The rockefeller university

The evolution of the field of neuroscience has been propelled by the advent of novel technological capabilities, and the pace at which these capabilities are being developed has accelerated dramatically in the past decade. Capitalizing on this momentum, the United States launched the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative to develop and apply new tools and technologies for revolutionizing our understanding of the brain. In this article, we review the scientific vision for this initiative set forth by the National Institutes of Health and discuss its implications for the future of neuroscience research. Particular emphasis is given to its potential impact on the mapping and study of neural circuits, and how this knowledge will transform our understanding of the complexity of the human brain and its diverse array of behaviours, perceptions, thoughts and emotions.

Transverse momentum spectra of charged particles are measured by the CMS experiment at the CERN LHC in pPb collisions at root s(NN) = 5.02 TeV, in the range 0.4 < pT < 120 GeV/c and pseudorapidity |eta(CM)| < 1.8 in the proton-nucleon center-of-mass frame. For p(T) < 10 GeV/c, the charged-particle production is asymmetric about eta(CM) = 0, with smaller yield observed in the direction of the proton beam, qualitatively consistent with expectations from shadowing in nuclear parton distribution functions (nPDF). A pp reference spectrum at root s = 5.02 TeV is obtained by interpolation from previous measurements at higher and lower center-of-mass energies. The p(T) distribution measured in pPb collisions shows an enhancement of charged particles with p(T) > 20 GeV/c compared to expectations from the pp reference. The enhancement is larger than predicted by perturbative quantum chromodynamics calculations that include antishadowing modifications of nPDFs.

Results are presented from a search for particle dark matter (DM), extra dimensions, and unparticles using events containing a jet and an imbalance in transverse momentum. The data were collected by the CMS detector in proton-proton collisions at the LHC and correspond to an integrated luminosity of 19.7 fb(-1) at a centre-of-mass energy of 8 TeV. The number of observed events is found to be consistent with the standard model prediction. Limits are placed on the DM-nucleon scattering cross section as a function of the DM particle mass for spin-dependent and spinin-dependent interactions. Limits are also placed on the scale parameter MD in the Arkani-Hamed, Dimopoulos, and Dvali (ADD) model of large extra dimensions, and on the unparticle model parameter Lambda(U). The constraints on ADD models and unparticles are the most stringent limits in this channel and those on the DM-nucleon scattering cross section are an improvement over previous collider results.

Enzyme-mediated modifications at the wobble position of tRNAs are essential for the translation of the genetic code. We report the genetic, biochemical and structural characterization of CmoB, the enzyme that recognizes the unique metabolite carboxy-S-adenosine-L-methionine (Cx-SAM) and catalyzes a carboxymethyl transfer reaction resulting in formation of 5-oxyacetyluridine at the wobble position of tRNAs. CmoB is distinctive in that it is the only known member of the SAM-dependent methyltransferase (SDMT) superfamily that utilizes a naturally occurring SAM analog as the alkyl donor to fulfill a biologically meaningful function. Biochemical and genetic studies define the in vitro and in vivo selectivity for Cx-SAM as alkyl donor over the vastly more abundant SAM. Complementary high-resolution structures of the apo- and Cx-SAM bound CmoB reveal the determinants responsible for this remarkable discrimination. Together, these studies provide mechanistic insight into the enzymatic and non-enzymatic feature of this alkyl transfer reaction which affords the broadened specificity required for tRNAs to recognize multiple synonymous codons.

Passively administered anti-tumor monoclonal antibodies (mAbs) rapidly kill tumor targets via Fc gamma R-mediated cytotoxicity (ADCC), a short-term process. However, anti-tumor mAb treatment can also induce a vaccinal effect, in which mAb-mediated tumor death induces a long-term anti-tumor cellular immune response. To determine how such responses are generated, we utilized a murine model of an anti-tumor vaccinal effect against a model neoantigen. We demonstrate that Fc gamma R expression by CD11c(+) antigen-presenting cells is required to generate antitumor T cell responses upon ADCC-mediated tumor clearance. Using Fc gamma R-humanized mice, we demonstrate that anti-tumor human (h)IgG1 must engage hFc gamma RIIIA on macrophages to mediate ADCC, but also engage hFc gamma RIIA, the sole hFc gamma R expressed by human dendritic cells (DCs), to generate a potent vaccinal effect. Thus, while next-generation antitumor antibodies with enhanced binding to only hFc gamma RIIIA are now in clinical use, ideal anti-tumor antibodies must be optimized for both cytotoxic effects as well as hFc gamma RIIA engagement on DCs to stimulate long-term anti-tumor cellular immunity.

Translocating proteins across the double membrane of Gram-negative bacteria, type III secretion systems (T3SS) occur in two evolutionarily related forms: injectisomes, delivering virulence factors into host cells, and the flagellar system, secreting the polymeric filament used for motility. While both systems share related elements of a cytoplasmic sorting platform that facilitates the hierarchical secretion of protein substrates, its assembly and regulation remain unclear. Here we describe a module mediating the assembly of the sorting platform in both secretion systems, and elucidate the structural basis for segregation of homologous components among these divergent T3SS subtypes sharing a common cytoplasmic milieu. These results provide a foundation for the subtype-specific assembly of T3SS sorting platforms and will support further mechanistic analysis and anti-virulence drug design.

Upon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs), yielding distinct classes of tRFs. We identify a novel class of tRFs derived from tRNA(Glu), tRNA(Asp), tRNA(Gly), and tRNA(Tyr) that, upon induction, suppress the stability of multiple oncogenic transcripts in breast cancer cells by displacing their 30 untranslated regions (UTRs) from the RNA-binding protein YBX1. This mode of post-transcriptional silencing is sequence specific, as these fragments all share a common motif that matches the YBX1 recognition sequence. Loss-of-function and gain-of-function studies, using anti-sense locked-nucleic acids (LNAs) and synthetic RNA mimetics, respectively, revealed that these fragments suppress growth under serum-starvation, cancer cell invasion, and metastasis by breast cancer cells. Highly metastatic cells evade this tumor-suppressive pathway by attenuating the induction of these tRFs. Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action. This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans. Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients. We report three patients from unrelated kindreds, aged 8, 12, and 37 yr with isolated CMC, who display AR IL-17RC deficiency. The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface. The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. However, in contrast to what is observed for the IL-17RA- and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients. These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.

A search for new physics in proton-proton collisions having final states with an electron or muon and missing transverse energy is presented. The analysis uses data collected in 2012 with the CMS detector, at an LHC center-of-mass energy of 8 TeV, and corresponding to an integrated luminosity of 19.7 fb(-1). No significant deviation of the transverse mass distribution of the charged lepton-neutrino system from the standard model prediction is found. Mass exclusion limits of up to 3.28 TeVat 95% confidence level for a W0-boson with the same couplings as that of the standard model W-boson are determined. Results are also derived in the framework of split universal extra dimensions, and exclusion limits on Kaluza-Klein Wd(KK)((2)) states are found. The final state with large missing transverse energy also enables a search for dark matter production with a recoiling W-boson, with limits set on the mass and the production cross section of potential candidates. Finally, limits are established for a model including interference between a left-handed W'-boson and the standard model W-boson and for a compositeness model.