The rockefeller university

Nuclear factor kappa B (NF-kappa B) essential modulator (NEMO), a regulatory component of the I kappa B kinase (IKK) complex, controls NF-kappa B activation through its interaction with ubiquitin chains. We show here that stimulation with interleukin-1 (IL-1) and TNF induces a rapid and transient recruitment of NEMO into punctate structures that are anchored at the cell periphery. These structures are enriched in activated IKK kinases and ubiquitinated NEMO molecules, which suggests that they serve as organizing centers for the activation of NF-kappa B. These NEMO-containing structures colocalize with activated TNF receptors but not with activated IL-1 receptors. We investigated the involvement of nondegradative ubiquitination in the formation of these structures, using cells deficient in K63 ubiquitin chains or linear ubiquitin chain assembly complex (LUBAC)mediated linear ubiquitination. Our results indicate that, unlike TNF, IL-1 requires K63-linked and linear ubiquitin chains to recruit NEMO into higher-order complexes. Thus, different mechanisms are involved in the recruitment of NEMO into supramolecular complexes, which appear to be essential for NF-kappa B activation.

The DNA damage response factor 53BP1 functions at the intersection of two major double strand break (DSB) repair pathways - promoting nonhomologous end-joining (NHEJ) and inhibiting homology-directed repair (HDR) - and integrates cellular inputs to ensure their timely execution in the proper cellular contexts. Recent work has revealed that 53BP1 controls 5' end resection at DNA ends, mediates synapsis of DNA ends, promotes the mobility of damaged chromatin, improves DSB repair in heterochromatic regions, and contributes to lethal mis-repair of DSBs in BRCA1-deficient cells. Here we review these aspects of 53BP1 and discuss new data revealing how 53BP1 is loaded onto chromatin and uses its interacting factors Rif1 and PTIP to promote NHEJ and inhibit HDR.

The functional properties of adult cortical neurons are subject to alterations in sensory experience. Retinal lesions lead to remapping of cortical topography in the region of primary visual cortex representing the lesioned part of the retina, the lesion projection zone (LPZ), with receptive fields shifting to the intact parts of the retina. Neurons within the LPZ receive strengthened input from the surrounding region by growth of the plexus of excitatory long-range horizontal connections. Here, by combining cell type-specific labeling with a genetically engineered recombinant adeno-associated virus and in vivo two-photon microscopy in adult macaques, we showed that the remapping was also associated with alterations in the axonal arbors of inhibitory neurons, which underwent a parallel process of pruning and growth. The axons of inhibitory neurons located within the LPZ extended across the LPZ border, suggesting a mechanism by which new excitatory input arising from the peri-LPZ is balanced by reciprocal inhibition arising from the LPZ.

A central issue when designing multidimensional biological and psychosocial interventions for children who are exposed to multiple developmental risks is identification of the age period(s) in which such interventions will have the strongest and longest lasting effects (sensitive periods). In this paper, we review nutritional, neuroscientific, and psychological evidence on this issue. Nutritional evidence is used to identify nutrient-sensitive periods of age-linked dimensions of brain development, with specific reference to iron deficiency. Neuroscience evidence is used to assess the importance of timing of exposures to environmental stressors for maintaining neural, neuroendocrine, and immune systems integrity. Psychological evidence illustrates the sensitivity of cognitive and social-emotional development to contextual risk and protective influences encountered at different ages. Evidence reviewed documents that the early years of life are a sensitive period when biological or psychosocial interventions or exposure to risk or protective contextual influences can produce unique long-term influences upon human brain, neuroendocrine, and cognitive or psychosocial development. However, the evidence does not identify the early years as the sole sensitive time period within which to have a significant influence upon development. Choice of age(s) to initiate interventions should be based on what outcomes are targeted and what interventions are used.

The nuclear pore complex (NPC) mediates trafficking between the cytoplasm and nucleoplasm. It also plays key roles in other nuclear processes such as chromatin silencing, transcriptional regulation, and DNA damage repair. Nucleoporins, the structural components of the NPC, have been linked to a multitude of cancers through chromosomal translocations generating fusion proteins, changes in protein expression levels, and single point mutations. Only a small number of nucleoporins have been linked to tumorigenesis thus far, and these proteins-Nup62, Nup88, Nup98, Nup214, Nup358/RanBP2, and Tpr-line the trafficking pathway and are particularly associated with mRNA export. Overexpression of several associated nuclear export factors, most also involved in various stages of mRNA export, has been linked to cancers as well. Some oncogenic nucleoporin mutants are mislocalized to either the cytoplasm or nucleoplasm while others are incorporated into the NPC, and in all these cases they are thought to misregulate signaling pathways and transcription through either altered or diminished nucleoporin functionality. Intriguingly, many viruses target the same cancer-linked nucleoporins, often causing their degradation or mislocalization, implying that these viruses exploit some of the same weaknesses as the oncogenic defects.

Maintenance of nuclear architecture is crucial for gene regulation, cell proliferation, and tissue development. However, during every open mitosis and meiosis, chromosomes are exposed to cytoskeletal forces until they are fully reassembled into mature nuclei. Here we discuss our recent study of nuclear assembly in Xenopus egg extracts, where we showed that the DNA binding protein developmental pluripotency associated 2 (Dppa2) directly inhibits microtubule polymerization during nuclear formation, and that this is essential for normal nuclear shape and replication. We explore mechanisms by which microtubule dynamics could regulate nuclear formation and morphology, and discuss the importance of both spatial and temporal regulation of microtubules in this process. Moreover, expression of Dppa2 is limited to the early embryo and pluripotent tissues, and we highlight the specific demands of mitosis in these often rapidly dividing cells, in which telophase nuclear assembly must be expedited and may facilitate developmental changes in nuclear architecture.

The inclusive cross section for top-quark pair production measured by the CMS experiment in protonproton collisions at a center-of-mass energy of 7 TeV is compared to the QCD prediction at next-to-next-to-leading order with various parton distribution functions to determine the top-quark pole mass, m(t)(pole), or the strong coupling constant, alpha(S). With the parton distribution function set NNPDF2.3, a pole mass of 176.7(-3.4)(+3.8) GeV is obtained when constraining alpha(S) at the scale of the Z boson mass, m(Z), to the current world average. Alternatively, by constraining m(t)(pole) to the latest average from direct mass measurements, a value of alpha(S)(m(Z)) = 0.1151(-0.0032)(+0.0033) is extracted. This is the first determination of alpha(S) using events from top-quark production. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.

A search for the standard model Higgs boson (H) decaying to b (b) over bar when produced in association with a weak vector boson (V) is reported for the following channels: W(mu nu)H, W(e nu)H, W(tau nu)H, Z(mu mu)H, Z(ee)H and Z(nu nu)H. The search is performed in data samples corresponding to integrated luminosities of up to 5.1 inverse femtobarns at root s = 7 TeV and up to 18.9 fb(-1) at root s = 8 TeV, recorded by the CMS experiment at the LHC. An excess of events is observed above the expected background with a local significance of 2.1 standard deviations for a Higgs boson mass of 125 GeV, consistent with the expectation from the production of the standard model Higgs boson. The signal strength corresponding to this excess, relative to that of the standard model Higgs boson, is 1.0 +/- 0.5.

Senescence is a form of cellular aging that limits the proliferative capacity of cells. Senescence can be triggered by different stress stimuli, such as DNA damage or oncogene activation. Two recent articles published in Cell have uncovered an unexpected role for cellular senescence during development, as a process that contributes to remodeling and patterning of the embryo. These findings are exciting and have important implications for the understanding of normal developmental and the evolutionary origin of senescence.

Toward improving early detection of melanoma by accurate diagnosis and avoidance of unnecessary surgical excisions of common moles, we are developing noninvasive quantitative spectral fingerprinting of protein expression using Raman spectroscopy within confocally gated volumes of tissue. Our first target is the L-tryptophan catabolism pathway, which is unregulated in the tumor micro-environment and inhibits the immune response that usually is tumor suppressive. The tryptophan pathway is therefore worthy of diagnostic measurement and finding the ratio of L-tryptophan to its metabolites may aid a melanoma diagnosis. We report the intensity of the Raman signal from L-tryptophan and quinolinic acid, which are found during different stages of the tryptophan metabolic pathway.