Biology subjects

Park, K.

Publications and source records attributed to Park, K..

6 recordsLinked to original sources

bioRxiv2018

Optimal diameter reduction ratio of acinar airways in human lungs

In the airway network of a human lung, the airway diameter gradually decreases through multiple branching. The diameter reduction ratio of the conducting airways that transport gases without gas exchange is 0.79, but this reduction ratio changes to 0.94 in acinar airways beyond transitional bronchioles. While the reduction in the conducting airways was previously rationalized on the basis of Murrays law, our understanding of the design principle behind the acinar airways has been far from clear. Here we elucidate that the change in gas transfer mode is responsible for the transition in the diameter reduction ratio. The oxygen transfer rate per unit surface area is maximized at the observed geometry of acinar airways, which suggests the minimum cost for the construction and maintenance of the acinar airways. The results revitalize and extend the framework of Murrays law over an entire human lung.

bioengineering↗

bioRxiv2018

Structural capture of an intermediate transport state of a CLC Cl-/H+ antiporter

The CLC family proteins are involved in a variety of cellular processes, where chloride homeostasis needs to be controlled. Two distinct classes of CLC proteins, Cl- channels and Cl-/H+ antiporters, have been functionally and structurally investigated over the last several decades. Recent studies have revealed that the conformational heterogeneity of the critical glutamate residue, Gluex could explain the transport cycle of CLC-type Cl-/H+ antiporters. However, the presence of multiple conformations of the Gluex has been suggested from combined structural snapshots of two different CLC antiporters. Thus, we aimed to investigate the presence of these three intermediate conformations in CLC-ec1, the most deeply studied CLC at both functional and structural levels. By comparing crystal structures of E148D, E148A mutant and wildtype CLC-ec1 with varying anion concentrations, we suggest that the Gluex indeed take at least three distinct conformational states in a single CLC antiporter, CLC-ec1.

biochemistry↗

bioRxiv2018

Development of an imaging toolbox to assess the therapeutic potential and biodistribution of macrophages in a mouse model of multiple organ dysfunction

Cell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multi-spectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver and cardiac injury and the extent of functional recovery to be assessed non-invasively in a mouse model of multi-organ dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred M2 macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy improved kidney and liver function to a limited extent, but did not ameliorate histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver, but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages.

pharmacology and toxicology↗

bioRxiv2018

The impact of 10-valent Pneumococcal Conjugate Vaccine on the incidence of radiologically-confirmed pneumonia and clinically-defined pneumonia in Kenyan children.

BackgroundPneumococcal conjugate vaccines (PCV) are highly protective against invasive pneumococcal disease caused by vaccine serotypes but the burden of pneumococcal disease in developing countries is dominated by pneumonia, most of which is non-bacteraemic. We examined the impact of PCV on pneumonia incidence.\n\nMethodsWe linked prospective hospital surveillance for clinically-defined WHO severe or very-severe pneumonia at Kilifi County Hospital from 2002-2015 to population surveillance at Kilifi Health and Demographic Surveillance System, comprising 45,000 children aged <5 years. Chest radiographs were read according to a WHO standard. A 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PCV10) was introduced in Kenya in January 2011. In Kilifi, there was a catch-up campaign for children aged <5 years. We estimated the impact of PCV10 on pneumonia incidence through interrupted time series analysis accounting for seasonal and temporal trends.\n\nFindingsThe incidence of admission with clinically-defined pneumonia in 2002/3 was 21{middle dot}7/1000/year in children aged 2-59 months. This declined progressively over 13 years. By the end of March 2011, 61{middle dot}1% of children aged 2-11 months received [≥]2 doses and 62{middle dot}3% of children aged 12-59 months received [≥]1 dose of PCV10. Adjusted incidence rate ratios for admissions with radiologically-confirmed pneumonia, clinically-defined pneumonia, and diarrhoea (control condition), associated with PCV10 introduction, were 0{middle dot}52 (95% CI 0{middle dot}32-0{middle dot}86), 0{middle dot}73 (95% CI 0{middle dot}54-0{middle dot}97) and 0{middle dot}63, (95% CI 0{middle dot}31-1{middle dot}26), respectively. The annual incidence of clinically-defined pneumonia in December 2010 was 12{middle dot}2/1000; this was reduced by 3{middle dot}3/1000 with PCV10 introduction.\n\nInterpretationOver 13 years, hospitalisations for clinically-defined pneumonia declined progressively at Kilifi County Hospital but fell abruptly by 27% in association with PCV10 introduction. The incidence of radiologically-confirmed pneumonia fell by 48%. The burden of childhood pneumonia in Kilifi, Kenya, has been reduced substantially by PCV10.\n\nFundingGavi, Wellcome Trust

epidemiology↗

bioRxiv2018

BALLI: Bartlett-Adjusted Likelihood-based LInear Model Approach for Identifying Differentially Expressed Gene with RNA-seq Data

MotivationTranscriptomic profiles can improve our understanding of the phenotypic molecular basis of biological research, and many statistical methods have been proposed to identify differentially expressed genes under two or more conditions with RNA-seq data. However, statistical analyses with RNA-seq data often suffer from small sample sizes, and global variance estimates of RNA expression levels have been utilized as prior distributions for gene-specific variance estimates, making it difficult to generalize the methods to more complicated settings. We herein proposed a Bartlett-Adjusted Likelihood based LInear mixed model approach (BALLI) to analyze more complicated RNA-seq data. The proposed method estimates the technical and biological variances with a linear mixed effect model, with and without adjusting small sample bias using Bartletts corrections.\n\nResultsWe conducted extensive simulations to compare the performance of BALLI with those of existing approaches (edgeR, DESeq2, and voom). Results from the simulation studies showed that BALLI correctly controlled the type-1 error rates at the various nominal significance levels, and produced better statistical power and precision estimates than those of other competing methods in various scenarios. Furthermore, BALLI was robust to variation of library size. It was also successfully applied to Holstein milk yield data, illustrating its practical value.\n\nAvailability and ImplementationBALLI is implemented as R package and freely available at http://healthstat.snu.ac.kr/software/balli/.\n\nContactwon1@snu.ac.kr\n\nSupplementary InformationSupplementary data are available at Bioinformatics online

bioinformatics↗

bioRxiv2017

Comprehensive Molecular Characterization of Mitochondrial Genomes in Human Cancers

Mitochondria are essential cellular organelles that play critical roles in cancer development. Through International Cancer Genome Consortium, we performed a multidimensional characterization of mitochondrial genomes using the whole-genome sequencing data of ~2,700 patients across 37 cancer types and related RNA-sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes including a novel hypermutated case. We observe similar mutational signatures across cancer types, suggesting powerful endogenous mutational processes in mitochondria. Truncating mutations are remarkably enriched in kidney, colorectal and thyroid cancers and associated with the activation of critical signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA (especially in skin and lung cancers), some of which disrupt therapeutic target genes (e.g., ERBB2). The mitochondrial DNA copy number shows great variations within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair, and cell cycle; and reveals their connections with clinically actionable genes. Our study, including an open-access data portal, lays a foundation for understanding the interplays between the cancer mitochondrial and nuclear genomes and translating mitochondrial biology into clinical applications.

genomics↗