β-Adrenergic Signal and Epigenomic Regulatory Process for Adaptive Thermogenesis.

Activation of β-adrenergic (β-AR) signaling induces fight-or-flight stress responses which include enhancement of cardiopulmonary function, metabolic regulation, and muscle contraction. Classical dogma for β-AR signaling has dictated that the receptor-mediated response results in an acute and transient signal. However, more recent studies support more wide-ranging roles for β-AR signaling with long-term effects including cell differentiation that requires precisely timed and coordinated integration of many signaling pathways that culminate in precise epigenomic chromatin modifications.

Multi-armed bandit algorithm for sequential experiments of molecular properties with dynamic feature selection.

Sequential optimization is one of the promising approaches in identifying the optimal candidate(s) (molecules, reactants, drugs, etc.) with desired properties (reaction yield, selectivity, efficacy, etc.) from a large set of potential candidates, while minimizing the number of experiments required.

Conformational Dynamics in Proteins: Entangled Slow Fluctuations and Nonequilibrium Reaction Events.

Proteins exhibit conformational fluctuations and changes over various time scales, ranging from rapid picosecond-scale local atomic motions to slower microsecond-scale global conformational transformations. In the presence of these intricate fluctuations, chemical reactions occur and functions emerge. These conformational fluctuations of proteins are not merely stochastic random motions but possess distinct spatiotemporal characteristics.

Environmental factor reversibly determines cellular identity through opposing Integrators that unify epigenetic and transcriptional pathways.

Organisms must adapt to environmental stresses to ensure their survival and prosperity. Different types of stresses, including thermal, mechanical, and hypoxic stresses, can alter the cellular state that accompanies changes in gene expression but not the cellular identity determined by a chromatin state that remains stable throughout life. Some tissues, such as adipose tissue, demonstrate remarkable plasticity and adaptability in response to environmental cues, enabling reversible cellular identity changes; however, the mechanisms underlying these changes are not well understood.

Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth.

Bone 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.

Automatic Detection of Putative Mild Cognitive Impairment from Speech Acoustic Features in Mandarin-Speaking Elders.

Background: To date, the reliable detection of mild cognitive impairment (MCI) remains a significant challenge for clinicians. Very few studies investigated the sensitivity of acoustic features in detecting Mandarin-speaking elders at risk for MCI, defined as "putative MCI" (pMCI).

Objective: This study sought to investigate the possibility of using automatically extracted speech acoustic features to detect elderly people with pMCI and reveal the potential acoustic markers of cognitive decline at an early stage.

Epitranscriptomics in metabolic disease.

While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease.

MYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis.

Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis.

Machine learning-based muscle mass estimation using gait parameters in community-dwelling older adults: A cross-sectional study.

Background: Loss of skeletal muscle mass is associated with numerous factors such as metabolic diseases, lack of independence, and mortality in older adults. Therefore, developing simple, safe, and reliable tools for assessing skeletal muscle mass is needed. Some studies recently reported that the risks of the incidence of geriatric conditions could be estimated by analyzing older adults' gait; however, no studies have assessed the association between gait parameters and skeletal muscle loss in older adults.

Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors.

Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis.

Epigenetic and environmental regulation of adipocyte function.

Adipocytes play an essential role in the maintenance of whole-body energy homeostasis. White adipocytes regulate energy storage, whereas brown and beige adipocytes regulate energy expenditure and heat production. De novo production of adipocytes (i.

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis.

Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia.

Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis.

Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated "primed" state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation.

Microscopic insights into dynamic disorder in the isomerization dynamics of the protein BPTI.

Understanding the dynamic disorder behind a process, i.e., the dynamic effect of fluctuations that occur on a timescale slower or comparable with the timescale of the process, is essential for elucidating the dynamics and kinetics of complicated molecular processes in biomolecules and liquids.

PPARα activation directly upregulates thrombomodulin in the diabetic retina.

Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM).

Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content.

Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM).

Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate.

Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces and , which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes.

Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis.

Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition.

Endothelial cell (EC) plasticity in pathological settings has recently been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood.

A kinetics study of ligand substitution reaction on dinuclear platinum complexes: Stochastic versus deterministic approach.

The kinetics on a basic ligand substitution reaction on dinuclear platinum complexes [Pt(PEt ) PhPt(PEt ) ] and [Pt(PEt ) PhCOPhPt(PEt ) ] , with the ligands pyridine and 3-chloropyridine, is studied. This is a fundamental step in a self-assembly, and the time evolution has been observed with a new experimental technique, QASAP (quantitative analysis of self-assembly process), which is recently developed by Hiraoka's group. As a result of numerical calculations based on master equation, we succeed in specifying the reaction rate constants with a simple reaction model.

Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch.

In acute cold stress in mammals, JMJD1A, a histone H3 lysine 9 (H3K9) demethylase, upregulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals have another mechanism to cope with long-term cold stress by inducing the browning of the subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A.

Overexpression of p54/NONO induces differential splicing and contributes to castration-resistant prostate cancer growth.

The non-POU domain-containing octamer binding protein p54/NONO is a multifunctional nuclear protein involved in RNA splicing, processing, and transcriptional regulation of nuclear hormone receptors. Through chromosome copy number analysis via whole-exome sequencing, we revealed amplification of the chromosome Xq11.22-q21.

A model electronic Hamiltonian for the self-assembly of an octahedron-shaped coordination capsule.

A model electronic Hamiltonian to describe ligand exchange reactions of palladium(ii) complexes with pyridine (Py) and tridentate (L) ligands was developed. It was shown that the model Hamiltonian can adequately reproduce the structures and potential energies of the reactant/product, intermediate, and transition state of the ligand exchange reaction of [PdPy] with free Py. The model Hamiltonian was extended to describe reactions of multi-metal complexes and was adequately applied to describe various clusters, [PdLPy], in the self-assembly of an octahedron-shaped coordination capsule, [PdL].