Two novel missense mutations in the myelin protein zero gene causes Charcot-Marie-Tooth type 2 and Déjérine-Sottas syndrome

<p>Abstract</p> <p>Background</p> <p>The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the <it>myelin protein zero (MPZ) </it>gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P₀) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P₀ex) is known, while the transmembrane and intracellular structure is unknown.</p> <p>Findings</p> <p>One novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome.</p> <p>Conclusions</p> <p>The phenotypic variation caused by different missense mutations in the <it>MPZ </it>gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.</p

Necdin, a Negative Growth Regulator, Is a Novel STAT3 Target Gene Down-Regulated in Human Cancer

Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin

A new RASS galaxy cluster catalogue with low contamination extending to z similar to 1 in the DES overlap region

We present the MARD-Y3 catalogue of between 1086 and 2171 galaxy clusters (52 per cent and 65 per cent new) produced using multicomponent matched filter (MCMF) follow-up in 5000 deg2 of DES-Y3 optical data of the ∼20 000 overlapping ROSAT All-Sky Survey source catalogue (2RXS) X-ray sources. Optical counterparts are identified as peaks in galaxy richness as a function of redshift along the line of sight towards each 2RXS source within a search region informed by an X-ray prior. All peaks are assigned a probability fcont of being a random superposition. The clusters lie at 0.02 <z< 1.1 with more than 100 clusters at z > 0.5. Residual contamination is 2.6 per cent and 9.6 per cent for the cuts adopted here. For each cluster we present the optical centre, redshift, rest frame X-ray luminosity, M500 mass, coincidence with NWAY infrared sources, and estimators of dynamical state. About 2 per cent of MARD-Y3 clusters have multiple possible counterparts, the photo-z’s are high quality with σ z/(1 + z) = 0.0046, and ∼1 per cent of clusters exhibit evidence of X-ray luminosity boosting from emission by cluster active galactic nuclei. Comparison with other catalogues (MCXC, RM, SPT-SZ, Planck) is performed to test consistency of richness, luminosity, and mass estimates. We measure the MARD-Y3 X-ray luminosity function and compare it to the expectation from a fiducial cosmology and externally calibrated luminosity- and richness–mass relations. Agreement is good, providing evidence that MARD-Y3 has low contamination and can be understood as a simple two step selection – X-ray and then optical – of an underlying cluster population described by the halo mass function

Exploring the contamination of the DES-Y1 cluster sample with SPT-SZ selected clusters

We perform a cross validation of the cluster catalogue selected by the red-sequence Matched-filter Probabilistic Percolation algorithm (redMaPPer) in Dark Energy Survey year 1 (DES-Y1) data by matching it with the Sunyaev–Zel’dovich effect (SZE) selected cluster catalogue from the South Pole Telescope SPT-SZ survey. Of the 1005 redMaPPer selected clusters with measured richness λ̂ >40 in the joint footprint, 207 are confirmed by SPT-SZ. Using the mass information from the SZE signal, we calibrate the richness–mass relation using a Bayesian cluster population model. We find a mass trend λ ∝ MB consistent with a linear relation (B ∼ 1), no significant redshift evolution and an intrinsic scatter in richness of σλ = 0.22 ± 0.06. By considering two error models, we explore the impact of projection effects on the richness–mass modelling, confirming that such effects are not detectable at the current level of systematic uncertainties. At low richness SPT-SZ confirms fewer redMaPPer clusters than expected. We interpret this richness dependent deficit in confirmed systems as due to the increased presence at low richness of low-mass objects not correctly accounted for by our richness-mass scatter model, which we call contaminants. At a richness λ̂ =40 ⁠, this population makes up >12 per cent (97.5 percentile) of the total population. Extrapolating this to a measured richness λ̂ =20 yields >22 per cent (97.5 percentile). With these contamination fractions, the predicted redMaPPer number counts in different plausible cosmologies are compatible with the measured abundance. The presence of such a population is also a plausible explanation for the different mass trends (B ∼ 0.75) obtained from mass calibration using purely optically selected clusters. The mean mass from stacked weak lensing (WL) measurements suggests that these low-mass contaminants are galaxy groups with masses ∼3–5 × 1013 M⊙ which are beyond the sensitivity of current SZE and X-ray surveys but a natural target for SPT-3G and eROSITA

Antimicrobial activity and rutin identification of honey produced by the stingless bee Melipona compressipes manaosensis and commercial honey

Background: Honey has been identified as a potential alternative to the widespread use of antibiotics, which are of significant concern considering the emergence of resistant bacteria. In this context, this study aimed to evaluate the antimicrobial activity of honey samples produced by a stingless bee species and by Apis sp. against pathogenic bacteria, as well as to identify the presence of phenolic compounds.Methods: Honey samples from the stingless bee M. compressipes manaosensis were collected twice, during the dry and rainy seasons. Three commercial honey samples from Apis sp. were also included in this study. Two different assays were performed to evaluate the antibacterial potential of the honey samples: agar-well diffusion and broth macrodilution. Liquid-liquid extraction was used to assess phenolic compounds from honey. HPLC analysis was performed in order to identify rutin and apigenin on honey samples. Chromatograms were recorded at 340 and 290 nm.Results: Two honey samples were identified as having the highest antimicrobial activity using the agar diffusion method. Honey produced by Melipona compressipes manaosensis inhibited the growth of Staphylococcus aureus, Escherichia coli (0157: H7), Proteus vulgaris, Shigella sonnei and Klebsiella sp. A sample of honey produced by Apis sp. also inhibited the growth of Salmonella paratyphi. The macrodilution technique presented greater sensitivity for the antibacterial testing, since all honey samples showed activity. Flavonoid rutin was identified in the honey sample produced by the stingless bee.Conclusions: Honey samples tested in this work showed antibacterial activity against Gram-positive and Gram-negative bacteria. The results reported herein highlight the potential of using honey to control bacterial growth. © 2013 Pimentel et al.; licensee BioMed Central Ltd

Dark Energy Survey year 1 results: cosmological constraints from cluster abundances and weak lensing

We perform a joint analysis of the counts and weak lensing signal of redMaPPer clusters selected from the Dark Energy Survey (DES) Year 1 dataset. Our analysis uses the same shear and source photometric redshifts estimates as were used in the DES combined probes analysis. Our analysis results in surprisingly low values for S8=σ8(Ωm/0.3)0.5=0.65±0.04, driven by a low matter density parameter, Ωm=0.179+0.031−0.038, with σ8−Ωm posteriors in 2.4σ tension with the DES Y1 3x2pt results, and in 5.6σ with the Planck CMB analysis. These results include the impact of post-unblinding changes to the analysis, which did not improve the level of consistency with other data sets compared to the results obtained at the unblinding. The fact that multiple cosmological probes (supernovae, baryon acoustic oscillations, cosmic shear, galaxy clustering and CMB anisotropies), and other galaxy cluster analyses all favor significantly higher matter densities suggests the presence of systematic errors in the data or an incomplete modeling of the relevant physics. Cross checks with x-ray and microwave data, as well as independent constraints on the observable-mass relation from Sunyaev-Zeldovich selected clusters, suggest that the discrepancy resides in our modeling of the weak lensing signal rather than the cluster abundance. Repeating our analysis using a higher richness threshold (λ≥30) significantly reduces the tension with other probes, and points to one or more richness-dependent effects not captured by our model

Effects of sulforaphane on the oxidative response, apoptosis, and the transcriptional profile of human stomach mucosa cells in vitro

Oxidative stress is a critical factor in the pathogenesis of several gastrointestinal diseases. Sulforaphane (SFN), a bioactive compound found in cruciferous vegetables, activates the redox-sensitive nuclear erythroid 2-related factor 2 (NRF2). In addition to its protective role, SFN exerts cytotoxic effects on cancer cells. However, there is a lack of information concerning the toxicity of SFN in normal cells. We investigated the effects of SFN on cell viability, antioxidant defenses, and gene expression in human stomach mucosa cells (MNP01). SFN reduced ROS formation and protected the cells against induced oxidative stress but high concentrations increased apoptosis. An intermediate SFN concentration (8 μM) was chosen for RNA sequencing studies. We observed upregulation of genes of the NRF2 (antioxidant) pathway, the DNA damage response, and apoptosis signaling; whereas SFN downregulated cell cycle and DNA repair pathway genes. SFN may be cytoprotective at low concentrations and cytotoxic at high concentrations