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

The Spin Periods and Rotational Profiles of Neutron Stars at Birth

We present results from an extensive set of one- and two-dimensional radiation-hydrodynamic simulations of the supernova core collapse, bounce, and postbounce phases, and focus on the protoneutron star (PNS) spin periods and rotational profiles as a function of initial iron core angular velocity, degree of differential rotation, and progenitor mass. For the models considered, we find a roughly linear mapping between initial iron core rotation rate and PNS spin. The results indicate that the magnitude of the precollapse iron core angular velocities is the single most important factor in determining the PNS spin. Differences in progenitor mass and degree of differential rotation lead only to small variations in the PNS rotational period and profile. Based on our calculated PNS spins, at ~ 200-300 milliseconds after bounce, and assuming angular momentum conservation, we estimate final neutron star rotation periods. We find periods of one millisecond and shorter for initial central iron core periods of below ~ 10 s. This is appreciably shorter than what previous studies have predicted and is in disagreement with current observational data from pulsar astronomy. After considering possible spindown mechanisms that could lead to longer periods we conclude that there is no mechanism that can robustly spin down a neutron star from ~ 1 ms periods to the "injection" periods of tens to hundreds of milliseconds observed for young pulsars. Our results indicate that, given current knowledge of the limitations of neutron star spindown mechanisms, precollapse iron cores must rotate with periods around 50-100 seconds to form neutron stars with periods generically near those inferred for the radio pulsar population.Comment: 31 pages, including 20 color figures. High-resolution figures available from the authors upon request. Accepted to Ap

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

Systemische Sklerose: Zielkriterien der Behandlung

Zusammenfassung: Die systemische Sklerose (SSc) ist eine Multisystemfibrose mit weltweitem Vorkommen und hoher Morbidität und Mortalität. Charakteristika der Erkrankung sind ausgedehnte Vaskulopathie, Entzündung, Autoimmunität und Fibrose. Therapieerfolge der letzten Jahre beinhalten im Wesentlichen ein besseres Management von Organkomplikationen. Bis heute gibt es jedoch keine zugelassene spezifische Therapie, die das Fortschreiten der Erkrankung verhindern oder auch nur verlangsamen kann. Konventionelle DMARDs ("disease-modifying antirheumatic drugs") haben keinen substanziellen Einfluss auf den Erkrankungsverlauf und verlängern das Gesamtüberleben nicht. Aufgrund molekularbiologischer Studien und verschiedener Tiermodelle konnten in den letzten Jahren Schlüsselmoleküle der Pathogenese von Fibrose und Vaskulopathie in SSc identifiziert werden. Vor diesem Hintergrund müssen nun Zielkriterien der Behandlung neu überdacht und definiert werden. In diesem Artikel werden mit Bezug auf pulmonal-arterielle Hypertonie, Lungenfibrose und Haut-/Systemfibrose aktuelle und künftige Therapiekonzepte, Ziele der Behandlung und Erfassung/Bewertung von Verlaufsparametern diskutier

A Holistic Scenario of Turbulent Molecular Cloud Evolution and Control of the Star Formation Efficiency. First Tests

We compile a holistic scenario for molecular cloud (MC) evolution and control of the star formation efficiency (SFE), and present a first set of numerical tests of it. A {\it lossy} compressible cascade can generate density fluctuations and further turbulence at small scales from large-scale motions, implying that the turbulence in MCs may originate from the compressions that form them. Below a {\it sonic} scale \ls, turbulence cannot induce any further subfragmentation, nor be a dominant support agent against gravity. Since progressively smaller density peaks contain progressively smaller fractions of the mass, we expect the SFE to decrease with decreasing \ls, at least when the cloud is globally supported by turbulence. Our numerical experiments confirm this prediction. We also find that the collapsed mass fraction in the simulations always saturates below 100% efficiency. This may be due to the decreased mean density of the leftover interclump medium, which in real clouds (not confined to a box) should then be more easily dispersed, marking the ``death'' of the cloud. We identify two different functional dependences (``modes'') of the SFE on \ls, which roughly correspond to globally supported and unsupported cases. Globally supported runs with most of the turbulent energy at the largest scales have similar SFEs to those of unsupported runs, providing numerical evidence of the dual role of turbulence, whereby large-scale turbulent modes induce collapse at smaller scales. We tentatively suggest that these modes may correspond to the clustered and isolated modes of star formation, although here they are seen to form part of a continuum rather than being separate modes. Finally, we compare with previous proposals that the relevant parameter is the energy injection scale.Comment: 6 pages, 3 figures. Uses emulateapj. Accepted in ApJ Letter

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

DualVAE: Controlling Colours of Generated and Real Images

Colour controlled image generation and manipulation are of interest to artists and graphic designers. Vector Quantised Variational AutoEncoders (VQ-VAEs) with autoregressive (AR) prior are able to produce high quality images, but lack an explicit representation mechanism to control colour attributes. We introduce DualVAE, a hybrid representation model that provides such control by learning disentangled representations for colour and geometry. The geometry is represented by an image intensity mapping that identifies structural features. The disentangled representation is obtained by two novel mechanisms: (i) a dual branch architecture that separates image colour attributes from geometric attributes, and (ii) a new ELBO that trains the combined colour and geometry representations. DualVAE can control the colour of generated images, and recolour existing images by transferring the colour latent representation obtained from an exemplar image. We demonstrate that DualVAE generates images with FID nearly two times better than VQ-GAN on a diverse collection of datasets, including animated faces, logos and artistic landscapes

Genetic variation associated with hypersensitivity to mercury

OBJECTIVES: Very little is known about mechanisms of idiosyncratic sensitivity to the damaging effects of mercury (Hg); however, there is likely a genetic component. The aim of the present study was to search for genetic variation in genes thought to be involved in Hg metabolism and transport in a group of individuals identified as having elevated Hg sensitivity compared to a normal control group. MATERIALS AND METHODS: Survivors of pink disease (PD; infantile acrodynia) are a population of clinically identifiable individuals who are Hg sensitive. In the present study, single nucleotide polymorphisms in genes thought to be involved in Hg transport and metabolism were compared across two groups: (i) PD survivors (n = 25); and (ii) age- and sex-matched healthy controls (n = 25). RESULTS: Analyses revealed significant differences between groups in genotype frequencies for rs662 in the gene encoding paraoxanase 1 (PON1) and rs1801131 in the gene encoding methylenetetrahydrofolate reductase (MTHFR). CONCLUSIONS: We have identified two genetic polymorphisms associated with increased sensitivity to Hg. Genetic variation in MTHFR and PON1 significantly differentiated a group formerly diagnosed with PD (a condition of Hg hypersensitivity) with age- and gender-matched healthy controls

3D simulations of RS Oph: from accretion to nova blast

RS Ophiuchi is a recurrent nova with a period of about 22 years, consisting of a wind accreting binary system with a white dwarf (WD) very close to the Chandrasekhar limit and a red giant star (RG). The system is considered a prime candidate to evolve into an SNIa. We present a 3D hydrodynamic simulation of the quiescent accretion and the subsequent explosive phase. The computed circumstellar mass distribution in the quiescent phase is highly structured with a mass enhancement in the orbital plane of about a factor of 2 as compared to the poleward directions. The simulated nova remnant evolves aspherically, propagating faster toward the poles. The shock velocities derived from the simulations are in agreement with those derived from observations. For v_RG = 20 km/s and for nearly isothermal flows, we derive a mass transfer rate to the WD of 10% of the mass loss of the RG. For an RG mass loss of 10^{-7} solar masses per year, we found the orbit of the system to decay by 3% per million years. With the derived mass transfer rate, multi-cycle nova models provide a qualitatively correct recurrence time, amplitude, and fastness of the nova. Our simulations provide, along with the observations and nova models, the third ingredient for a deeper understanding of the recurrent novae of the RS Oph type. In combination with recent multi-cycle nova models, our results suggests that the WD in RS Oph will increase in mass. Several speculative outcomes then seem plausible. The WD may reach the Chandrasekhar limit and explode as an SN Ia. Alternatively, the mass loss of the RG could result in a smaller Roche volume, a common envelope phase, and a narrow WD+WD system. Angular momentum loss due to graviational wave emission could trigger the merger of the two WDs and - perhaps - an SN Ia via the double degenerate scenario.Comment: Accepted by Astronomy & Astrophysics Letters, 4 pages, 5 figures; Version with high resolution figures and movie can be found at http://www.astro.phys.ethz.ch/staff/folini/private/research/rsoph/rsoph.htm