

bioRxiv2024

Inhibiting EZH2 complements steroid effects in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by mutations in the dystrophin gene. Despite recent advances in understanding the disease etiology and applying emerging treatment methodologies, glucocorticoid derivatives remain the only general therapeutic option that can slow disease development. However, the precise molecular mechanism of glucocorticoid action remains unclear, and there is still need for additional remedies to complement the treatment. Here, using single-nucleus RNA-sequencing and spatial transcriptome analyses of human and mouse muscles, we investigated pathogenic features in DMD patients and palliative effects of glucocorticoids. Our approach further illuminated the importance of proliferating satellite cells, and revealed increased activity of a signal transduction pathway involving EZH2 in the patient cells. Subsequent administration of EZH2 inhibitors to Dmd mutant mice resulted in improved muscle phenotype through maintaining the immune-suppressing effect but overriding the muscle weakness and fibrogenic effects exerted by glucocorticoids. Our analysis reveals pathogenic mechanisms that can be readily targeted by extant therapeutic options for DMD. TeaserA survey of DMD tissues in human and mouse suggests EZH2 as a critical factor in DMD satellite cells; its inhibition resulted in better prognosis.

genetics↗

bioRxiv2024

How the window of visibility varies around polar angle

Contrast sensitivity, the amount of contrast required to detect or discriminate an object, depends on spatial frequency (SF): The Contrast Sensitivity Function (CSF) peaks at intermediate SFs and drops at lower and higher SFs and is the basis of computational models of visual object recognition. The CSF varies from foveal to peripheral vision, but only a couple studies have assessed changes around polar angle of the visual field. Sensitivity is generally better along the horizontal than the vertical meridian, and better at the lower vertical than the upper vertical meridian, yielding polar angle asymmetries. Here, we investigate CSF attributes at polar angle locations at both group and individual levels, using Hierarchical Bayesian Modeling. This method enables precise estimation of CSF parameters by decomposing the variability of the dataset into multiple levels and analyzing covariance across observers. At the group level, peak contrast sensitivity and corresponding spatial frequency with the highest sensitivity are higher at the horizontal than vertical meridian, and at the lower than upper vertical meridian. At an individual level, CSF attributes (e.g., maximum sensitivity, the most preferred SF) across locations are highly correlated, indicating that although the CSFs differ across locations, the CSF at one location is predictive of the CSF at another location. Within each location, the CSF attributes co-vary, indicating that CSFs across individuals vary in a consistent manner (e.g., as maximum sensitivity increases, wso does the SF at which sensitivity peaks), but more so at the horizontal than the vertical meridian locations. These results show similarities and uncover some critical polar angle differences across locations and individuals, suggesting that the CSF should not be generalized across iso-eccentric locations around the visual field. Our window of visibility varies with polar angle: It is enhanced and more consistent at the horizontal meridian. Author summaryThe contrast sensitivity function (CSF), depicting how our ability to perceive contrast depends on spatial frequency, characterizes our "window of visibility": We can only see objects with contrast and spatial frequency properties encompassed by this function. The CSF is mostly assessed only along the horizontal meridian of the visual field and sometimes averaged across locations, but visual performance varies with polar angle (e.g., we are more sensitive to objects along the horizontal than the vertical meridian). Here, we systematically assess the key attributes of the CSF and show critical differences in the window of visibility across polar angles and individuals. We found that at the horizontal meridian, our overall contrast sensitivity and preferred SF are higher, and CSFs of individual observers co-vary more than at the vertical meridian. This research highlights that this fundamental perceptual measure is not the same and should be assessed around the visual field. Polar angle thus should be a key consideration for applications of the CSF in computational models of vision.

neuroscience↗

bioRxiv2023

Presaccadic attention enhances and reshapes the Contrast Sensitivity Function around the visual field

Contrast sensitivity, which constrains our vision, decreases from fovea to periphery, from the horizontal to the vertical meridian, and from the lower vertical to the upper vertical meridian. The Contrast Sensitivity Function (CSF) depicts how contrast sensitivity varies with spatial frequency (SF). To overcome these visual constraints, we constantly make saccadic eye movements to foveate on relevant objects in the scene. Already before saccade onset, presaccadic attention shifts to the saccade target and enhances perception. However, it is unknown whether and how it modulates the interplay between contrast sensitivity and SF, and if this effect varies around polar angle locations. Contrast sensitivity enhancement may result from a horizontal or vertical shift of the CSF, increase in bandwidth, or any combination. Here, we investigated these possibilities by extracting key attributes of the CSF using Hierarchical Bayesian Modeling, which enables precise estimation of the CSF parameters by decomposing the variability of the dataset into multiple levels. The results reveal that presaccadic attention (1) enhances contrast sensitivity across SF, (2) increases the most preferred and the highest discernable SF, and (3) narrows the bandwidth. Therefore, presaccadic attention bridges the gap between presaccadic and post-saccadic input by increasing visibility at the saccade target. Counterintuitively, the presaccadic enhancement in contrast sensitivity was more pronounced where perception is better -along the horizontal than the vertical meridian- exacerbating polar angle asymmetries. Our results call for an investigation of the differential neural modulations underlying presaccadic perceptual changes for different saccade directions. Significance statementThe contrast sensitivity function (CSF) describes how our ability to perceive contrast depends on spatial frequency. Contrast sensitivity is highest at the fovea and decreases in the periphery, especially at vertical locations. We thus make saccadic eye movements to view objects in detail. Already before moving our eyes, presaccadic attention enhances perception at the target location. But how does it influence the interplay between spatial frequency and contrast sensitivity, and does its effect vary around the visual field? Using Hierarchical Bayesian Modeling, we show that presaccadic attention enhances and reshapes the CSF to prepare the periphery for upcoming fixation. Counterintuitively, it does so more at horizontal locations where vision is stronger, suggesting smoother perception across horizontal than vertical eye movements.

neuroscience↗

bioRxiv2023

READRetro: Natural Product Biosynthesis Planning with Retrieval-Augmented Dual-View Retrosynthesis

Elucidating the biosynthetic pathways of natural products has been a major focus of biochemistry and pharmacy. However, predicting the whole pathways from target molecules to metabolic building blocks remains a challenge. Here we propose READRetro as a practical bio-retrosynthesis tool for planning the biosynthetic pathways of natural products. READRetro effectively resolves the tradeoff between generalizability and memorability in bio-retrosynthesis by implementing two separate modules; each module is responsible for either generalizability or memorability. Specifically, READRetro utilizes a rule-based retriever for memorability and an ensemble of two dual-representation-based deep learning models for generalizability. Through extensive experiments, READRetro was demonstrated to outperform existing models by a large margin in terms of both generalizability and memorability. READRetro was also capable of predicting the known pathways of complex plant secondary metabolites such as monoterpene indole alkaloids, demonstrating its applicability in the real-world bio-retrosynthesis planning of natural products. A website (https://readretro.net) and open-source code have been provided for READRetro, a practical tool with state-of-the-art performance for natural product biosynthesis research.

bioinformatics↗

bioRxiv2022

Presaccadic attention sharpens visual acuity

Visual perception is limited by spatial resolution, which declines with eccentricity and differs around polar angle locations. To compensate for poor peripheral resolution, we make rapid eye movements -saccades- to bring peripheral objects into high-acuity foveal vision. Already before saccade onset, visual attention shifts to the saccade target location and prioritizes visual processing. This presaccadic shift of attention improves performance in many visual tasks, but whether it changes resolution is unknown. Here, we investigated whether presaccadic attention sharpens peripheral spatial resolution; and if so, whether such effect interacts with polar angle locations. We measured acuity thresholds in an orientation discrimination task during fixation and saccade preparation around the visual field. The results revealed that presaccadic attention sharpens acuity, which can facilitate a smooth transition from peripheral to foveal representation. This acuity enhancement is similar across the four cardinal locations; thus, presaccadic attention does not change polar angle differences in resolution.

neuroscience↗

bioRxiv2022

Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation

ME/CFS is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we used single-cell RNA-seq (scRNA-seq) to examine immune cells in cohorts of patients and controls. Post-exertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. Thus, to detect changes coincident with PEM, we also performed scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients displayed dysregulation of classical monocytes suggestive of inappropriate differentiation and migration to tissue. We were able to identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlated with metrics of disease severity. Comparing the transcriptome at baseline and post-exercise challenge, we discovered patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation following exercise. HighlightsME/CFS is a debilitating disease with unknown causes. Here, we provide, for the first time, an extensive single cell resolution dataset detailing the gene expression programs of circulating immune cells of ME/CFS cases at baseline and after symptom provocation. We were able to detect robust dysregulation in certain immune cells from patients, with dysregulation of classical monocytes manifesting the strongest signal. Indeed, the fraction of aberrant monocytes in ME/CFS patients correlated with the degree of disease severity. Surprisingly, platelet transcriptomes were also altered in ME/CFS, and they were the only component of the immune system that showed large-scale changes following symptom provocation.

immunology↗

bioRxiv2021

Reward and expectancy effects on neural signals of motor preparation and execution

The prospect of rewards can have strong modulatory effects on response preparation. Importantly, selection and execution of movements in real life happens under an environment characterized by uncertainty and dynamic changes. The current study investigated how the brains motor system adapts to the dynamic changes in the environment in pursuit of rewards. In addition, we studied how the prefrontal cognitive control system contributes in this adaptive control of motor behavior. To this end, we tested the effect of rewards and expectancy on the hallmark neural signals that reflect activity in motor and prefrontal systems, the lateralized readiness potential (LRP) and the mediofrontal (mPFC) theta oscillations, while participants performed an expected and unexpected action to retrieve rewards. To better capture the dynamic changes in neural processes represented in the LRP waveform, we decomposed the LRP into the preparation (LRPprep) and execution (LRPexec) components. The overall pattern of LRPprep and LRPexec confirmed that they each reflect motor preparation based on the expectancy and motor execution when making a response that is either or not in line with the expectations. In the comparison of LRP magnitude across task conditions, we found a greater LRPprep when large rewards were more likely, reflecting a greater motor preparation to obtain larger rewards. We also found a greater LRPexec when large rewards were presented unexpectedly, suggesting a greater motor effort placed for executing a correct movement when presented with large rewards. In the analysis of mPFC theta, we found a greater theta power prior to performing an unexpected than expected response, indicating its contribution in response conflict resolution. Collectively, these results demonstrate an optimized motor control to maximize rewards under the dynamic changes of real-life environment.

neuroscience↗

bioRxiv2021

Anatomy of an Extensively Drug Resistant Klebsiella pneumoniae Outbreak in Tuscany, Italy

A protracted outbreak of New Delhi metallo-beta-lactamase (NDM)-producing carbapenem-resistant Klebsiella pneumoniae, started in Tuscany, Italy, in November 2018 and continued in 2020 and through 2021. To understand the regional emergence and transmission dynamics over time, we collected and sequenced the genomes of 117 extensively drug-resistant, NDM-producing K. pneumoniae isolates cultured over a 20-month period from 76 patients at several health care facilities in South-East Tuscany. All isolates belonged to high-risk clone ST-147 and were typically non-susceptible to all first line antibiotics. Albeit sporadic, resistances to colistin, tigecycline and fosfomycin were also observed as a result of repeated, independent mutations. Genomic analysis revealed that ST-147 isolates circulating in Tuscany were monophyletic, highly genetically related (including a network of 42 patients from the same hospital and sharing nearly identical isolates) and shared a recent ancestor with clinical isolates from the Middle East. While the blaNDM-1 gene was carried by an IncFIB-type plasmid, our investigations revealed that the ST-147 lineage from Italy also acquired a hybrid IncH-type plasmid carrying the 16S methyltransferase armA gene as well as key virulence biomarkers often found in hypervirulent isolates. This plasmid shared extensive homologies with mosaic plasmids circulating globally including from ST-11 and ST-307 convergent lineages. Phenotypically, the carriage of this hybrid plasmid resulted in increased siderophore production but did not confer virulence to the level of an archetypical, hypervirulent K. pneumoniae in a subcutaneous model of infection with immunocompetent CD1 mice. Our findings highlight the importance of performing genomic surveillance to identify emerging threats. Significance StatementCarbapenem-resistant Klebsiella pneumoniae belong to the "critical priority" tier of bacterial pathogens as identified by the World Health Organization. Emerging "high-risk" lineages are responsible for difficult-to-treat, hospital-acquired infections and outbreaks around the globe. By integrating genomic and epidemiological data for isolates collected over 20 months, this study revealed both the high, regional prevalence and the rapid spread, within a single hospital, of K. pneumoniae ST-147 in Italy. Besides resistance to nearly all antibiotics, we showed that this lineage carried a hybrid plasmid harboring a set of biomarker genes previously linked to hypervirulence. Convergence of multidrug resistance and hypervirulence is a major concern and these findings highlight the need for robust, global surveillance to monitor the emergence of high-risk K. pneumoniae.

microbiology↗

bioRxiv2018

Population-scale study of eRNA transcription reveals bipartite functional enhancer architecture

Enhancer RNAs (eRNA) are non-coding RNAs transcribed bidirectionally from active regulatory sequences. Their expression levels correlate with the activating potentials of the enhancers, but due to their instability, eRNAs have proven difficult to quantify in large scale. To overcome this, we use capped-nascent-RNA sequencing to efficiently capture the bidirectional initiation of eRNAs. We apply this in large scale to the human lymphoblastoid cell lines from the Yoruban population, and detected nearly 75,000 eRNA transcription sites with high sensitivity and specificity. We identify genetic variants significantly associated with overall eRNA initiation levels, as well as the transcription directionality between the two divergent eRNA pairs, namely the transcription initiation and directional initiation quantitative trait loci (tiQTLs and diQTLs) respectively. High-resolution analyses of these two types of eRNA QTLs reveal distinct positions of enrichment not only at the central transcription factor (TF) binding regions but also at the flanking eRNA initiation regions, both of which are equivalently associated with mRNA expression QTLs. These two regions - the central TF binding footprint and the eRNA initiation cores - define the bipartite architecture and the function of enhancers, and may provide further insights into interpreting the significance of non-coding regulatory variants.

genomics↗

bioRxiv2018

The interplay of immune components and ECM in oral cancer

We report that in Oral Squamous Cell Carcinoma (OSCC), extracellular matrix (ECM) plays a vitally important role in defining the characteristics of cancer vs. normal, as it is a compartment with significant enrichment of known OSCC biomarkers, and the number of genes constituting ECM are more prominently upregulated in OSCC than almost all the rest of the cancer types. This is probably due to the constant exposure of oral cavity to external stimuli, resulting in the ECM remodeling, which further is a key player in tumor invasion. While we showed ECM molecules alone could well distinguish oral cancer from normal tissue samples, a significant portion of these predictive ECM molecules, share the same transcriptional regulator, NFKB1, a master regulator of immune response. We further studied the level of involvement of the immune system in OSCC, and found that the immune composition in OSCC is distinctly different from the other cancer types. OSCC has a higher level of infiltration of adaptive immune cells, including B cell, T cell and neutrophil, compared with other cancer types, while a lower level of infiltration of innate immune, including macrophage and monocyte. Previous studies have revealed the roles of ECM and immune system in OSCC development, and our study showed that ECM plays a very prominent role in OSCC, subject to the complex microenvironment in oral cavity, particularly the immune system profile, and our association analysis revealed it is likely the interactions between ECM and immune cells that define the highly invasive property of OSCC.

bioinformatics↗