Gene Flow between the Korean Peninsula and Its Neighboring Countries

SNP markers provide the primary data for population structure analysis. In this study, we employed whole-genome autosomal SNPs as a marker set (54,836 SNP markers) and tested their possible effects on genetic ancestry using 320 subjects covering 24 regional groups including Northern ( = 16) and Southern ( = 3) Asians, Amerindians ( = 1), and four HapMap populations (YRI, CEU, JPT, and CHB). Additionally, we evaluated the effectiveness and robustness of 50K autosomal SNPs with various clustering methods, along with their dependencies on recombination hotspots (RH), linkage disequilibrium (LD), missing calls and regional specific markers. The RH- and LD-free multi-dimensional scaling (MDS) method showed a broad picture of human migration from Africa to North-East Asia on our genome map, supporting results from previous haploid DNA studies. Of the Asian groups, the East Asian group showed greater differentiation than the Northern and Southern Asian groups with respect to Fst statistics. By extension, the analysis of monomorphic markers implied that nine out of ten historical regions in South Korea, and Tokyo in Japan, showed signs of genetic drift caused by the later settlement of East Asia (South Korea, Japan and China), while Gyeongju in South East Korea showed signs of the earliest settlement in East Asia. In the genome map, the gene flow to the Korean Peninsula from its neighboring countries indicated that some genetic signals from Northern populations such as the Siberians and Mongolians still remain in the South East and West regions, while few signals remain from the early Southern lineages

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1 beta-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1 beta-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Development of Chemical Biology Probes for Elusive Protein Arginine and Histidine Phosphorylations

Department of Chemistryclos

Quest for Eukaryotic Histone H4 Histidine Kinases

Protein histidine (His) phosphorylation and responsible His kinases (HKs) have been well characterized in bacteria (two-component systems; TCSs), while little is known about the HKs in eukaryotic cells. Although eukaryotic HK activities towards histone H4 has been reported over 40 years ago, with their potential involvement in cell proliferation, the identity of the kinase remains elusive. Here we report our progress towards the isolation and identification of HKs using chemical biology tool

Fluorescent Probe for Dynamics of Arginine Phosphorylation

Protein phosphorylation plays a crucial role in cell signaling and other physiological processes, thus dysregulated phosphorylation has been related to various human diseases. While protein phosphorylations on serine, threonine, and tyrosine have been studied extensively, protein arginine phosphorylation has been less explored because it is incompatible with current phosphoproteomic methods due to its chemical instability. However, recent studies discovered the novel roles of pArg???s regulatory function in cells. In gram positive bacteria, pArg was reported to modulate a stress regulator protein (CtsR heat shock regulator). Furthermore, pArg as a protein degradation tag in bacteria recognized by ClpCP protease, suggests that arginine kinases and phosphatase can be novel antibacterial drug targets. Here, we introduce real-time fluorescence based chemosensors to monitor the dynamics of protein arginine phosphorylation and dephosphorylation. These chemosensors enabled continuous measurement of both McsB (protein arginine kinase) and YwlE (protein phosphoarginine phosphatase) activities. Given the growing interest in the protein arginine phosphorylation, mainly in bacteria, we believe this tool will facilitate further understanding of this underappreciated form of protein phosphorylation, paving the way for future drug discovery

A genetically encoded fluorescent sensor for protein Arg phosphorylation dynamics in live cells

Protein Arg phosphorylation is a crucial post-translational modification (PTM) for stress response, virulence, and protein quality control of Gram-positive bacteria. Although this PTM was first discovered in the 1970s, it is only recently that a protein Arg kinase (McsB) and a pArg phosphatase (YwlE) have been identified in Gram-positive bacteria. McsB marks misfolded protein by Arg phosphorylation, and the pArg tag is recognized by the bacterial proteasome for degradation, analogous to protein ubiquitination in eukaryotes. Recently, we reported a CHEF-based fluorescent probe for real-time monitoring of Arg kinase/phosphatase activities in vitro. However, the peptide-based probe was not applicable to live-cell studies. To overcome this limitation, we developed new genetically encoded FRET-based enzyme activity probes for studying Arg phosphorylation dynamics in live cells. This sensor should be invaluable in studying the regulatory mechanisms of Arg phosphorylation dynamics

Quest for the Crypto-phosphoproteome

Protein phosphorylation is one of the most studied post???translational modifications (PTMs). Despite the remarkable advances in phosphoproteomics, a chemically less???stable subset of the phosphosites, which we call the crypto???phosphoproteome, has remained underexplored due to technological challenges. In this Viewpoint, we briefly summarize the current understanding of these elusive protein phosphorylations and identify the missing pieces for future studies

A Fluorescent Probe for Protein Histidine Phosphatase Activity

Protein histidine phosphorylation plays an important role in cell signaling and metabolic processes, particularly in bacteria, fungi, and plans. In mammals, protein histidine phosphatase (PHPT1) is one of a few characterized protein phosphatases specific towards phosphohistidine (pHis), and it is shown to regulate the activities of diverse ion channels as well as metabolic proteins. Its activity has been linked to cancer metastasis and diabetes, but further studies have been hampered due to the lack of suitable tools including convenient and accurate phosphatase activity assays. Previous assays relying on a radiolabeling are hazardous and technically laborious. While chromogenic or fluorogenic small molecule substrates have also been used, they are nonselective towards PHPT1 and their kinetic parameters are different from native substrates. To address this, we herein report a fluorescent probe for the pHis activity of PHPT1. With this probe, we conveniently obtained the kinetic parameters of PHPT1 towards a pHis substrate, which showed orders of magnitude difference from the literature values. Our probe was also selective towards PHPT1 over a panel of phosphatases, potentially applicable in monitoring PHPT1 activities in biological samples