Inhibiting the inflammasome with MCC950 counteracts muscle pyroptosis and improves Duchenne muscular dystrophy

Background: Duchenne muscular dystrophy (DMD) is the most common inherited human myopathy. Typically, the secondary process involving severe inflammation and necrosis exacerbate disease progression. Previously, we reported that the NLRP3 inflammasome complex plays a crucial role in this disorder. Moreover, pyroptosis, a form of programmed necrotic cell death, is triggered by NLRP3 via gasdermin D (GSDMD). So far, pyroptosis has never been described either in healthy muscle or in dystrophic muscle. The aim of this study was to unravel the role of NLRP3 inflammasome in DMD and explore a potentially promising treatment with MCC950 that selectively inhibits NLRP3. Methods: Four‐week‐old mdx mice (n=6 per group) were orally treated for 2 months with MCC950 (mdx‐T), a highly potent, specific, small-molecule inhibitor of NLRP3, and compared with untreated (mdx) and wild-type (WT) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of DMD human myotubes. Results: After MCC950 treatment, mdx mice exhibited a significant reduction of inflammation, macrophage infiltration and oxidative stress (-20 to -65%, P<0.05 vs untreated mdx). Mdx‐T mice displayed considerably less myonecrosis (-54%, P<0.05 vs mdx) and fibrosis (-75%, P<0.01 vs mdx). Moreover, a more mature myofibre phenotype, characterized by larger-sized fibres and higher expression of mature myosin heavy chains 1 and 7 was observed. Mdx-T also exhibited enhanced force and resistance to fatigue (+20 to 60%, P<0.05 or less). These beneficial effects resulted from MCC950 inhibition of both active caspase-1 (-46%, P=0.075) and cleaved gasdermin D (N-GSDMD) (-42% in medium-sized-fibres, P<0.001). Finally, the anti-inflammatory action and the anti-pyroptotic effect of MCC950 were also recapitulated in DMD human myotubes. Conclusion: Specific inhibition of the NLRP3 inflammasome can significantly attenuate the dystrophic phenotype. A novel finding of this study is the overactivation of GSDMD, which is hampered by MCC950. This ultimately leads to less inflammation and pyroptosis and to a better muscle maturation and function. Targeting NLRP3 might lead to an effective therapeutic approach for a better management of DMD.Fund for Scientific Research de Bélgica (FNRS)-PDR/T.0026.2

Typhoid fever outbreak in the Democratic Republic of Congo: Case control and ecological study

During 2011 a large outbreak of typhoid fever affected an estimated 1430 people in Kikwit, Democratic Republic of Congo. The outbreak started in military camps in the city but then spread to the general population. This paper reports the results of an ecological analysis and a case-control study undertaken to examine water and other possible transmission pathways. Attack rates were determined for health areas and risk ratios were estimated with respect to spatial exposures. Approximately 15 months after the outbreak, demographic, environmental and exposure data were collected for 320 cases and 640 controls residing in the worst affected areas, using a structured interview questionnaire. Unadjusted and adjusted odds ratios were estimated. Complete data were available for 956 respondents. Residents of areas with water supplied via gravity on the mains network were at much greater risk of disease acquisition (risk ratio = 6.20, 95%CI 3.39-11.35) than residents of areas not supplied by this mains network. In the case control study, typhoid was found to be associated with ever using tap water from the municipal supply (OR = 4.29, 95% CI 2.20-8.38). Visible urine or faeces in the latrine was also associated with increased risk of typhoid and having chosen a water source because it is protected was negatively associated. Knowledge that washing hands can prevent typhoid fever, and stated habit of handwashing habits before cooking or after toileting was associated with increased risk of disease. However, observed associations between handwashing or plate-sharing with disease risk could very likely be due to recall bias. This outbreak of typhoid fever was strongly associated with drinking water from the municipal drinking water supply, based on the descriptive and analytic epidemiology and the finding of high levels of faecal contamination of drinking water. Future outbreaks of potentially waterborne disease need an integrated response that includes epidemiology and environmental microbiology during early stages of the outbreak

International Guillain-Barré Syndrome Outcome Study (IGOS): protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome in Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy with a highly variable clinical presentation, course, and outcome. The factors that determine the clinical variation of GBS are poorly understood which complicates the care and treatment of individual patients. The protocol of the ongoing International GBS Outcome Study (IGOS), a prospective, observational, multi-centre cohort study that aims to identify the clinical and biological determinants and predictors of disease onset, subtype, course and outcome of GBS is presented here. Patients fulfilling the diagnostic criteria for GBS, regardless of age, disease severity, variant forms, or treatment, can participate if included within two weeks after onset of weakness. Information about demography, preceding infections, clinical features, diagnostic findings, treatment, course and outcome is collected. In addition, cerebrospinal fluid and serial blood samples for serum and DNA is collected at standard time points. The original aim was to include at least 1000 patients with a follow-up of 1-3 years. Data are collected via a web-based data entry system and stored anonymously. IGOS started in May 2012 and by January 2017 included more than 1400 participants from 143 active centres in 19 countries across 5 continents. The IGOS data/biobank is available for research projects conducted by expertise groups focusing on specific topics including epidemiology, diagnostic criteria, clinimetrics, electrophysiology, antecedent events, antibodies, genetics, prognostic modelling, treatment effects and long-term outcome of GBS. The IGOS will help to standardize the international collection of data and biosamples for future research of GBS. ClinicalTrials.gov Identifier: NCT01582763

Radio Emission from the Composite Supernova Remnant G326.3-1.8 (MSH15-56)

High resolution radio observations of the composite supernova remnant (SNR) G326.3-1.8 or MSH 15-56 with the Australia Telescope Compact Array show details of both the shell and the bright plerion which is offset about 1/3 of the distance from the center of the SNR to the shell. The shell appears to be composed of thin filaments, typical of older shell SNRs. The central part of the elongated plerion is composed of a bundle of parallel ridges which bulge out at the ends and form a distinct ring structure on the northwestern end. The magnetic field with a strength of order 45 microGauss, is directed along the axis of the ridges but circles around the northwestern ring. This plerion is large and bright in the radio but is not detected in x-ray or optical wavelengths. There is, however, a faint hard x-ray feature closer to the shell outside the plerion. Perhaps if the supernova explosion left a rapidly moving magnetar with large energy input but initially rapid decay of both relativistic particles and magnetic field, the observed differences with wavelength could be explained.Comment: 15 pages, 10 figures, accepted by Ap

Mutation in triangulated categories and rigid Cohen-Macaulay modules

We introduce the notion of mutation of $n$-cluster tilting subcategories in a triangulated category with Auslander-Reiten-Serre duality. Using this idea, we are able to obtain the complete classifications of rigid Cohen-Macaulay modules over certain Veronese subrings.Comment: 52 pages. To appear in Invent. Mat

Extragalactic Globular Clusters and Galaxy Formation

Globular cluster (GC) systems have now been studied in galaxies ranging from dwarfs to giants and spanning the full Hubble sequence of morphological types. Imaging and spectroscopy with the Hubble Space Telescope and large ground-based telescopes have together established that most galaxies have bimodal color distributions that reflect two subpopulations of old GCs: metal-poor and metal-rich. The characteristics of both subpopulations are correlated with those of their parent galaxies. We argue that metal-poor GCs formed in low-mass dark matter halos in the early universe and that their properties reflect biased galaxy assembly. The metal-rich GCs were born in the subsequent dissipational buildup of their parent galaxies and their ages and abundances indicate that most massive early-type galaxies formed the bulk of their stars at early times. Detailed studies of both subpopulations offer some of the strongest constraints on hierarchical galaxy formation that can be obtained in the near-field.Comment: 74 pages, including 14 figures. In press for Annual Reviews of Astronomy and Astrophysic

Applications of patching to quadratic forms and central simple algebras

This paper provides applications of patching to quadratic forms and central simple algebras over function fields of curves over henselian valued fields. In particular, we use a patching approach to reprove and generalize a recent result of Parimala and Suresh on the u-invariant of p-adic function fields, for p odd. The strategy relies on a local-global principle for homogeneous spaces for rational algebraic groups, combined with local computations.Comment: 48 pages; connectivity now required in the definition of rational group; beginning of Section 4 reorganized; other minor change

Dynamical Compactification, Standard Cosmology and the Accelerating Universe

A cosmological model based on Kaluza-Klein theory is studied. A metric, in which the scale factor of the compact space evolves as an inverse power of the radius of the observable universe, is constructed. The Freedmann-Robertson-Walker equations of standard four-dimensional cosmology are obtained precisely. The pressure in our universe is an effective pressure expressed in terms of the components of the higher dimensional energy-momentum tensor. In particular, this effective pressure could be negative and might therefore explain the acceleration of our present universe. A special feature of this model is that, for a suitable choice of the parameters of the metric, the higher dimensional gravitational coupling constant could be negative.Comment: 11 pages, uses revte

UBVI Surface Photometry of the Spiral Galaxy NGC 300 in the Sculptor Group

We present UBVI surface photometry for 20.'5 X 20.'5 area of a late-type spiral galaxy NGC 300. In order to understand the morphological properties and luminosity distribution characteristics of NGC 300, we have derived isophotal maps, surface brightness profiles, ellipticity profiles, position angle profiles, and color profiles. By merging the I-band data of our surface brightness measurements with those of Boeker et al. (2002) based on Hubble Space Telescope observations, we have made combined I-band surface brightness profiles for the region of 0."02 < r < 500" and decomposed the profiles into three components: a nucleus, a bulge, and an exponential disk.Comment: 16 pages(cjaa209.sty), Accepted by the Chinese J. Astron. Astrophys., Fig 2 and 8 are degraded to reduce spac

The Massive Star Content of NGC 3603

We investigate the massive star content of NGC 3603, the closest known giant H II region. We have obtained spectra of 26 stars in the central cluster using the Baade 6.5-m telescope (Magellan I). Of these 26 stars, 16 had no previous spectroscopy. We also obtained photometry of all of the stars with previous or new spectroscopy, primarily using archival HST ACS/HRC images. We use these data to derive an improved distance to the cluster, and to construct an H-R diagram for discussing the masses and ages of the massive star content of this cluster.Comment: Accepted by the Astronomical Journal. This revision updates the coordinates in Table 1 by (-0.18sec, +0.2") to place them on the UCAC2 syste