Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.

IntroductionAcid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS).MethodsExperiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca(2+)](i), mitogen activated kinase (MAP kinase) expression, and cell death. [Ca(2+)](i) was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay.ResultsAcidic pH increased [Ca(2+)](i) and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca(2+)]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca(2+)](i), p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca(2+)](i) and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS.ConclusionsDecreased pH activates ASIC3 resulting in increased [Ca(2+)](i), and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca(2+)](i) and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage

A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin.

Extensive experience with isotransplants of 27 different tumours (leukaemias, sarcomata, carcinomata), all of strictly spontaneous origin in laboratory bred mice of low cancer strains CBA/Ht and WHT/Ht, has revealed no evidence of tumour immunogenicity. Of approximately 20,000 maintenance transplants, none failed and none regressed; of almost 10,000 carefully observed tumours arising from small or minimal inocula of tumour cells, none spontaneously regressed. The number of injected viable tumour cells required to give a 50% probability of successful transplantation (the TD50) ranged from approximately 1 cell to greater than 10,000 cells among the 27 tumours; high TD50 values, which were dramatically reduced by various procedures having no immunological significance, did not signify active "resistance" of the hosts. In the case of all of 7 randomly selected tumours, prior "immunization" of recipients with homologous lethally irradiated cells increased their tumour receptivity. Several experiments using various tumours failed to give evidence that immunity could be non-specifically induced or that a massive preponderance of lymphocytes from specifically sensitized mice could inhibit tumour transplantation or growth in vivo; no trace of "resistance" to tumour was adopted by isogeneic recipients of lymphocytes from regional nodes of tumour bearers. A limited review of the recent literature on tumour immunity shows that practically all the animal data presented in support of a general theory of tumour immunogenicity or to provide a basis for active clinical immunotherapy have been obtained from transplanted tumour systems which entail artefactual immunity associated with viral or chemical induction of the tumours or their allogeneic transplantation. It is suggested that isotransplants of spontaneously arising tumours are the only appropriate models of human cancer and that any genuine rapport between the animal laboratory and the clinic requires their exclusive use

The Dynamics of Radiative Shock Waves: Linear and Nonlinear Evolution

The stability properties of one-dimensional radiative shocks with a power-law cooling function of the form $\Lambda \propto \rho^2T^\alpha$ are the main subject of this work. The linear analysis originally presented by Chevalier & Imamura, is thoroughfully reviewed for several values of the cooling index $\alpha$ and higher overtone modes. Consistently with previous results, it is shown that the spectrum of the linear operator consists in a series of modes with increasing oscillation frequency. For each mode a critical value of the cooling index, $\alpha_\textrm{c}$, can be defined so that modes with $\alpha < \alpha_\textrm{c}$ are unstable, while modes with $\alpha > \alpha_\textrm{c}$ are stable. The perturbative analysis is complemented by several numerical simulations to follow the time-dependent evolution of the system for different values of $\alpha$. Particular attention is given to the comparison between numerical and analytical results (during the early phases of the evolution) and to the role played by different boundary conditions. It is shown that an appropriate treatment of the lower boundary yields results that closely follow the predicted linear behavior. During the nonlinear regime, the shock oscillations saturate at a finite amplitude and tend to a quasi-periodic cycle. The modes of oscillations during this phase do not necessarily coincide with those predicted by linear theory, but may be accounted for by mode-mode coupling.Comment: 33 pages, 12 figures, accepted for publication on the Astrophysical Journa

Benzoyl­dicarbon­yl(η5-inden­yl)ruthenium(II)

In the title mol­ecule, [Ru(C9H7)(C7H5O)(CO)2], the dihedral angle between the mean plane of the indene ring system and the phenyl ring is 86.28 (8)°. The crystal structure is stabilized by weak inter­molecular C—H⋯O and C—H⋯π(arene) inter­actions. The Ru—η5-cyclopentadienyl centroid bond length is 1.946 (11) 

A prospective observational study of on-treatment plasma homocysteine levels as a biomarker of toxicity, depression and vitamin supplementation lead-in time pre pemetrexed, in patients with non-small cell lung cancer and malignant mesothelioma

OBJECTIVES: Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity. MATERIAL AND METHODS: Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities. RESULTS: Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities. CONCLUSION: On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short

Luminosity- and morphology-dependent clustering of galaxies

How does the clustering of galaxies depend on their inner properties like morphological type and luminosity? We address this question in the mathematical framework of marked point processes and clarify the notion of luminosity and morphological segregation. A number of test quantities such as conditional mark-weighted two-point correlation functions are introduced. These descriptors allow for a scale-dependent analysis of luminosity and morphology segregation. Moreover, they break the degeneracy between an inhomogeneous fractal point set and actual present luminosity segregation. Using the Southern Sky Redshift Survey~2 (da Costa et al. 1998, SSRS2) we find both luminosity and morphological segregation at a high level of significance, confirming claims by previous works using these data (Benoist et al. 1996, Willmer et al. 1998). Specifically, the average luminosity and the fluctuations in the luminosity of pairs of galaxies are enhanced out to separations of 15Mpc/h. On scales smaller than 3Mpc/h the luminosities on galaxy pairs show a tight correlation. A comparison with the random-field model indicates that galaxy luminosities depend on the spatial distribution and galaxy-galaxy interactions. Early-type galaxies are also more strongly correlated, indicating morphological segregation. The galaxies in the PSCz catalog (Saunders et al. 2000) do not show significant luminosity segregation. This again illustrates that mainly early-type galaxies contribute to luminosity segregation. However, based on several independent investigations we show that the observed luminosity segregation can not be explained by the morphology-density relation alone.Comment: aastex, emulateapj5, 20 pages, 13 figures, several clarifying comments added, ApJ accepte

UBVRI observations of the flickering of RS Ophiuchi at Quiescence

We report observations of the flickering variability of the recurrent nova RS Oph at quiescence on the basis of simultaneous observations in 5 bands (UBVRI). RS Oph has flickering source with (U-B)_0=-0.62 \pm 0.07, (B-V)_0=0.15 \pm 0.10, (V-R)_0=0.25 \pm 0.05. We find for the flickering source a temperature T_fl = 9500 \pm 500 K, and luminosity L_fl = 50 - 150 L_sun (using a distance of d=1.6kpc). We also find that on a (U-B) vs (B-V) diagram the flickering of the symbiotic stars differs from that of the cataclysmic variables. The possible source of the flickering is discussed. The data are available upon request from the authors and on the web www.astro.bas.bg/~rz/RSOph.UBVRI.2010.MNRAS.tar.gz.Comment: 7 pages, MNRAS (accepted

Fingerprinting of chlorinated paraffins and their transformation products in plastic consumer products

Chlorinated paraffins (CPs) can be classified according to their length as short-chain (SC, C10-C13), medium-chain (MC, C14-C17) and long-chain (LC, C ≥ 18) CPs. Technical CP-mixtures can contain a wide range of carbon- (C-, nC = 10-30) and chlorine- (Cl-, nCl = 3-19) homologues. CPs are high-production volume chemicals (>106 t/y). They are used as flame-retardants, plasticizers and coolant fluids. Due to the persistence, bioaccumulation, long-range environmental transport potential and adverse effects, SCCPs are regulated as persistent organic pollutants (POPs) by the Stockholm Convention. Transformation of CPs can lead to the formation of unsaturated compounds such as chlorinated mono- (CO), di- (CdiO) and tri-olefins (CtriO). Such transformation reactions can occur at different stages of CP manipulation providing characteristic C-/Cl-homologue distributions. All this results in unique patterns that collectively create a fingerprint, which can be distinguished from CP-containing samples. Therefore, CP-fingerprinting can develop into a promising tool for future source apportionment studies and with it, the reduction of environmental burden of CPs and hazards to humans. Herein, CP-containing plastics were studied to establish fingerprints and develop this method. We analyzed four household items by reverse-phase liquid-chromatography coupled with a mass spectrometer with an atmospheric pressure chemical ionization source and an Orbitrap mass analyzer (RP-LC-APCI-Orbitrap-MS) operated at a resolution of 120000 (FWHM at m/z 200). MS-data of different CP-, CO-, CdiO- and CtriO-homologues were efficiently processed with an R-based automatic mass spectra evaluation routine (RASER). From the 16720 ions searched for, up to 4300 ions per sample were assigned to 340 C-/Cl-homologues of CPs and their transformation products. Specific fingerprints were deduced from the C-/Cl-homologues distributions, the carbon- (nC) and chlorine- (nCl) numbers and saturation degree. These fingerprints were compared with the ones obtained by a GC-ECNI-Orbitrap-MS method