Direct angiotensin AT2 receptor stimulation using a novel AT2 receptor agonist, compound 21, evokes neuroprotection in conscious hypertensive rats

Background: In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents. Methods and Results: Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury. Conclusion: These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development

Parallel-propagating Fluctuations at Proton-kinetic Scales in the Solar Wind are Dominated by Kinetic Instabilities

We use magnetic helicity to characterise solar wind fluctuations at proton-kinetic scales from Wind observations. For the first time, we separate the contributions to helicity from fluctuations propagating at angles quasi-parallel and oblique to the local mean magnetic field, $\mathbf{B}_0$. We find that the helicity of quasi-parallel fluctuations is consistent with Alfv\'en-ion cyclotron and fast magnetosonic-whistler modes driven by proton temperature anisotropy instabilities and the presence of a relative drift between $\alpha$-particles and protons. We also find that the helicity of oblique fluctuations has little dependence on proton temperature anisotropy and is consistent with fluctuations from the anisotropic turbulent cascade. Our results show that parallel-propagating fluctuations at proton-kinetic scales in the solar wind are dominated by proton temperature anisotropy instabilities and not the turbulent cascade. We also provide evidence that the behaviour of fluctuations at these scales is independent of the origin and macroscopic properties of the solar wind.Comment: Accepted for publication in ApJL. 6 Pages, 3 figures, 1 tabl

Explicit L2L^2 bounds for the Riemann ζ\zeta function

Bounds on the tails of the zeta function $\zeta$, and in particular explicit bounds, are needed for applications, notably for integrals involving $\zeta$ on vertical lines or other paths going to infinity. An explicit version of the traditional `convexity bound' has long been known (Backlund 1918). To do better, one must either provide explicit versions of subconvexity bounds, or give explicit bounds on means of $\zeta$. Here we take the second road, bounding weighted $L^2$ norms of tails of $\zeta$. Two approaches are followed, each giving the better result on a different range. One of them is inspired by the proof of the standard mean value theorem for Dirichlet polynomials (Montgomery 1971). The main technical idea is the use of a carefully chosen smooth approximation to $1_{\lbrack 0,1\rbrack}$ so as to eliminate off-diagonal terms. The second approach, superior for large $T$, is based on classical lines, starting with an approximation to $\zeta$ via Euler-Maclaurin. Both bounds give main terms of the correct order for $0<\sigma\leq 1$ and are strong enough to be of practical use in giving precise values for integrals when combined with (rigorous) numerical integration. We also present bounds for the $L^{2}$ norm of $\zeta$ in $[1,T]$ for $0\leq\sigma\leq 1$.Comment: 44 pages; v6: corrections, improvements and clarifications, added reference

Interaction of laser generated ultrasonic waves with wedge-shaped samples

Wedge-shaped samples can be used as a model of acoustic interactions with samples ranging from ocean wedges, to angled defects such as rolling contact fatigue, to thickness measurements of samples with non-parallel faces. We present work on laser generated ultrasonic waves on metal samples; one can measure the dominant Rayleigh-wave mode, but longitudinal and shear waves are also generated. We present calculations, models, and measurements giving the dependence of the arrival times and amplitudes of these modes on the wedge apex angle and the separation of generation and detection points, and hence give a measure of the wedge characteristics

Short Communication DIRECT IDENTIFICATION OF CYTOCHROME P450 ISOZYMES BY MATRIX-ASSISTED LASER DESORPTION/IONIZATION TIME OF FLIGHT-BASED PROTEOMIC APPROACH

ABSTRACT: The main targets of our investigation were cytochrome P450 isozymes (P450), the key enzymes of the hepatic drug-metabolizing system. Current research approaches to the identification of individual P450 forms include specific P450 inhibitors or substrates, antibody-based identification, and mRNA-based expression profiling. All of these approaches suffer from one common disadvantage-they all are indirect methods. On the other hand, current developments in mass spectrometry provide a direct and reliable approach to protein identification with sensitivity in the femtomole or low picomole range. In this study we have used high-accuracy, matrix-assisted laser desorption/ionization time of flight (MALDI TOF)-based peptide mapping to perform direct identification of distinct P450 isozymes in various rat and rabbit liver microsomes. For the first time, the P450 isozyme composition of clofibrate-induced rat and phenobarbital-induced rabbit liver microsomes was determined by peptide mass fingerprinting (PMF). Application of MALDI TOF-based PMF allows differential identification of such highly homologous P450s as CYP2B1 and CYP2B2. We have found that CYP2A10 previously reported only in rabbit olfactory and respiratory nasal mucosa is present in phenobarbital (PB)-induced rabbit liver microsomes. Two other rabbit P450s, earlier identified only by screening a cDNA library, were found to be present in PB-induced rabbit liver microsomes. In summary, direct identification of P450s by proteomic technique offers advantages over other methods with regard to identification of distinct P450 isozymes and should become a standard approach for characterizing microsomes. Cytochrome P450 isozymes (P450) are the key enzymes of the hepatic drug-metabolizing system. Eukaryotic P450s are membrane proteins that are expressed in varying amounts, and many forms differ very little in their amino acid sequence and catalytic properties. Currently the number of sequenced and named distinct P450s exceeds 1925 (dnelson. utmem.edu/CytochromeP450.html). Since individual P450 isozymes exhibit a broad, often overlapping substrate specificity, knowledge of the P450 composition in a particular type of microsomes is critical in predicting drug/substrate interactions and formation of reactive intermediates. Current research approaches to the identification of individual P450 forms include: specific P450 inhibitors or substrates On the other hand, tryptic peptide mass fingerprinting (PMF) in conjunction with MALDI TOF mass spectrometry has become the main analytical tool in protein identification due to its ability to analyze picomole quantities of gel-or HPLC-separated proteins in short time In this study we have used MALDI TOF-based peptide mass fingerprinting to perform a detailed direct identification of distinct P450 isozymes in various rat and rabbit liver microsomes and have shown that identification of P450s by proteomic technique offers advantages over other methods with regard to identification of distinct P450 isozymes and should become a standard approach for characterizing microsomes

The Effect of Crystallization on the Pulsations of White Dwarf Stars

We consider the pulsational properties of white dwarf star models with temperatures appropriate for the ZZ Ceti instability strip and with masses large enough that they should be substantially crystallized. Our work is motivated by the existence of a potentially crystallized DAV, BPM 37093, and the expectation that digital surveys in progress will yield many more such massive pulsators. A crystallized core makes possible a new class of oscillations, the torsional modes, although we expect these modes to couple at most weakly to any motions in the fluid and therefore to remain unobservable. The p-modes should be affected at the level of a few percent in period, but are unlikely to be present with observable amplitudes in crystallizing white dwarfs any more than they are in the other ZZ Ceti's. Most relevant to the observed light variations in white dwarfs are the g-modes. We find that the kinetic energy of these modes is effectively excluded from the crystallized cores of our models. As increasing crystallization pushes these modes farther out from the center, the mean period spacing between radial overtones increases substantially with the crystallized mass fraction. In addition, the degree and structure of mode trapping is affected. The fact that some periods are strongly affected by changes in the crystallized mass fraction while others are not suggests that we may be able to disentangle the effects of crystallization from those due to different surface layer masses.Comment: 18 pages, 5 figures, accepted on 1999 July 2 for publication in the Astrophysical Journa

Solar Cycle Variation of 0.3-1.29 MeV/nucleon Heavy Ion Composition during Quiet Times near 1 AU in Solar Cycles 23 and 24

We report on the annual variation of quiet-time suprathermal ion composition for C through Fe using Advanced Composition Explorer (ACE)/Ultra-Low Energy Isotope Spectrometer (ULEIS) data over the energy range 0.3 MeV/nuc to 1.28 MeV/nuc from 1998 through 2019, covering solar cycle 23's rising phase through Solar Cycle 24's declining phase. Our findings are (1) quiet time suprathermal abundances resemble CIR-associated particles during solar minima; (2) quiet time suprathermals are M/Q fractionated in a manner that is consistent with M/Q fractionation in large gradual solar energetic particle events (GSEP) during solar maxima; and (3) variability within the quiet time suprathermal pool increases as a function of M/Q and is consistent with the analogous variability in GSEP events. From these observations, we infer that quiet time suprathermal ions are remnants of CIRs in solar minima and GSEP events in solar maxima. Coincident with these results, we also unexpectedly show that S behaves like a low FIP ion in the suprathermal regime and therefore drawn from low FIP solar sources.Comment: Accepted in Astrophysical Journal. 19 pages, 10 figures, 4 table