Laser astrophysics experiment on the amplification of magnetic fields by shock-induced interfacial instabilities.

Laser experiments are becoming established as tools for astronomical research that complement observations and theoretical modeling. Localized strong magnetic fields have been observed at a shock front of supernova explosions. Experimental confirmation and identification of the physical mechanism for this observation are of great importance in understanding the evolution of the interstellar medium. However, it has been challenging to treat the interaction between hydrodynamic instabilities and an ambient magnetic field in the laboratory. Here, we developed an experimental platform to examine magnetized Richtmyer-Meshkov instability (RMI). The measured growth velocity was consistent with the linear theory, and the magnetic-field amplification was correlated with RMI growth. Our experiment validated the turbulent amplification of magnetic fields associated with the shock-induced interfacial instability in astrophysical conditions. Experimental elucidation of fundamental processes in magnetized plasmas is generally essential in various situations such as fusion plasmas and planetary sciences.

Petapascal Pressure Driven by Fast Isochoric Heating with a Multipicosecond Intense Laser Pulse.

Fast isochoric laser heating is a scheme to heat matter with a relativistic intensity (>10^{18} W/cm^{2}) laser pulse for producing an ultrahigh-energy-density (UHED) state. We have demonstrated an efficient fast isochoric heating of a compressed dense plasma core with a multipicosecond kilojoule-class petawatt laser and an assistance of externally applied kilotesla magnetic fields for guiding fast electrons to the dense plasma. A UHED state of 2.2 PPa is achieved experimentally with 4.6 kJ of total laser energy that is one order of magnitude lower than the energy used in the conventional implosion scheme. A two-dimensional particle-in-cell simulation confirmed that diffusive heating from a laser-plasma interaction zone to the dense plasma plays an essential role to the efficient creation of the UHED state.

Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity.

SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing.

Magnetized fast isochoric laser heating for efficient creation of ultra-high-energy-density states.

Fast isochoric heating of a pre-compressed plasma core with a high-intensity short-pulse laser is an attractive and alternative approach to create ultra-high-energy-density states like those found in inertial confinement fusion (ICF) ignition sparks. Laser-produced relativistic electron beam (REB) deposits a part of kinetic energy in the core, and then the heated region becomes the hot spark to trigger the ignition. However, due to the inherent large angular spread of the produced REB, only a small portion of the REB collides with the core. Here, we demonstrate a factor-of-two enhancement of laser-to-core energy coupling with the magnetized fast isochoric heating. The method employs a magnetic field of hundreds of Tesla that is applied to the transport region from the REB generation zone to the core which results in guiding the REB along the magnetic field lines to the core. This scheme may provide more efficient energy coupling compared to the conventional ICF scheme.

Magnetohydrodynamics of laser-produced high-energy-density plasma in a strong external magnetic field.

Recent progress in the generation in the laboratory of a strong (>100-T) magnetic field enables us to investigate experimentally unexplored magnetohydrodynamics phenomena of a high-energy-density plasma, which an external magnetic field of 200-300 T notably affects due to anisotropic thermal conduction, even when the magnetic field pressure is much lower than the plasma pressure. The external magnetic field reduces electron thermal conduction across the external magnetic field lines because the Larmor radius of the thermal electrons in the external magnetic field is much shorter than the mean free path of the thermal electrons. The velocity of a thin polystyrene foil driven by intense laser beams in the strong external magnetic field is faster than that in the absence of the external magnetic field. Growth of sinusoidal corrugation imposed initially on the laser-driven polystyrene surface is enhanced by the external magnetic field because the plasma pressure distribution becomes nonuniform due to the external magnetic-field structure modulated by the perturbed plasma flow ablated from the corrugated surface.

Development of Compton X-ray spectrometer for high energy resolution single-shot high-flux hard X-ray spectroscopy.

Hard X-ray spectroscopy is an essential diagnostics used to understand physical processes that take place in high energy density plasmas produced by intense laser-plasma interactions. A bundle of hard X-ray detectors, of which the responses have different energy thresholds, is used as a conventional single-shot spectrometer for high-flux (>10(13) photons/shot) hard X-rays. However, high energy resolution (Δhv/hv < 0.1) is not achievable with a differential energy threshold (DET) X-ray spectrometer because its energy resolution is limited by energy differences between the response thresholds. Experimental demonstration of a Compton X-ray spectrometer has already been performed for obtaining higher energy resolution than that of DET spectrometers. In this paper, we describe design details of the Compton X-ray spectrometer, especially dependence of energy resolution and absolute response on photon-electron converter design and its background reduction scheme, and also its application to the laser-plasma interaction experiment. The developed spectrometer was used for spectroscopy of bremsstrahlung X-rays generated by intense laser-plasma interactions using a 200 µm thickness SiO2 converter. The X-ray spectrum obtained with the Compton X-ray spectrometer is consistent with that obtained with a DET X-ray spectrometer, furthermore higher certainly of a spectral intensity is obtained with the Compton X-ray spectrometer than that with the DET X-ray spectrometer in the photon energy range above 5 MeV.

Heating efficiency evaluation with mimicking plasma conditions of integrated fast-ignition experiment.

A series of experiments were carried out to evaluate the energy-coupling efficiency from heating laser to a fuel core in the fast-ignition scheme of laser-driven inertial confinement fusion. Although the efficiency is determined by a wide variety of complex physics, from intense laser plasma interactions to the properties of high-energy density plasmas and the transport of relativistic electron beams (REB), here we simplify the physics by breaking down the efficiency into three measurable parameters: (i) energy conversion ratio from laser to REB, (ii) probability of collision between the REB and the fusion fuel core, and (iii) fraction of energy deposited in the fuel core from the REB. These three parameters were measured with the newly developed experimental platform designed for mimicking the plasma conditions of a realistic integrated fast-ignition experiment. The experimental results indicate that the high-energy tail of REB must be suppressed to heat the fuel core efficiently.

JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis.

AIM: Monoacyglycerol acyltransferases (MGATs) are known to play important roles in intestinal TG absorption. In contrast, the role of MGATs in the liver is still unclear. We investigated the effects of JTP-103237, a novel MGAT inhibitor, on hepatic MGAT activity and hepatic lipid metabolism. RESULTS: JTP-103237 reduced hepatic triglyceride content and hepatic MGAT activity in a high sucrose very low fat (HSVLF) diet induced fatty liver model. Interestingly, JTP-103237 suppressed not only triglyceride (TG) and diacylglycerol (DG) synthesis, but also fatty acid (FA) synthesis (de novo lipogenesis) in this model. JTP-103237 also suppressed lipogenesis-related gene expression, such as sterol regulatory element-binding protein 1-c. Moreover, JTP-103237 decreased plasma glucose levels and total cholesterol and reduced the accumulation of epididymal fats in HSVLF diet fed mice. CONCLUSION: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

Mechanism of action of hypoglycemic effects of an intestine-specific inhibitor of microsomal triglyceride transfer protein (MTP) in obese rats.

Diminished insulin sensitivity in the peripheral tissues and failure of pancreatic beta cells to secrete insulin are known major determinants of type 2 diabetes mellitus. JTT-130, an intestine-specific microsomal transfer protein inhibitor, has been shown to suppress high fat-induced obesity and ameliorate impaired glucose tolerance while enhancing glucagon-like peptide-1 (GLP-1) secretion. We investigated the effects of JTT-130 on glucose metabolism and elucidated the mechanism of action, direct effects on insulin sensitivity and glucose-stimulated insulin secretion in a high fat diet-induced obesity rat model. Male Sprague Dawley rats fed a high-fat diet were treated with a single administration of JTT-130. Glucose tolerance, hyperglycemic clamp and hyperinsulinemic-euglycemic testing were performed to assess effects on insulin sensitivity and glucose-stimulated insulin secretion, respectively. Plasma GLP-1 and tissue triglyceride content were also determined under the same conditions. A single administration of JTT-130 suppressed plasma glucose elevations after oral glucose loading and increased the disposition index while elevating GLP-1. JTT-130 also enhanced glucose-stimulated insulin secretion in hyperglycemic clamp tests, whereas increased insulin sensitivity was observed in hyperinsulinemic-euglycemic clamp tests. Single-dose administration of JTT-130 decreased lipid content in the liver and skeletal muscle. JTT-130 demonstrated acute and direct hypoglycemic effects by enhancing insulin secretion and/or insulin sensitivity.

Pharmacological effects of JTT-551, a novel protein tyrosine phosphatase 1B inhibitor, in diet-induced obesity mice.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin signaling as well as insulin signaling. JTT-551 is a new PTP1B inhibitor, which is reported to improve glucose metabolism by enhancement of insulin signaling. We have evaluated an antiobesity effect of JTT-551 using diet-induced obesity (DIO) mice. A single administration of JTT-551 was provided to DIO mice with or without leptin, and DIO mice were given food containing JTT-551 for six weeks. A single administration of JTT-551 with leptin treatment enhanced the food inhibition and the signal transducer and activator of transcription 3 (STAT3) phosphorylation in hypothalamus. Moreover, chronic administration of JTT-551 showed an antiobesity effect and an improvement of glucose and lipid metabolism in DIO mice. JTT-551 shows an antiobesity effect possibly by enhancement of leptin signaling and could be useful in the treatment of type 2 diabetes and obesity.

JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, improves hyperglycemia and dyslipidemia independent of suppression of food intake in diabetic rats.

We investigated the effects of JTT-130 on glucose and lipid metabolism independent of the suppression of feeding by comparing with pair-fed animals. Male Zucker diabetic fatty (ZDF) rats were divided into control, JTT-130 treatment, and pair-fed groups. The rats were fed with a regular powdered diet with or without JTT-130 as a food admixture for 6 weeks. We compared the effects on glucose and lipid metabolism in JTT-130 treatment group with those in pair-fed group. RESULTS. Hyperglycemia in ZDF rats was prevented in both JTT-130 treatment and pair-fed groups, but the prevention in pair-fed group became poor with time. Moreover, reduction in plasma cholesterol levels was observed only in JTT-130 treatment group. JTT-130 treatment group showed improved glucose tolerance at 5 weeks after treatment and significant elevation of portal glucagon-like peptide-1 (GLP-1) levels. The hepatic lipid content in JTT-130 treatment group was decreased as compared with pair-fed group. Furthermore, pancreatic protection effects, such as an increase in pancreatic weight and an elevation of insulin-positive area in islets, were observed after JTT-130 treatment. CONCLUSIONS. JTT-130 improves hyperglycemia and dyslipidemia via a mechanism independent of suppression of food intake, which is ascribed to an enhancement of GLP-1 secretion and a reduction of lipotoxicity.

Combination therapy of an intestine-specific inhibitor of microsomal triglyceride transfer protein and peroxisome proliferator-activated receptor γ agonist in diabetic rat.

We investigated effects on glucose and lipid metabolism in combination of JTT-130, a novel intestine-specific microsomal triglyceride transfer protein (MTP) inhibitor, and pioglitazone, peroxisome proliferator-activated receptor (PPAR) γ agonist. Male Zucker diabetic fatty rats were divided into 4 groups: control group, JTT-130 treatment group, pioglitazone treatment group, and combination group. The Zucker diabetic fatty rats were fed a regular powdered diet with JTT-130 and/or pioglitazone as a food admixture for 6 weeks. Effects on glucose and lipid metabolism were compared mainly between JTT-130 treatment group and combination group. JTT-130 treatment showed good glycemic control, while the plasma glucose and glycated hemoglobin levels in combination group were significantly decreased as compared with those JTT-130 treatment group. The reduction in the plasma triglyceride and free fatty acid levels in combination group was higher than that in JTT-130 treatment group, and glucose utilization was significantly elevated in adipose tissues. In Zucker diabetic fatty rats, combination treatment of JTT-130 and pioglitazone showed better glycemic control and a strong hypolipidemic action with an enhancement of insulin sensitivity. Combination therapy of MTP inhibitor and PPAR γ agonist might be more useful in the treatment of type 2 diabetes accompanied with obesity and insulin resistance.

Genomic structure and 5'-flanking sequences of rat N-acetylglucosaminyltransferase I gene and regulatory role of its transcriptional diversity.

It has been known that mouse, rat, and human N-acetylglucosaminyltransferase I (GnT-I) genes produce at least two transcripts, which differ in their 5'-untranslated region (5'-UTR) length, and the longer transcript is preferentially expressed in brains. However, the physiological meaning of this brain-specific expression pattern was unknown. We cloned the rat GnT-I gene and analyzed its structure. It consisted of five exons, and four of them coded only 5'-UTRs. A putative NF-kappaB binding site was found in the 5'-flanking sequence for the transcript that was previously shown to be induced by inflammation. The unusually long 5'-UTR of the major GnT-I transcript in rat brain was shown to inhibit protein production from the following coding sequence in COS7 cells. Comparison of the GnT-I protein/mRNA ratio in rat brain and liver showed that GnT-I mRNA in the brain was translated 3.8-times less efficiently than in the liver. Implications are discussed of these results in regulation of GnT-I expression in rat brain.