The rockefeller university

Purpose Chronic granulomatous disease (CGD) is characterized by an inability of phagocytes to produce reactive oxygen species (ROS), which are required to kill some microorganisms. CGD patients are known to suffer from recurrent bacterial and/or fungal infections from the first year of life onwards. From 2009 to 2013, 12 cases of CGD were diagnosed in Morocco. We describe here these Moroccan cases of CGD. Methods We investigated the genetic, immunological and clinical features of 12 Moroccan patients with CGD from 10 unrelated kindreds. Results All patients were children suffering from recurrent bacterial and/or fungal infections. All cases displayed impaired NADPH oxidase activity in nitroblue tetrazolium (NBT), dihydrorhodamine (DHR) or 2',7' dichlorofluorescein diacetate (DCFH-DA) assays. Mutation analysis revealed the presence of four different mutations of CYBB in four kindreds, a recurrent mutation of NCF1 in three kindreds, and a new mutation of NCF2 in three patients from a single kindred. A large deletion of CYBB gene has detected in a patient. The causal mutation in the remaining one kindred was not identified. Conclusion The clinical features and infectious agents found in these patients were similar to those in CGD patients from elsewhere. The results of mutation analysis differed between kindreds, revealing a high level of genetic and allelic heterogeneity among Moroccan CGD patients. The small number of patients in our cohort probably reflects a lack of awareness of physicians. Further studies on a large cohort are required to determine the incidence and prevalence of the disease, and to improve the description of the genetic and clinical features of CGD patients in Morocco.

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Reversible thiol oxidation of cysteine residues occurs in many intracellular catalytic and signaling processes. Here we describe an optimized protocol, which can be completed in similar to 5 d, to unambiguously identify specific cysteine residues that are transiently and reversibly oxidized by comparing two complex biological samples obtained from yeast cell cultures at the proteome level. After ` freezing' the in vivo thiol stage of cysteine residues by medium acidification, we first block reduced thiols in extracts with iodoacetamide (IAM), and then we sequentially reduce and label reversible oxidized thiols with the biotin-based heavy or light IAM derivatives, which are known as isotope-coded affinity tag (ICAT) reagents, so that the two samples can be compared at once after combination of the labeled extracts, trypsin digestion, streptavidin-affinity purification of peptides containing oxidized cysteines, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. For the same protein extracts, before cysteine-containing peptide enrichment, individual relative protein concentrations are obtained by stable-isotope dimethyl labeling.

Tawny crazy ants are spreading across the southern U.S., replacing one of the most notorious invasive pests, the red imported fire ant. A crucial factor in this process is that tawny crazy ants are able to efficiently detoxify fire ant venom.

Spin correlations and polarization in the top quark-antiquark system are measured using dilepton final states produced in pp collisions at the LHC at root s = 7 TeV. The data correspond to an integrated luminosity of 5.0 fb(-1) collected with the CMS detector. The measurements are performed using events with two oppositely charged leptons (electrons or muons), a significant imbalance in transverse momentum, and two or more jets, where at least one of the jets is identified as originating from a b quark. The spin correlations and polarization are measured through asymmetries in angular distributions of the two selected leptons, unfolded to the parton level. All measurements are found to be in agreement with predictions of the standard model.

Overwhelming evidence exists to show that the inclusion of weak-intensity, high-resolution X-ray diffraction data helps improve the refinement of atomic models by imposing strong constraints on individual and overall temperature B factors and thus the quality of crystal structures. Some researchers consider these data to be of little value and opt to discard them during data processing, particularly at medium and low resolution, at which individual B factors of atomic models cannot be refined. Here, new evidence is provided to show that the inclusion of these data helps to improve the quality of experimental phases by imposing proper constraints on electron-density models during noncrystallographic symmetry (NCS) averaging. Using electron-density correlation coefficients as criteria, the resolution of data has successfully been extended from 3.1 to 2.5 angstrom resolution with redundancy-independent merging R factors from below 100% to about 310%. It is further demonstrated that phase information can be fully extracted from observed amplitudes through de novo NCS averaging. Averaging starts with uniform density inside double-shelled spherical masks and NCS matrices that are derived from bound heavy-atom clusters at the vertices of cuboctahedrally symmetric protein particles.

Taylor's power law of fluctuation scaling (TL) states that for population density, population abundance, biomass density, biomass abundance, cell mass, protein copy number, or any other nonnegative-valued random variable in which the mean and the variance are positive, variance = a(mean)(b), a > 0, or equivalently log variance = log a + b x log mean. Many empirical examples and practical applications of TL are known, but understanding of TL's origins and interpretations remains incomplete. We show here that, as time becomes large, TL arises from multiplicative population growth in which successive random factors are chosen by a Markov chain. We give exact formulas for a and b in terms of the Markov transition matrix and the values of the successive multiplicative factors. In this model, the mean and variance asymptotically increase exponentially if and only if b > 2 and asymptotically decrease exponentially if and only if b < 2. (c) 2014 Elsevier Inc. All rights reserved.

We report the identification of a new type of histone mark, lysine 2-hydroxyisobutyrylation (K-hib), and identify the mark at 63 human and mouse histone Khib sites, including 27 unique lysine sites that are not known to be modified by lysine acetylation (K-ac) and lysine crotonylation (K-cr). This histone mark was initially identified by MS and then validated by chemical and biochemical methods. Histone Khib shows distinct genomic distributions from histone Kac or histone Kcr during male germ cell differentiation. Using chromatin immunoprecipitation sequencing, gene expression analysis and immunodetection, we show that in male germ cells, H4K8(hib) is associated with active gene transcription in meiotic and post-meiotic cells. In addition, H4K8(ac)-associated genes are included in and constitute only a subfraction of H4K8hib-labeled genes. The histone Khib mark is conserved and widely distributed, has high stoichiometry and induces a large structural change. These findings suggest its critical role on the regulation of chromatin functions.

Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the skin-draining lymph nodes (LNs). In mice, Langerin-CD11b - dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin-CD11b - migDCs). Here, we build on the observation that Langerin-CD11b - migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin-CD11b - Flt3L-responsive DCs are largely CD24(+) and CX(3)CR1(low) and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11b - migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8 alpha cDCs and Langerin +CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin-CD11b - dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment.