Crystal structure of lipoate-protein ligase A from Escherichia coli : Determination of the lipoic acid-binding site

This research was originally published in Journal of Biological Chemistry. Kazuko Fujiwara, Sachiko Toma, Kazuko Okamura-Ikeda, Yutaro Motokawa, Atsushi Nakagawa and Hisaaki Taniguchi. Crystal structure of lipoate-protein ligase A from Escherichia coli : Determination of the lipoic acid-binding site. Journal of Biological Chemistry. 2005; 280, 33645-33651. © the American Society for Biochemistry and Molecular Biology

Simple of syntheses of marine alkaloid, (±)-helonin A, and its analogs

金沢大学大学院自然科学研究科生理活性物質科学金沢大学薬学

Immunization of Mice against Infection with Salmonella blegdam : Especially Protection of Mice from Typhoid Infection by Immunization with Living Rough Variants of Salmonella

It is generally known that immunization with killed bacilli has a protective effect on bacterienda. 11 But typhoid fever, paratyphoid fever and anthrax, which are also accompanied with bacierienda, have been considered to be exceptional cases. For anthrax effective immunity could not be introduced with killed vaccine, though Louis Pasteur1) invented a preventive inoculation method hi 1881, until recently low virulent living organism inoculations have been considered to be the only effectivemethod, as far as anthrax is concerned. Recently Cromartie, Watson, Bloom and others2) have proved why immunization with living bacilli is the only preventive measure for anthrax. Based on their findings, it is now possible to provide protection with vaccines containing no living organisms. Thus one of the exceptional cases has been removed, leaving mechanism of immunity of typhoid diseases as the remaining problem. In typhoid and paratyphoid fever, it is statistically known that preventive inoculation with killed bacilli has lowered morbidity and lethality. But the immunity resulting from this vaccination is not as strong and effective as in immunity after recovery Moreover its effectiveness is not completely supported, either experimentally or theoretically. This Subject has been studied at a high level in our country, particular), by Kobayashi and his collabora- tors3). According to their opinion, the protective power against typhoid and paratyphoid. infectioncan be established by vaccination with living bacilli, whether in smooth or in rough type, but not with killed vaccine. However, Hazato and his collaborators4) have reported that intravenous injectionsof killed bacilli have given satisfactory protection to mice against the infection of Salmonella enteritidis I , equal to those of living bacilli. Hosoya and others5) have recently stated that immunization with theirso-called T.T.T. or T.A.T. vaccine, which contains no living bacilli, has protective effect on infectionof Salmonella enteritidis of mice and Salmonella abortus equi of guinea-pigs. Ominaga6) has denied

Sex Differences in the Renal Function Decline of Patients with Type 2 Diabetes

Aims. We aimed to investigate the sex differences in the renal function decline among patients with type 2 diabetic mellitus (T2DM), focusing on the differences in the risk factors at early stage of renal dysfunction. Methods. A clinic-based retrospective longitudinal study (follow-up duration: 8.1±1.4 years) was conducted to assess the sex differences in the annual estimated glomerular filtration rate (eGFR) change in 344 (247 male and 97 female) Japanese T2DM patients. The sex differences in the risk factors of annual eGFR decline were subjected to linear regression analyses. Results. The mean annual eGFR change was -3.5±2.7%/year in females and -2.0±2.2%/year in males (P<0.001). Baseline retinopathy and proteinuria were significantly associated with a larger eGFR decline, irrespective of sex, while HbA1c and LDL-cholesterol levels were significantly associated with an eGFR decline in females only. Interactive effects were observed between sex and the HbA1c, LDL-cholesterol, retinopathy, or proteinuria levels on the annual eGFR decline. Conclusions. The increased susceptibility to poor metabolic control seemed to contribute to a higher risk of renal dysfunction in females with T2DM. Our study highlights the importance of aggressive therapeutic intervention to improve metabolic profiles at early stage, especially in females

Abnormally High Levels of Virus-Infected IFN-γ+CCR4+CD4+CD25+ T Cells in a Retrovirus-Associated Neuroinflammatory Disorder

BACKGROUND:Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with both HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic neuroinflammatory disease, and adult T-cell leukemia (ATL). The pathogenesis of HAM/TSP is known to be as follows: HTLV-1-infected T cells trigger a hyperimmune response leading to neuroinflammation. However, the HTLV-1-infected T cell subset that plays a major role in the accelerated immune response has not yet been identified. PRINCIPAL FINDINGS:Here, we demonstrate that CD4(+)CD25(+)CCR4(+) T cells are the predominant viral reservoir, and their levels are increased in HAM/TSP patients. While CCR4 is known to be selectively expressed on T helper type 2 (Th2), Th17, and regulatory T (Treg) cells in healthy individuals, we demonstrate that IFN-gamma production is extraordinarily increased and IL-4, IL-10, IL-17, and Foxp3 expression is decreased in the CD4(+)CD25(+)CCR4(+) T cells of HAM/TSP patients as compared to those in healthy individuals, and the alteration in function is specific to this cell subtype. Notably, the frequency of IFN-gamma-producing CD4(+)CD25(+)CCR4(+)Foxp3(-) T cells is dramatically increased in HAM/TSP patients, and this was found to be correlated with disease activity and severity. CONCLUSIONS:We have defined a unique T cell subset--IFN-gamma(+)CCR4(+)CD4(+)CD25(+) T cells--that is abnormally increased and functionally altered in this retrovirus-associated inflammatory disorder of the central nervous system

Exercise training reduces ventricular arrhythmias through restoring calcium handling and sympathetic tone in myocardial infarction mice

Exercise can improve morbidity and mortality in heart failure patients; however, the underlying mechanisms remain to be fully investigated. Thus, we investigated the effects of exercise on cardiac function and ventricular arrhythmias in myocardial infarction (MI) induced heart failure mice. Wild‐type male mice underwent sham‐operation or permanent left coronary artery ligation to induce MI. MI mice were divided into a sedentary (MI‐Sed) and two intervention groups: MI‐Ex (underwent 6‐week treadmill exercise training) and MI‐βb (oral bisoprolol treatment (1 mg/kg/d) without exercise). Cardiac function and structure were assessed by echocardiography and histology. Exercise capacity and cardiopulmonary function was accepted as oxygen consumption at peak exercise (peak VO2). Autonomic nervous system function and the incidence of spontaneous ventricular arrhythmia were evaluated via telemetry recording. mRNA and protein expressions in the left ventricle (LV) were investigated by real‐time PCR and Western blotting. There were no differences in survival rate, MI size, cardiac function and structure, while exercise training improved peak VO2. Compared with MI‐Sed, MI‐Ex, and MI‐βb showed decreased sympathetic tone and lower incidence of spontaneous ventricular arrhythmia. By Western blot, the hyperphosphorylation of CaMKII and RyR2 were restored by exercise and β‐blocker treatment. Furthermore, elevated expression of miR‐1 and decreased expression of its target protein PP2A were recovered by exercise and β‐blocker treatment. Continuous intensive exercise training can suppress ventricular arrhythmias in subacute to chronic phase of MI through restoring autonomic imbalance and impaired calcium handling, similarly to that for β‐blockers

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era