4,673 research outputs found
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 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
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, , can be defined so that modes with are unstable, while modes with
are stable. The perturbative analysis is complemented by several numerical
simulations to follow the time-dependent evolution of the system for different
values of . 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
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