Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates ...energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.
Highlights • ATP administration to cultured neurons killed them via mitochondrial dysfunction. • Levels of ATP-induced neuronal death depended on expression levels of P2X7 receptor. • ATP-induced ...neuronal death was exacerbated by co-cultured astrocytes.
Purpose
We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in ...gastric cancer patients with peritoneal carcinomatosis (PC).
Methods
Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m
2
) on days 1–14 every 4 weeks.
Results
In the phase I part (
n
= 12), each cohort received escalating doses of docetaxel (35–50 mg/m
2
); the MTD was determined to be 50 mg/m
2
and the RD was determined to be 45 mg/m
2
. Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (
n
= 27), the median number of courses was 4 (range 2–11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53–87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %).
Conclusion
IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC.
A novel platform for transient photodetector component screening has been developed whereby an optical fiber tip serves as the counter electrode when placed in a variety of dielectric media, ...connected to a photoresponsive working electrode. The soft processing conditions allow for ubiquitous photodetection for organic and biological systems.
Beam test performance of the SKIROC2 ASIC Amjad, M.S.; Anduze, M.; Augustin, J.-E. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2015, Letnik:
778
Journal Article
Recenzirano
Beam tests of the first layers of CALICE silicon tungsten ECAL technological prototype were performed in April and July 2012 using 1–6GeV electron beam at DESY. This paper presents an analysis of the ...SKIROC2 readout ASIC performance under test beam conditions.
Angular dependence of Gilbert's damping constant alpha for Ni-Fe(001) single-crystal thin films were investigated by employing Q-band (35 GHz) and X-band (9 GHz) ferromagnetic resonance analysis in ...terms of the specimen's crystal structure. The alpha for 10-nm-thick specimen had constant values of 0.006, which were estimated by the Q-band ferromagnetic resonance (FMR) spectra, when the spectra were measured with changing external field directions in the film plane and out of plane. The alpha for the Ni-Fe specimens did not depend on the crystal directions. The alpha values estimated by X-band FMR spectra were in good agreement with those by Q-band FMR spectra, when the magnetization of the specimens was saturated at the X-band resonance field. The alpha values were overestimated, when the magnetization was not saturated and the specimens had multidomain structures at the resonance field.
Four rhodopsins, bacteriorhodopsin (bR), halorhodopsin (hR), sensory rhodopsin (sR) and phoborhodopsin (pR) exist in archaeal membranes. bR and hR work as a light-driven ion pump. sR and pR work as a ...photo-sensor of phototaxis, and form signaling complexes in membranes with their respective cognate transducer proteins HtrI (with sR) and HtrII (with pR), through which light signals are transmitted to the cytoplasm. What is the determining factor(s) of the specific binding to form the complex? Binding of the wild-type or mutated rhodopsins with HtrII was measured by isothermal titration calorimetric analysis (ITC). bR and hR could not bind with HtrII. On the other hand, sR could bind to HtrII, although the dissociation constant (
K
D) was about 100 times larger than that of pR. An X-ray crystallographic structure of the pR/HtrII complex revealed formation of two specific hydrogen bonds whose pairs are Tyr199
pR/Asn74
HtrII and Thr189
pR/Glu43
HtrII/Ser62
HtrII. To investigate the importance of these hydrogen bonds, the
K
D value for the binding of various mutants of bR, hR, sR and pR with HtrII was estimated by ITC. The
K
D value of T189V
pR/Y199F
pR, double mutant/HtrII complex, was about 100-fold larger than that of the wild-type pR, whose
K
D value was 0.16
μM. On the other hand, bR and hR double mutants, P200T
bR/V210Y
bR and P240T
hR/F250Y
hR, were able to bind with HtrII. The
K
D value of these complexes was estimated to be 60.1(±10.7)
μM for bR and to be 29.1(±6.1)
μM for hR, while the wild-type bR and hR did not bind with HtrII. We concluded that these two specific hydrogen bonds play important roles in the binding between the rhodopsins and transducer protein.
Archaeal rhodopsins possess a retinal molecule as their chromophores, and their light energy and light signal conversions are triggered by all-trans to 13-cis isomerization of the retinal ...chromophore. Relaxation through structural changes of the protein then leads to functional processes, proton pump in bacteriorhodopsin and transducer activation in sensory rhodopsins. In the present paper, low-temperature Fourier transform infrared spectroscopy is applied to phoborhodopsin from Natronobacterium pharaonis (ppR), a photoreceptor for the negative phototaxis of the bacteria, and infrared spectral changes before and after photoisomerization are compared with those of bacteriorhodopsin (BR) at 77 K. Spectral comparison of the C−C stretching vibrations of the retinal chromophore shows that chromophore conformation of the polyene chain is similar between ppR and BR. This fact implies that the unique chromophore−protein interaction in ppR, such as the blue-shifted absorption spectrum with vibrational fine structure, originates from both ends, the β-ionone ring and the Schiff base regions. In fact, less planer ring structure and stronger hydrogen bond of the Schiff base were suggested for ppR. Similar frequency changes upon photoisomerization are observed for the CN stretch of the retinal Schiff base and the stretch of the neighboring threonine side chain (Thr79 in ppR and Thr89 in BR), suggesting that photoisomerization in ppR is driven by the motion of the Schiff base like BR. Nevertheless, the structure of the K state after photoisomerization is different between ppR and BR. In BR, chromophore distortion is localized in the Schiff base region, as shown in its hydrogen out-of-plane vibrations. In contrast, more extended structural changes take place in ppR in view of chromophore distortion and protein structural changes. Such structure of the K intermediate of ppR is probably correlated with its high thermal stability. In fact, almost identical infrared spectra are obtained between 77 and 170 K in ppR. Unique chromophore−protein interaction and photoisomerization processes in ppR are discussed on the basis of the present infrared spectral comparison with BR.
Phoborhodopsin (pR or sensory rhodopsin II, sRII) is a photoreceptor of the negative phototaxis of Halobacterium salinarum, and pharaonis phoborhodopsin (ppR or pharaonis sensory rhodopsin II, psRII) ...is a corresponding protein of Natronobacterium pharaonis. The photocycle of ppR is essentially as follows: ppR(498) --> ppRK(approximately 540) --> ppRKL(512) --> ppRL(488) --> ppRM(390) --> ppRO(560) --> ppR (numbers in parenthesis denote the maximum absorbance). The photocycle is very similar to that of bacteriorhodopsin, but the rate of initial pigment recovery is about two-orders of magnitude slower. By low-temperature spectroscopy, two K-intermediates were found but the L intermediate was not detected. The lack of L indicates extraordinary stability of K at low temperature. ppRM is photoactive similar to M of bR. The ground state ppR contains only all-trans retinal whereas ppRM and ppRO contain 13-cis and all-trans, respectively. ppR has the ability of light-induced proton transport from the inside to the outside. Proton uptake occurs at the formation of ppRO and the release at its decay. ppR associates with its transducer and this complex transmits a signal to the cytoplasm. The proton transport ability is lost when the complex forms, but the proton uptake and release still occur, suggesting that the proton movement is non-electrogenic (release and uptake occur from the same side). The stoichiometry of the complex between ppR and the transducer is 1 : 1. ppR or pR has absorption maximum at approximately 500 nm, which is blue-shifted from those of other archaeal rhodopsins. The molecular mechanism of this color regulation is not yet solved.
PDF
