Design of sec-Benzyl Vinyl Ethers toward the Synthesis of Alternating Copolymers Composed of Vinyl Alcohol and Vinyl Ether Units.

In this work, we designed benzyl vinyl ethers carrying alkyl substituents at the benzyl position (i.e., sec-BnVEs) as bulky, reactive, and transformable monomers to realize the alternating cationic copolymerization with an alkyl vinyl ether (VE). In particular, the isopropyl substitution caused not only the bulkiness to suppress the successive propagation but also an enhancement of the vinyl group reactivity to promote crossover propagation with a less bulky VE comonomer. The isopropyl-substituted BnVE (iPr-BnVE) underwent living cationic alternating copolymerization with n-butyl VE (nBVE), and the alternating propagation was strongly suggested by the reactivity ratios. The subsequent deprotection of the sec-benzyl pendant afforded the vinyl alcohol (VA)-nBVE alternating copolymer, and the corresponding statistical copolymer was also synthesized by using the nonsubstituted monomer (BnVE) instead of iPr-BnVE. The alternating copolymer exhibited a higher glass transition temperature, which likely stems from the uniform and efficient hydrogen-bonding formation due to the periodic sequence.

DNA hypomethylation characterizes genes encoding tissue-dominant functional proteins in liver and skeletal muscle.

Each tissue has a dominant set of functional proteins required to mediate tissue-specific functions. Epigenetic modifications, transcription, and translational efficiency control tissue-dominant protein production. However, the coordination of these regulatory mechanisms to achieve such tissue-specific protein production remains unclear. Here, we analyzed the DNA methylome, transcriptome, and proteome in mouse liver and skeletal muscle. We found that DNA hypomethylation at promoter regions is globally associated with liver-dominant or skeletal muscle-dominant functional protein production within each tissue, as well as with genes encoding proteins involved in ubiquitous functions in both tissues. Thus, genes encoding liver-dominant proteins, such as those involved in glycolysis or gluconeogenesis, the urea cycle, complement and coagulation systems, enzymes of tryptophan metabolism, and cytochrome P450-related metabolism, were hypomethylated in the liver, whereas those encoding-skeletal muscle-dominant proteins, such as those involved in sarcomere organization, were hypomethylated in the skeletal muscle. Thus, DNA hypomethylation characterizes genes encoding tissue-dominant functional proteins.

Hepatic FASN deficiency differentially affects nonalcoholic fatty liver disease and diabetes in mouse obesity models.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor-deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

An Investigation of the Non-selective Etching of Synthetic Polymers by Electrospray Droplet Impact/Secondary Ion Mass Spectrometry (EDI/SIMS).

Among the various types of cluster secondary ion mass spectrometry (SIMS), electrospray droplet impact/secondary ion mass spectrometry (EDI/SIMS) is unique due to its high ionization efficiency and non-selective atomic/molecular-level surface etching ability. In this study, EDI/SIMS was applied to the non-selective etching of synthetic polymers of polystyrene (PS) and poly(9,9-di-n-octylfluonyl-2,7diyl) (PFO) deposited on a silicon substrate. The polymers gave characteristic fragment ions and the mass spectra remained unchanged with prolonged EDI irradiation time, indicating that non-selective etching can be achieved by EDI irradiation, a finding that is consistent with our previous reports based on EDI/X-ray photoelectron spectroscopy analyses. From the irradiation time and film thickness, the etching rates for PS and PFO were roughly estimated to be 0.6 nm/min and 0.15 nm/min, respectively, under the experimental conditions that were used. After the depletion of polymer sample on the surface, ion signals originating from the exposed silicon substrate were observed. This indicates that EDI/SIMS is applicable to the analysis of the interface of multilayered films composed of organic and inorganic materials.

Independent risk factors of rapid glomerular filtration rate decline in patients with type 2 diabetes with preserved kidney function and normoalbuminuria: A multicenter cohort study.

AIMS/INTRODUCTION: Research on the incidence and underlying mechanisms of rapid renal function decline in patients with type 2 diabetes mellitus with preserved renal function and normoalbuminuria is limited. This study aimed to investigate the involvement of hemoglobin level as a risk factor for rapid decliners among patients with type 2 diabetes with preserved renal function and normoalbuminuria. MATERIALS AND METHODS: This was a retrospective observational study of 242 patients with type 2 diabetes with a baseline estimated glomerular filtration rate of ≥60 mL/min/1.73 m2 and normoalbuminuria (<30 mg/gCr), followed up for >1 year. The annual rate of estimated glomerular filtration rate decline during the follow-up period was calculated using least square regression analysis; rapid decliners defined at ≥3.3%/year. Risk factors associated with rapid decliners were identified using a logistic regression analysis of variables previously identified as risk factors of rapid decliners. RESULTS: The median follow-up period was 6.7 years, and 34 patients showed rapid decliners. On multivariate analysis, lower baseline hemoglobin level was a risk factor of rapid decliners (odds ratio 0.69, 95% confidence interval 0.47-0.99; P = 0.045). Furthermore, the baseline hemoglobin levels were correlated positively with iron and ferritin levels, implying that an impaired iron metabolism might cause lower hemoglobin levels in rapid decliners. CONCLUSIONS: In patients with type 2 diabetes with preserved renal function and normoalbuminuria, lower hemoglobin levels were a risk factor for rapid decliners, where disturbed iron metabolism might precede the development of diabetic kidney disease.

Detection of Glycolytically Active Lacticaseibacillus paracasei Strain Shirota by Flow Cytometry Targeting the Efflux Activity of Fluorescent Dye: a Potential Tool for Quality Assessment of Probiotic Cells in Milk Products.

The rapid and accurate detection of viable probiotic cells in dairy products is important for assessing product quality in manufacturing. Flow cytometry is widely used for the rapid analysis of bacterial cells. However, further investigation is needed into the optimum property to use it for assessing cell viability. Here, we proposed using the efflux activity of a fluorescent dye, carboxyfluorescein (CF), as an indicator of cell viability. CF is generated from 5(6)-carboxyfluorescein diacetate as a result of cleavage by intracellular esterase. It generally accumulates in the cell, but certain bacterial species are known to extrude it. We found here that the probiotic strain Lacticaseibacillus paracasei strain Shirota (LcS) also extruded CF in the presence of energy sources, such as glucose. To investigate the mechanism of its CF-efflux activity, we screened CF-efflux-negative mutants from a random mutagenesis LcS library and examined the whole genome for genes responsible for CF efflux. We identified a base substitution in the pfkA gene in the glycolytic pathway, and we demonstrated that intact pfkA was essential for CF efflux, indicating that CF-efflux-positive cells must have uncompromised glycolytic activity. We also confirmed that there was a good correlation between the rate of CF-efflux-positive cells and that of colony-forming cells of LcS in a fermented milk product, whereas other properties, such as esterase activity and cell membrane integrity, lost their correlation with the colony-forming activity after long storage. We propose that CF-efflux activity could be an appropriate indicator of cell viability in certain probiotic strains. IMPORTANCE To our knowledge, this is the first report to demonstrate that CF efflux requires uncompromised glycolytic activity in certain lactic acid bacteria. Compared with the cell properties currently widely used for cell viability assessment, such as intracellular esterase activity and membrane integrity, CF-efflux activity enables the accurate detection of culturable cells, especially in products stored for long periods at cold temperatures. These results indicate strongly that CF-efflux activity can be an adequate cell-viability indicator and that flow cytometric quantification could be an alternative to conventional CFU counting. Our findings should be especially informative for dairy/probiotic product manufacturing.

A case of eosinophilic polyangiitis with granulomatosis that evolved to cardiac arrest due to advanced atrioventricular block.

Cardiac manifestations are the major cause of mortality in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Among these manifestations in EGPA patients, in the literature, there are fewer reports describing bradycardia in EGPA patients than those describing tachycardia. A 50-year-old woman with a history of childhood-onset asthma. At age 28, she was diagnosed with eosinophilic gastroenteritis without the diagnosis of EGPA and was started on a systemic steroid and had maintenance daily dose of 2.5 mg after gradually tapered. She had experiencing dizziness and palpitations 2 weeks after discontinuation of the steroid treatment. At emergency visit, electrocardiography revealed an advanced atrioventricular block of 3:1 or less. Forty-eight minutes after the start of electrocardiography, only a P wave was observed and cardiac arrest occurred for 9 s and temporary emergency pacing was performed immediately. She was diagnosed as EGPA presenting leukocyte count, 16,500/µL, 42.8% of which were eosinophils and sinusitis in computed-tomography. She could be survival by treatment of steroid, following the patient to withdraw from an external pacemaker. She received prednisolone of 60 mg, intravenous cyclophosphamide and intravenous immunoglobulin. She had relapsed presenting peripheral eosinophilia, abdominal and numbness in the toes of the left leg pain, but not arrythmia after tapered of prednisolone. Following additional steroid pulse, she had an increase of prednisolone and continued by intravenous cyclophosphamide, intravenous immunoglobulin and started mepolizumab. We presented a severe case of EGPA presenting an advanced atrioventricular block into cardiac arrest.

Comparison of hepatic responses to glucose perturbation between healthy and obese mice based on the edge type of network structures.

Interactions between various molecular species in biological phenomena give rise to numerous networks. The investigation of these networks, including their statistical and biochemical interactions, supports a deeper understanding of biological phenomena. The clustering of nodes associated with molecular species and enrichment analysis is frequently applied to examine the biological significance of such network structures. However, these methods focus on delineating the function of a node. As such, in-depth investigations of the edges, which are the connections between the nodes, are rarely explored. In the current study, we aimed to investigate the functions of the edges rather than the nodes. To accomplish this, for each network, we categorized the edges and defined the edge type based on their biological annotations. Subsequently, we used the edge type to compare the network structures of the metabolome and transcriptome in the livers of healthy (wild-type) and obese (ob/ob) mice following oral glucose administration (OGTT). The findings demonstrate that the edge type can facilitate the characterization of the state of a network structure, thereby reducing the information available through datasets containing the OGTT response in the metabolome and transcriptome.

Rapid and Selective Photo-degradation of Polymers: Design of an Alternating Copolymer with an o-Nitrobenzyl Ether Pendant.

The development of polymers with on-demand degradability is required to alleviate the current global issues on polymer-waste pollution. Therefore, we designed a vinyl ether monomer with an o-nitrobenzyl (oNBn) group as a photo-deprotectable pendant (oNBnVE) and synthesized an alternating copolymer with an oNBn-capped acetal backbone via cationic copolymerization with p-tolualdehyde (pMeBzA). The resultant alternating copolymer could be rapidly degraded into lower-molecular-weight compounds upon simple exposure to UV irradiation without any reactants or catalysts, while it was sufficiently stable toward heat and ambient light. This degradation proceeds via cleavage of the hemiacetal structure generated upon photo-deprotection of the oNBn pendant. The oNBn-peculiar degradability allowed the exclusive photo-degradation of the oNBnVE/pMeBzA segments in a diblock copolymer composed of oNBnVE/pMeBzA and benzyl vinyl ether (BnVE)/pMeBzA segments.

In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states.

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

Multi-omics-based label-free metabolic flux inference reveals obesity-associated dysregulatory mechanisms in liver glucose metabolism.

Glucose homeostasis is maintained by modulation of metabolic flux. Enzymes and metabolites regulate the involved metabolic pathways. Dysregulation of glucose homeostasis is a pathological event in obesity. Analyzing metabolic pathways and the mechanisms contributing to obesity-associated dysregulation in vivo is challenging. Here, we introduce OMELET: Omics-Based Metabolic Flux Estimation without Labeling for Extended Trans-omic Analysis. OMELET uses metabolomic, proteomic, and transcriptomic data to identify relative changes in metabolic flux, and to calculate contributions of metabolites, enzymes, and transcripts to the changes in metabolic flux. By evaluating the livers of fasting ob/ob mice, we found that increased metabolic flux through gluconeogenesis resulted primarily from increased transcripts, whereas that through the pyruvate cycle resulted from both increased transcripts and changes in substrates of metabolic enzymes. With OMELET, we identified mechanisms underlying the obesity-associated dysregulation of metabolic flux in the liver.

Evaluation of the QIAstat-Dx Respiratory SARS-CoV-2 panel, a rapid multiplex PCR method for the diagnosis of COVID-19.

INTRODUCTION: Rapid, simple, and accurate methods are required to diagnose coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to evaluate the performance of the QIAstat-Dx Respiratory SARS-CoV-2 Panel (QIAstat-SARS-CoV-2), a rapid multiplex PCR assay for SARS-CoV-2 detection. METHODS: Nasopharyngeal swabs (NPS) that were obtained from patients with COVID-19 who were diagnosed at the National Center for Global Health and Medicine were used in this study. When the NPS samples were found to be negative for SARS-CoV-2 after treatment, they were used as negative samples. We evaluated the performance of the QIAstat-SARS-CoV-2 comparing SARS-CoV-2 detection with the National Institute of Infectious Diseases in Japan-recommended real-time polymerase chain reaction (RT-PCR) method (NIID-RT-PCR). RESULTS: In total, 45 NPS samples were analyzed. The proportion of overall agreement between QIAstat-SARS-CoV-2 and NIID-RT-PCR on 45 samples was 91.0% with a sensitivity of 84.0% (21/25), specificity at 100% (20/20), negative predictive value at 83.3% (20/24), and positive predictive value at 100% (21/21). There were no patients with co-infections with pathogens other than SARS-CoV-2. CONCLUSIONS: QIAstat-SARS-CoV-2 showed a high agreement in comparison with the NIID-RT-PCR for the detection of SARS-CoV-2. The QIAstat-SARS-CoV-2 also provided a rapid and accurate diagnosis for COVID-19, even when the concurrent detection of other respiratory pathogens was desired, and therefore, has the potential to direct appropriate therapy and infection control precautions.

Four features of temporal patterns characterize similarity among individuals and molecules by glucose ingestion in humans.

Oral glucose ingestion induces systemic changes of many blood metabolites related not only to glucose, but also other metabolites such as amino acids and lipids through many blood hormones. However, the detailed temporal changes in the concentrations of comprehensive metabolites and hormones over a long time by oral glucose ingestion are uncharacterized. We measured 83 metabolites and 7 hormones in 20 healthy human subjects in response to glucose ingestion. We characterized temporal patterns of blood molecules by four features: (i) the decomposability into "amplitude" and "rate" components, (ii) the similarity of temporal patterns among individuals, (iii) the relation of molecules over time among individuals, and (iv) the similarity of temporal patterns among molecules. Glucose and glucose metabolism-related hormones indicated a rapid increase, and citrulline and lipids, which indicated a rapid decrease, returned to fasting levels faster than amino acids. Compared to glucose metabolism-related molecules and lipids, amino acids showed similar temporal patterns among individuals. The four features of temporal patterns of blood molecules by oral glucose ingestion characterize the differences among individuals and among molecules.

High-frequency identification of monetary policy shocks in Japan.

We identify monetary policy shocks in Japan during the unconventional monetary policy period using high-frequency data for interest rate futures. Following the empirical strategy of Gürkaynak et al. (Int J Cent Bank 1: 55-93, 2005), we conduct an event-study analysis to estimate the effects of the monetary policy surprises on asset prices around the timing of policy announcements made by the Bank of Japan between 1999 and 2020. We find that a monetary policy shock can be described by two factors that have statistically significant effects on the financial market. A surprise monetary tightening has negative effects on stock returns and positive effects on government bond yields, even in the low-interest environment. We also find that the responses of the longer term yields tend to be larger than those of the shorter term yields. The response is the largest for the 10-year government bond yield, which has, in the last 2 decades, been effectively targeted by the Bank of Japan. This finding contrasts with those of previous studies of the conventional monetary policy period, in which responses are larger for the shorter term yields.

An extensive and dynamic trans-omic network illustrating prominent regulatory mechanisms in response to insulin in the liver.

An effective combination of multi-omic datasets can enhance our understanding of complex biological phenomena. To build a context-dependent network with multiple omic layers, i.e., a trans-omic network, we perform phosphoproteomics, transcriptomics, proteomics, and metabolomics of murine liver for 4 h after insulin administration and integrate the resulting time series. Structural characteristics and dynamic nature of the network are analyzed to elucidate the impact of insulin. Early and prominent changes in protein phosphorylation and persistent and asynchronous changes in mRNA and protein levels through non-transcriptional mechanisms indicate enhanced crosstalk between phosphorylation-mediated signaling and protein expression regulation. Metabolic response shows different temporal regulation with transient increases at early time points across categories and enhanced response in the amino acid and nucleotide categories at later time points as a result of process convergence. This extensive and dynamic view of the trans-omic network elucidates prominent regulatory mechanisms that drive insulin responses through intricate interlayer coordination.

Trans-omic analysis reveals obesity-associated dysregulation of inter-organ metabolic cycles between the liver and skeletal muscle.

Systemic metabolic homeostasis is regulated by inter-organ metabolic cycles involving multiple organs. Obesity impairs inter-organ metabolic cycles, resulting in metabolic diseases. The systemic landscape of dysregulated inter-organ metabolic cycles in obesity has yet to be explored. Here, we measured the transcriptome, proteome, and metabolome in the liver and skeletal muscle and the metabolome in blood of fasted wild-type and leptin-deficient obese (ob/ob) mice, identifying components with differential abundance and differential regulation in ob/ob mice. By constructing and evaluating the trans-omic network controlling the differences in metabolic reactions between fasted wild-type and ob/ob mice, we provided potential mechanisms of the obesity-associated dysfunctions of metabolic cycles between liver and skeletal muscle involving glucose-alanine, glucose-lactate, and ketone bodies. Our study revealed obesity-associated systemic pathological mechanisms of dysfunction of inter-organ metabolic cycles.

Metal-Catalyzed Switching Degradation of Vinyl Polymers via Introduction of an "In-Chain" Carbon-Halogen Bond as the Trigger.

In this work, we achieved switching degradation of vinyl polymers made of a carbon-carbon bonded backbone. Crucial in this strategy was a small feed of methyl α-chloroacrylate (MCA) as the comonomer in radical polymerization of methyl methacrylate (MMA) so that the carbon-halogen bonds were introduced as the triggers for degradation. The "in-chain" trigger was activated by a one-electron redox metal catalyst as the chemical stimulus to generate the carbon-centered radical species, and subsequently, the neighboring carbon-carbon bond was cleaved via an electron transfer of the radical species giving the terminal olefin. Particularly, an iron complex (FeCl2) in conjunction with tributylamine (n-Bu3N) was effective as the chemical stimulus to allow the switching degradation, where the molecular weight was gradually decreased over time. The switching feature was confirmed by some control experiments.

Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity.

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme-encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.

A confocal Raman microscopic visualization of small penetrants in cellulose acetate using a deuterium-labeling technique.

The purpose of the present study was to visualize the sorption dynamics of small compounds, such as propylene glycol (PG) in cellulose acetate (CA) film, by deuterium (d) labeling-aided confocal Raman spectroscopy (CRM). Substitution of hydrogen atoms in the target molecule with deuterium caused a marked shift of C-H bond-related Raman bands to low wavenumbers, while the number of deuterium did not affect the magnitude of the shift. Raman bands derived from the stretching vibration of C-H near 2900 cm-1 for PG and ethanol were shifted to approximately 2100 cm-1 for PG-d6 and ethanol-d5 in the silent region of the CA Raman spectrum. When PG-d6 was dissolved in glycerol triacetate (GTA), the observed Raman intensity ratio at 2123 cm-1 of PG-d6 against 1739 cm-1 of GTA (C=O bond-related) showed a linear relationship between the molar and intensity ratios, indicating that the observed Raman intensity can be used for quantitative assay of the target in polymer film. The depth profiling experiments by CRM revealed that the distribution (or sorption) of PG-d6 in CA film was successfully visualized as a function of Raman band at the characteristic 2123 cm-1 intensity ratio.

[A case of gastrointestinal stromal tumor of the duodenum with ruptured liver metastasis during administration of imatinib].

A fifty-year-old man with a liver metastasis of a duodenal gastrointestinal stromal tumor (GIST) previously treated with imatinib. Thirty-three months following initiation of the therapy, he visited the emergency room of our hospital presenting with an upper abdominal pain. Dynamic CT scan revealed a ruptured liver metastasis of duodenal GIST. We used transcatheter arterial embolization to stop the bleeding. Due to the rarity of this condition, we herein report this case with an article review.