Messenger RNA splicing and degradation are critical for gene expression regulation, the abnormality of which leads to diseases. Previous methods for estimating kinetic rates have limitations, assuming uniform rates across cells. DeepKINET is a deep generative model that estimates splicing and degradation rates at single-cell resolution from scRNA-seq data.
View Article and Find Full Text PDFMotivation: Single-cell RNA sequencing (scRNA-seq) enables comprehensive characterization of the cell state. However, its destructive nature prohibits measuring gene expression changes during dynamic processes such as embryogenesis or cell state divergence due to injury or disease. Although recent studies integrating scRNA-seq with lineage tracing have provided clonal insights between progenitor and mature cells, challenges remain.
View Article and Find Full Text PDFSingle-cell RNA-seq analysis coupled with CRISPR-based perturbation has enabled the inference of gene regulatory networks with causal relationships. However, a snapshot of single-cell CRISPR data may not lead to an accurate inference, since a gene knockout can influence multi-layered downstream over time. Here, we developed RENGE, a computational method that infers gene regulatory networks using a time-series single-cell CRISPR dataset.
View Article and Find Full Text PDFBone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner.
View Article and Find Full Text PDFThe presence of some amino acid mutations in the amino acid sequence that determines a protein's structure can significantly affect that 3D structure and its biological function. However, the effects upon structural and functional changes differ for each displaced amino acid, and it is very difficult to predict these changes in advance. Although computer simulations are very effective at predicting conformational changes, they struggle to determine whether the amino acid mutation of interest induces sufficient conformational changes, unless the researcher is a specialist in molecular structure calculations.
View Article and Find Full Text PDFMotivation: Evolve and resequence (E&R) experiments show promise in capturing real-time evolution at genome-wide scales, enabling the assessment of allele frequency changes SNPs in evolving populations and thus the estimation of population genetic parameters in the Wright-Fisher model (WF) that quantify the selection on SNPs. Currently, these analyses face two key difficulties: the numerous SNPs in E&R data and the frequent unreliability of estimates. Hence, a methodology for efficiently estimating WF parameters is needed to understand the evolutionary processes that shape genomes.
View Article and Find Full Text PDFBackground: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months.
View Article and Find Full Text PDFAm J Respir Cell Mol Biol
February 2019
Recapitulative animal models of idiopathic pulmonary fibrosis (IPF) and related diseases are lacking, which inhibits our ability to fully clarify the pathogenesis of these diseases. Although lung fibrosis in mouse models is often induced by bleomycin, silica-induced lung fibrosis is more sustainable and more progressive. Therefore, in this study, we sought to elucidate the mediator(s) responsible for the pathogenesis of lung fibrosis, through the use of a mouse model of silica-induced lung fibrosis.
View Article and Find Full Text PDFBackground: Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration.
View Article and Find Full Text PDFClin Neurophysiol Pract
February 2017
Objective: This paper reports a patient with bulbospinal muscular atrophy (BSMA) who presented with spinal myoclonus, documented by video and surface electromyography.
Case Report: A 66-year-old man had progressive gait disturbance, dysphagia, and easy fatigability of all extremities over a period of 4 years. Neurologically, muscle atrophy, fasciculation, and weakness were observed in the bulbar and limb muscles.
The total synthesis of KB-3346-5A, named naphthacemycin A, has been accomplished by combining the Dötz reaction and Suzuki-Miyaura cross coupling as well as employing Friedel-Crafts reaction with dienone-phenol rearrangement as key steps. We also describe the preparation of the simplified tetarimycin A and naphthacemycin A analogs as a model study, which coincidentally reveal unique properties of naturally occurring naphthacene-5,6,11(12H)-trione framework. The synthesized compounds were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE) to elucidate their structure-activity relationships (SARs), the results of which agreed with a previously reported preliminary SAR study of tetarimycin A.
View Article and Find Full Text PDFJ Hand Surg Asian Pac Vol
February 2016