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Biology subjects

Lim, H. S.

Publications and source records attributed to Lim, H. S..

12 recordsLinked to original sources

A novel sequential sampling algorithm for the application of mechanistic models to species occurrence patterns

AimSpecies occurrence patterns are typically analysed using data-randomisation approaches, which reveal when observed patterns deviate from random expectation, but give little insight why. When non-randomness is detected, the analysis reaches a dead end. Mechanistic models, such as neutral models, offer an alternative: when their predictions fail to match data, the specific nature of each mismatch can implicate candidate mechanisms, turning null-model rejection into a diagnostic process. However, mechanistic models can be computationally expensive. Here, we use an efficient method to simulate such models and explore possible mechanisms governing the occurrence patterns of birds on islands. LocationRiau archipelago, Indonesia. TaxonBirds. MethodsWe used species richness and island-area data to fit a niche-neutral model, where species obey neutral dynamics within non-overlapping discrete niches. We used a sequential sampling algorithm that can efficiently sample presence-absence matrices under the niche-neutral model, and used mismatches to identify which mechanisms were potentially important to occurrence patterns. In particular, we compared model to observed data using standardised effect sizes on segregation (C-score) and nestedness (NODF) metrics. ResultsBirds were more segregated and less nested than expected from both data randomisation and the niche-neutral model. Further, while the niche-neutral model reproduced the mean relationship between island size and species richness, it could not produce sufficient variability to account for richness variation across islands. However, while the niche-neutral model was rejected as a null, it was possible to reproduce the species-occurrence patterns by allowing niche diversity and per-capita immigration rate to vary across islands, which increased segregation and decreased nestedness, respectively. Main conclusionWhile the species-area relationship could be explained by a model with constant per-capita immigration rates and number of niches across islands, inter-island heterogeneity was needed to explain species-occurrence patterns. Unlike data randomisation, which would have identified the patterns as non-random but offered no further insight, the mechanistic approach identified habitat diversity and immigration-rate variation as candidate mechanisms, demonstrating the diagnostic value of using niche-neutral models as an exploratory framework. The sequential sampling algorithm allowed us to explore different scenarios efficiently and may be useful for identifying potential mechanisms structuring patterns in other systems.

ecology↗

Improving Functional Muscle Regeneration in Volumetric Muscle Loss Injuries by Shifting the Balance of Inflammatory and Pro-Resolving Lipid Mediators

Severe tissue loss resulting from extremity trauma, such as volumetric muscle loss (VML), poses significant clinical challenges for both general and military populations. VML disrupts the endogenous tissue repair mechanisms, resulting in acute and unresolved chronic inflammation and immune cell presence, impaired muscle healing, scar tissue formation, persistent pain, and permanent functional deficits. The aberrant healing response is preceded by acute inflammation and immune cell infiltration which does not resolve. We analyzed the biosynthesis of inflammatory and specialized pro-resolving lipid mediators (SPMs) after VML injury in two different models; muscle with critical-sized defects had a decreased capacity to biosynthesize SPMs, leading to dysregulated and persistent inflammation. We developed a modular poly(ethylene glycol)-maleimide hydrogel platform to locally release a stable isomer of Resolvin D1 (AT-RvD1) and promote endogenous pathways of inflammation resolution in the two muscle models. The local delivery of AT-RvD1 enhanced muscle regeneration, improved muscle function, and reduced pain sensitivity after VML by promoting molecular and cellular resolution of inflammation. These findings provide new insights into the pathogenesis of VML and establish a pro-resolving hydrogel therapeutic as a promising strategy for promoting functional muscle regeneration after traumatic injury.

bioengineering↗

Stromal STAT5-mediated trophic activity regulates hematopoietic multipotent progenitor niche factors

Signal transducer and activator of transcription 5 (STAT5a and STAT5b) are intrinsically critical for normal hematopoiesis but are also expressed in stromal cells. Here, STAT5ab knockout (KO) was generated with a variety of bone marrow hematopoietic and stromal Cre transgenic mouse strains. Vav1-Cre, the positive control for loss of multipotent hematopoietic function, surprisingly dysregulated niche factor mRNA expression and deleted STAT5ab in CD45neg cells. Single cell transcriptome analysis of bone marrow from wild-type or Vav1-Cre KO mice showed hematopoietic stem cell myeloid commitment priming and upregulated protein translation genes. Nes+ cells were detected in both CD45neg and CD45+ clusters and deletion of STAT5ab with Nes-Cre caused hematopoietic repopulating defects. To follow up on these promiscuous Cre promoter deletions in CD45neg and CD45+ bone marrow cell populations, more stroma-specific Cre strains were generated and demonstrated reduction in multipotent hematopoietic progenitors. Functional support for niche-supporting activity was assessed using STAT5-deficient MSCs. With Lepr-Cre, niche factor mRNAs were downregulated by STAT5ab deletion with validation of reduced IGF-1 and CXCL12 proteins. Furthermore, computational analyses (differential expression/co-expression) revealed a key role for STAT5ab/Cish balance with Cish strongly co-expressed in MSCs and HSCs primed for differentiation. Therefore STAT5ab-associated gene regulation supports the bone marrow microenvironment.

cell biology↗

Quantifying Cell-type-specific Differences of Single-cell Datasets using UMAP and SHAP

With the rapid advances in single-cell profiling technologies, larger-scale investigations that require comparisons of multiple single-cell datasets can lead to novel findings. Specifically, quantifying cell-type-specific responses to different conditions across single-cell datasets could be useful in understanding how the difference in conditions is induced at a cellular level. Here we present a computational pipeline that quantifies the cell-type-specific differences and identifies genes responsible for the differences. We quantify differences observed in a low-dimensional UMAP space as a proxy for the difference present in the high-dimensional space and use SHAP to quantify genes driving the differences. Here we applied our algorithm to the Iris flower dataset, scRNA-seq dataset, and mass cytometry dataset, and demonstrate that it can robustly quantify the cell-type-specific differences and it can also identify genes that are responsible for the differences.

bioinformatics↗

Manipulating the 3D organization of the largest synthetic yeast chromosome

Whether synthetic genomes can power life has attracted broad interest in the synthetic biology field, especially when the synthetic genomes are extensively modified with thousands of designer features. Here we report de novo synthesis of the largest eukaryotic chromosome thus far, synIV, a 1,454,621-bp Saccharomyces cerevisiae chromosome resulting from extensive genome streamlining and modification. During the construction of synIV, we developed megachunk assembly combined with a hierarchical integration strategy, which significantly increased the accuracy and flexibility of synthetic chromosome construction and facilitated chromosome debugging. In addition to the drastic sequence changes made to synIV by rewriting it, we further manipulated the three-dimensional structure of synIV in the yeast nucleus to explore spatial gene regulation within the nuclear space. Surprisingly, we found few gene expression changes, suggesting that positioning inside the yeast nucleoplasm plays a minor role in gene regulation. Lastly, we tethered synIV to the inner nuclear membrane via its hundreds of loxPsym sites and observed transcriptional repression of the entire chromosome, demonstrating chromosome-wide transcription manipulation without changing the DNA sequences. Our manipulation of the spatial structure of the largest synthetic yeast chromosome shed light on higher-order architectural design of the synthetic genomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/487066v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@18bf586org.highwire.dtl.DTLVardef@1a471d5org.highwire.dtl.DTLVardef@12d7690org.highwire.dtl.DTLVardef@1c32510_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDe novo synthesis of the largest eukaryotic chromosome, synIV C_LIO_LISynIV shows similar 3D structure to wild-type IV, despite thousands of changes made to it C_LIO_LI"Inside-out" repositioning of synIV in nucleus shows minor transcriptional changes C_LIO_LIMultipoint tethering synIV to inner nuclear membrane represses transcription of whole chromosome C_LI

synthetic biology↗

Embracing enzyme promiscuity with activity-based compressed biosensing

Genome-scale activity-based profiling of proteases requires identifying substrates that are specific to each individual protease. However, this process becomes increasingly difficult as the number of target proteases increases because most substrates are promiscuously cleaved by multiple proteases. We introduce a method - Substrate Libraries for Compressed sensing of Enzymes (SLICE) - for selecting complementary sets of promiscuous substrates to compile libraries that classify complex protease samples (1) without requiring deconvolution of the compressed signals and (2) without the use of highly specific substrates. SLICE ranks substrate libraries according to two features: substrate orthogonality and protease coverage. To quantify these features, we design a compression score that was predictive of classification accuracy across 140 in silico libraries (Pearson r = 0.71) and 55 in vitro libraries (Pearson r = 0.55) of protease substrates. We demonstrate that a library comprising only two protease substrates selected with SLICE can accurately classify twenty complex mixtures of 11 enzymes with perfect accuracy. We envision that SLICE will enable the selection of peptide libraries that capture information from hundreds of enzymes while using fewer substrates for applications such as the design of activity-based sensors for imaging and diagnostics.

bioengineering↗

Identifying dysregulated immune cell subsets following critical volumetric muscle loss with pseudo-time trajectories

Volumetric muscle loss (VML) results in permanent functional deficits and remains a substantial regenerative medicine challenge. A coordinated immune response is crucial for timely myofiber regeneration, however the immune response following VML has yet to be fully characterized. Here, we leveraged dimensionality reduction and pseudo-time analysis techniques to elucidate the cellular players underlying a functional or pathological outcome as a result of subcritical or critical VML in the murine quadriceps, respectively. We found that critical VML presented with a sustained presence of M2-like and CD206hiLy6Chi hybrid macrophages whereas subcritical defects resolved these populations. These macrophage subsets may contribute to fibrogenesis in critical VML, especially in the presence of TGF-{beta}. Furthermore, several T cell populations were significantly elevated in critical VML compared to subcritical injuries. Specifically, there was a significant increase of CD127+ T cells at days 3 and 7, and upregulated CD127 expression may indicate aberrant IL-7 signaling in critical VML. These results demonstrate a dysregulated immune response in critical VML that is unable to resolve the chronic inflammatory state and transition to a pro-regenerative microenvironment. These data provide important insights into potential therapeutic strategies which could reduce the immune cell burden and pro-fibrotic signaling characteristic of VML.

immunology↗

Synthetic chromosome fusion: effects on genome structure and function

As part of the Synthetic Yeast 2.0 (Sc2.0) project, we designed and synthesized synthetic chromosome I. The total length of synI is [~]21.4% shorter than wild-type chromosome I, the smallest chromosome in Saccharomyces cerevisiae. SynI was designed for attachment to another synthetic chromosome due to concerns of potential instability and karyotype imbalance. We used a variation of a previously developed, robust CRISPR-Cas9 method to fuse chromosome I to other chromosome arms of varying length: chrIXR (84kb), chrIIIR (202kb) and chrIVR (1Mb). All fusion chromosome strains grew like wild-type so we decided to attach synI to synIII. Through the investigation of three-dimensional structures of fusion chromosome strains, unexpected loops and twisted structures were formed in chrIII-I and chrIX-III-I fusion chromosomes, which depend on silencing protein Sir3. These results suggest a previously unappreciated 3D interaction between HMR and the adjacent telomere. We used these fusion chromosomes to show that axial element Red1 binding in meiosis is not strictly chromosome size dependent even though Red1 binding is enriched on the three smallest chromosomes in wild-type yeast, and we discovered an unexpected role for centromeres in Red1 binding patterns.

synthetic biology↗

Onset, Time to Recurrence, and Recurrence Risk Factors of Myocardial Infarction and Ischemic Stroke: 10-Year Nationwide one-Million Population Database

Background and PurposeWe aimed to determine the differences in the pathophysiology of myocardial infarction (MI) and ischemic stroke (IS) and present their basic epidemiologic data for public health policy.\n\nMethodsWe included patients with a history of admission with diagnostic codes of MI and IS in the National Health Information Database (NHID) of the National Health Insurance Service (NHIS) Sample Cohort 2002-2013. We investigated the time to primary and secondary events, difference in incidence based on sex, time interval for the secondary event following the primary event in MI and IS, and the relative risk of recurrent events compared with that of primary events.\n\nResultsThe mean age of onset of IS was significantly higher than that of MI (65.67{+/-}12.25 vs. 60.4{+/-}13.07 years; P<0.05). The mean period from primary IS to secondary IS was significantly shorter than that from primary IS to secondary MI (2.09{+/-}2.80 vs. 5.35{+/-}2.90 years; P=0.016). The mean period from primary MI to secondary MI was significantly shorter than that from primary MI to secondary IS (2.30{+/-}2.75 vs. 5.16{+/-}3.26 years; P<0.001). The incidence of IS in men was significantly higher than that in women. The relative risk of recurrent IS and MI was greater than that of the primary event. In patients younger than 70 years, the incidence of MI was higher than that of IS, while in those above 70 years it was lower (P<0.05).\n\nConclusionsThe age at onset, time to recurrence, sex, and relative risks are significantly different between ischemic stroke and myocardial infarction, suggesting that the underlying pathophysiologic mechanisms might be different between the two.

epidemiology↗

Socioeconomic status associated with carpal tunnel syndrome: A retrospective nationwide 11-year population-based cohort study in South Korea

ImportanceThere have only been a few large-scale studies that have included a risk factor analysis for CTS. No prior study has investigated the relationship between the occurrence of CTS and stratified socioeconomic status, which is closely related to a persons type of job.\n\nObjectiveTo confirm the known risk factors for CTS and also to determine the correlation between stratified socioeconomic status and the occurrence of CTS.\n\nDesignWe conducted this study using a retrospective cohort model based on the combined databases of the Korean National Health Insurance System from 2003-2013, a database compiled using information from a national periodic health-screening program that is used for reimbursement claims.\n\nSettingThe setting was a population-based retrospective cohort study.\n\nParticipantsFirst, we randomly sampled 514,795 patients who represented 10% of the 5,147,950 people who took part in periodic health screenings from 2002-2003. Existing CTS patients were excluded from this group. Therefore, this study finally included 512,942 participants and followed their medical records from 2003-2013.\n\nMain Outcomes and MeasuresDesired outcomes were the incidence rate of CTS and the hazard ratios according to stratified socioeconomic status.\n\nResultsA correlation analysis showed that CTS was more likely to occur in patients from a lower socioeconomic status.\n\nConclusions and RelevanceCTS was associated with people of a lower socioeconomic status who work in simple but repetitive manual labor jobs. We believe that the results of our study will be helpful to determine the pathophysiology of CTS and to set up a new industrial health policy for this condition.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the relationship between stratified socioeconomic status and the incidence of carpal tunnel syndrome (CTS)?\n\nFindingsIn this retrospective population-based cohort study that included 512,942 participants sampled from the Korean National Health Insurance System(KNHIS) database, the incidence rate and hazard ratios for CTS tended to increase with lower socioeconomic status.\n\nImplicationsLow socioeconomic status was identified as a risk factor for the incidence of CTS.

epidemiology↗

Validation of known risk factors associated with carpal tunnel syndrome: A retrospective nationwide 11-year population-based cohort study in South Korea

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the relationship between the previously known risk factors and occurrence of carpal tunnel syndrome (CTS)?\n\nFindingsIn this retrospective population-based cohort study that included 512,942 participants sampled from the Korean National Health Insurance System database, we determined the following known risk factors were related to the occurrence of CTS: the age of 40s, female, being overweight, diabetes, rheumatoid arthritis, gout, and Raynauds syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.\n\nImplicationsWe identified the age of 40s, female, overweight, diabetes, rheumatoid arthritis, gout, and Raynauds syndrome as risk factors for the occurrence of CTS.\n\nAbstractO_ST_ABSImportanceC_ST_ABSThere have been few large-scale studies that have included a risk factor analysis for CTS. No prior study has investigated and validated the relationship between the occurrence of CTS and known risk factors using nationwide health care database.\n\nObjectiveTo confirm the actual risk factors for CTS out of various known risk factors\n\nDesignWe conducted this study using a retrospective cohort model based on the combined two databases of the Korean National Health Insurance System; the national periodic health screening program database from 2002-2003 and health insurance database of reimbursement claims from 2003 through 2013.\n\nSettingA population-based retrospective cohort study.\n\nParticipantsFirst, we randomly sampled 514,795 patients who represented 10% of the 5,147,950 people who took part in periodic health screenings in 2002-2003. Existing CTS patients were excluded from this group. Therefore, this study finally included 512,942 participants and followed up their medical records from 2003-2013.\n\nMain Outcomes and MeasuresDesired outcomes were the incidence rate of CTS in patients with various risk factors and the hazard ratios of risk factors affecting the diseases occurrence.\n\nResultsThe incidence of CTS was highest in patients in the age of 40s, in the moderate obesity group, in females, and in patients with diabetes mellitus (DM). The hazard ratio analysis revealed that the following risk factors were strongly related to the occurrence of CTS: age of 40s, female, obesity, DM, rheumatoid arthritis, gout, and Raynauds syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.\n\nConclusions and RelevanceIn our large-scale cohort study, risk factors such as being in ones 40s, obesity, being female, suffering from DM, and rheumatoid arthritis were reaffirmed as those of CTS occurrence.

epidemiology↗

10 Year Epidemiologic data of Parkinson`s Disease: A Nationwide Population-based Retrospective Cohort of South Korea

ObjectivesThe aims of this study were to determine the prevalence, incidence, and P/I ratio of Parkinsons disease (PD) in South Korea and to present basic epidemiological information on PD patients for making effective health policies.\n\nMethodsWe used National Health Insurance Service-National Sample Cohort (KNHIS-NSC) data to analyze the prevalence, incidence, and P/I ratio of PD from 2003 to 2013 and then followed up using the NHID in 2008 to obtain the hazard ratio (HR) of death in PD itself and other comorbidities from 2008 to 2013.\n\nResultsThe prevalence and incidence of PD increased rapidly from 72.9 and 32.8 in 2003 to 213.4 and 58.0 in 2013, and the P/I ratio increased from 2.22 in 2003 to 3.62 in 2013. The prevalence, incidence, and P/I ratio of PD were all higher in women than in men. The hazard ratio for death was significantly higher in PD patients (15.36) compared to subjects without the disease. Stroke was the most frequent cause of death in the PD patient population followed by cancer and pneumonia.\n\nConclusionThe prevalence, incidence, and P/I ratio of PD rapidly increased as the years progressed. This indirectly proves that the health insurance system in Korea is efficient and has allowed patients with PD to access medical facilities more easily. However, a newer public healthy strategy should be established for patients with PD because PD itself has a high HR for death, and patients with PD have a high mortality rate when stroke and pneumonia are also involved.\n\nDisclosureAll authors have reported no biomedical interests and potential conflicts of interests.

epidemiology↗