The rockefeller university

Sensing, integrating, and processing of stressogenic signals must be followed by accurate differential response(s) for a cell to survive and avoid malignant transformation. The DNA damage response (DDR) pathway is vital in this process, as it deals with genotoxic/oncogenic insults, having p53 as a nodal effector that performs most of the above tasks. Accumulating data reveal that other pathways are also involved in the same or similar processes, conveying also to p53. Emerging questions are if, how, and when these additional pathways communicate with the DDR axis. Two such stress response pathways, involving the MKK7 stress-activated protein kinase (SAPK) and ARF, have been shown to be interlocked with the ATM/ATR-regulated DDR axis in a highly ordered manner. This creates a new landscape in the DDR orchestrated response to genotoxic/oncogenic insults that is currently discussed.

Toll-like receptors (TLRs) play an important role in immunity and mediate their actions via multiple signaling pathways, in particular, the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappa B) pathway. Rare inherited defects of TLR- and NF-kappa B-dependent responses have recently been recognized. These primary immunodeficiencies predispose children to life-threatening infections and often remain undiagnosed. Establishing a sensitive, specific, cost-effective and simple method for diagnosis is therefore important. In this article, we review the known defects of TLR- and NF-kappa B-mediated pathways and the assays that can be used to screen for such defects.

The t(t)Overbar charge asymmetry in proton-proton collisions root s = 7TeV is measured using the dilepton decay channel (ee, e mu, or mu mu). The data correspond to a total integrated luminosity of 5.0 fb(-1), collected by the CMS experiment at the LHC. The t(t) Overbar and lepton charge asymmetries, defined as the differences in absolute values of the rapidities between the reconstructed top quarks and antiquarks and of the pseudorapidities between the positive and negative leptons, respectively, are measured to be A(C) = -0.010 +/- 0.017 (stat.) +/- 0.008 (syst.) and A(C)(lep) = 0.009 +/- 0.010 (stat.) +/- 0.006 (syst.). The lepton charge asymmetry is also measured as a function of the invariant mass, rapidity, and transverse momentum of the system. All measurements are consistent with the expectations of the standard model.

A search for baryon number violation (BNV) in top-quark decays is performed using pp collisions produced by the LHC at root s = 8 TeV. The top-quark decay considered in this search results in one light lepton (muon or electron), two jets, but no neutrino in the final state. Data used for the analysis were collected by the CMS detector and correspond to an integrated luminosity of 19.5 fb(-1). The event selection is optimized for top quarks produced in pairs, with one undergoing the BNV decay and the other the standard model hadronic decay to three jets. No significant excess of events over the expected yield from standard model processes is observed. The upper limits at 95% confidence level on the branching fraction of the BNV top-quark decay are calculated to be 0.0016 and 0.0017 for the muon and the electron channels, respectively. Assuming lepton universality, an upper limit of 0.0015 results from the combination of the two channels. These limits are the first that have been obtained on a BNV process involving the top quark. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license

Methylation of histones by lysine methyltransferases (KMTases) plays important roles in regulating chromatin function. It is also now clear that improper KMTases activity is linked to human diseases, such as cancer. We report an approach that employs drug-like 'privileged' scaffolds biased with motifs present in S-adenosyl methionine, the cofactor used by KMTases, to efficiently generate inhibitors for Set7, a biochemically well-characterized KMTase. Setin-1, the most potent inhibitor of Set7 we have developed also inhibits the KMTase G9a. Together these data suggest that these inhibitors should provide good starting points to generate useful probes for KMTase biology and guide the design of KMTase inhibitors with drug-like properties. (C) 2014 Elsevier Ltd. All rights reserved.

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top quark (the top squark) and the Higgs boson (Higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 fb(-1) of proton-proton collision data at root s = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the top squark mass below 360 to 410 GeV, depending on the Higgsino mass.

Despite a conserved role for histones as general DNA packaging agents, it is now clear that another key function of these proteins is to confer variations in chromatin structure to ensure dynamic patterns of transcriptional regulation in eukaryotes. The incorporation of histone variants is particularly important to this process. Recent knockdown and knockout studies in various cellular systems, as well as direct mutational evidence from human cancers, now suggest a crucial role for histone variant regulation in processes as diverse as differentiation and proliferation, meiosis and nuclear reprogramming. In this Review, we provide an overview of histone variants in the context of their unique functions during mammalian germ cell and embryonic development, and examine the consequences of aberrant histone variant regulation in human disease.

We have reported previously that autophagy is responsible for amyloid precursor protein-C-terminal fragment (APP-CTF) degradation and therefore A clearance. To elucidate the underlying mechanism, using LC3 affinity purification and mass spectrometry analysis, immunoprecipitation (IP), as well as live imaging analysis, we identified and demonstrated that the adaptor-related protein complex 2 (AP2) and PICALM (phosphatidylinositol binding clathrin assembly protein) are in a complex with LC3 and APP-CTF. Taken together, this new set of data suggests that the AP2-PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-dependent autophagic degradation pathway. Interestingly this AP2-LC3 connection seems to be involved in chemically-induced APP-CTF clearance as we observed using the small compound SMER28. The effect observed following SMER28 was significantly reduced after silencing AP2. While more work is required to elucidate the detailed molecular mechanisms involved, our actual data suggest that there is some level of specificity in the steps mentioned above.

Flow cytometry-based diagnostic technique should facilitate the diagnosis of patients with CMCD, with gain-of-function STAT1 mutations. CMCD is a rare congenital disorder characterized by persistent or recurrent skin, nail, and mucosal membrane infections caused by Candida albicans. Heterozygous GOF STAT1 mutations have been shown to confer AD CMCD as a result of impaired dephosphorylation of STAT1. We aimed to identify and characterize STAT1 mutations in CMCD patients and to develop a simple diagnostic assay of CMCD. Genetic analysis of STAT1 was performed in patients and their relatives. The mutations identified were characterized by immunoblot and reporter assay using transient gene expression experiments. Patients' leukocytes are investigated by flow cytometry and immunoblot. Six GOF mutations were identified, three of which are reported for the first time, that affect the CCD and DBD of STAT1 in two sporadic and four multiplex cases in 10 CMCD patients from Japan. Two of the 10 patients presented with clinical symptoms atypical to CMCD, including other fungal and viral infections, and three patients developed bronchiectasis. Immunoblot analyses of patients' leukocytes showed abnormally high levels of pSTAT1 following IFN- stimulation. Based on this finding, we performed a flow cytometry-based functional analysis of STAT1 GOF alleles using IFN- stimulation and the tyrosine kinase inhibitor, staurosporine. The higher levels of pSTAT1 observed in primary CD14(+) cells from patients compared with control cells persisted and were amplified by the presence of staurosporine. We developed a flow cytometry-based STAT1 functional screening method that would greatly facilitate the diagnosis of CMCD patients with GOF STAT1 mutations.