The application of an orthostatic stress such as lower body negative pressure (LBNP) has been proposed to minimize the effects of weightlessness on the cardiovascular system and subsequently to reduce the cardiovascular deconditioning. The KAATSU training is a novel method to induce muscle strength and hypertrophy with blood pooling in capacitance vessels by restricting venous return. Here, we studied the hemodynamic, autonomic nervous and hormonal responses to the restriction of femoral blood flow by KAATSU in healthy male subjects, using the ultrasonography and impedance cardiography. The pressurization on both thighs induced pooling of blood into the legs with pressure-dependent reduction of femoral arterial blood flow. The application of 200 mmHg KAATSU significantly decreased left ventricular diastolic dimension (LVDd), cardiac output (CO) and diameter of inferior vena cava (IVC). Similarly, 200 mmHg KAATSU also decreased stroke volume (SV), which was almost equal to the value in standing. Heart rate (HR) and total peripheral resistance (TPR) increased in a similar manner to standing with slight change of mean blood pressure (mBP). High-frequency power (HF(RR)) decreased during both 200 mmHg KAATSU and standing, while low-frequency/high-frequency power (LF(RR)/HF(RR)) increased significantly. During KAATSU and standing, the concentration of noradrenaline (NA) and vasopressin (ADH) and plasma renin activity (PRA) increased. These results indicate that KAATSU in supine subjects reproduces the effects of standing on HR, SV, TPR, etc., thus stimulating an orthostatic stimulus. And, KAATSU training appears to be a useful method for potential countermeasure like LBNP against orthostatic intolerance after spaceflight.
We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CL(pro). A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CL(pro) motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1' site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC(50) or K(i) values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with K(i) values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CL(pro) may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1'-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site.
Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.
Pattern dynamics of directional crack propagation phenomena observed in drying process of starch-water mixture is investigated. To visualize the three-dimensional structure of the drying-fracture process two kinds of experiments are performed, i.e., resin solidification planing method and real-time measurement of water content distribution with MR instruments. A cross section with polygonal structure is visualized in both experiments. The depth dependency of cell size is measured. The phenomenological model for water transportation is also discussed.
We present experimental results of colony formation in bacteria as an example of pattern formation resulting from reproduction and movement in biological populations. The bacterium Bacillus subtilis is known to exhibit at least five distinct types of colony pattern, depending on the substrate softness and nutrient concentration: diffusion-limited aggregation (DLA), compact Eden-like, dense branching morphology (DBM), concentric ring-like, and disk. We established a morphological diagram of the colony patterns, and then examined and characterized both macroscopically and microscopically how the the colonies grow. There seem to be two kinds of bacterial cells – active and inactive – and the active form drives the colony interfaces outwards. The active cells may be clearly distinguished from the inactive ones as they form the characteristic fingernail-like structure at the tips of growing branches of the DBM colony. The concentric ring-like colony is formed as a consequence of repeated alternate migration and resting of the growing interface, the cycle time for which seems to be independent of the substrate softness and nutrient concentration. So far there have been several phenomenological models proposed to qualitatively explain or reproduce the patterns observed in bacterial colonies. A few of them are reviewed here, systematically and critically, in light of our experimental results.
Purposes: The KAATSU training is performed under the reduction of muscle blood flow by a speciallydesigned belt (KAATSU belt), which induces blood pooling in capacitance vessels by restricting venous return. However, no prior studies have examined the effects of KAATSU training on haemostasis. The purpose of the present study was to investigate acute effects of KAATSU training on haemostasis including fibrinolytic responses in healthy subjects. Methods: Two protocols have been performed. (1) 6 healthy men (mean age= 48 ± 5 yr) performed KAATSU (160 mmHg) of both thighs for 15 minutes and then KAASTU training combined with low-intensity leg and foot aerobic exercises for ~10 minutes in hypobaric chamber, which mimics 8000 feet in airflight. (2) Another 7 men (mean age=30 ± 4 yr) performed leg press exercises (30 % 1 RM) with and without KAATSU of both thighs 24 h after bed rest. Blood samples were taken at rest, immediately after KAATSU, and exercises with or without KAATSU, and after exercise. For the investigation of blood fibrinolysis, determinations of tissue-type plasminogen activator (tPA) activity or antigen, plasminogen activator inhibitor (PAI)-1 activity or antigen, fibrin degradation product (FDP) and D-dimer were used. Prothrombin time (PT) and platelet counts were also measured. Results: (1) In hypobaric chamber, KAATSU by itself significantly increased tPA activity, while PAI-1 activity was unchanged. Furthermore, immediately after the exercise, tPA activity increased significantly. (2) During the exercises combined with KAATSU 24 h after bed rest, tPA antigen significantly increased, compared with control exercises, but PAI-1 antigen was unchanged. In both cases, KAATSU training did not induce fibrin formation as assessed by fibrin D-dimer and FDP. Conclusions: This study indicates that potentially favorable changes occur in fibrinolytic factors after KAATSU and KAATSU training in healthy subjects.
The formation of concentric ring-like colonies by bacterial species Bacillus subtilis has been investigated, focusing our attention on the effect of local cell density upon the bacterial motility: (i) Neither any chemicals nor a pacemaker at the center of the ring takes part in the concentric ring formation. (ii) Phase entrainment between two colonies having different phase of concentric ring does not occur. (iii) From the measurement of lag-phase time when varying the initial cell density, the start of the first migration phase is found to depend on the cell density. (iv) When cutting the part of a colony which is behind a migration phase just after the start of migration, the migration phase becomes shorter. On the other hand, the following consolidation phase becomes longer. (v) By the replica-printing method, active bacteria move collectively from inside to outside of the outermost consolidation terrace. Our present experimental results are qualitatively consistent with the results of the other bacterial species P. mirabilis, although the individual cell motility is quite different from each other. The present results suggest that the essential factor of the change of the bacterial motility of B. subtilis during concetric ring formation is the local cell density.
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