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A description is provided of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices. Despite the very hostile environment at the LHC, the performance obtained with these algorithms is found to be excellent. For t (t) over bar events under typical 2011 pileup conditions, the average track-reconstruction efficiency for promptly-produced charged particles with transverse momenta of p(T) > 0.9GeV is 94% for pseudorapidities of vertical bar eta vertical bar < 0.9 and 85% for 0.9 < vertical bar eta vertical bar < 2.5. The inefficiency is caused mainly by hadrons that undergo nuclear interactions in the tracker material. For isolated muons, the corresponding efficiencies are essentially 100%. For isolated muons of p(T) = 100GeV emitted at vertical bar eta vertical bar < 1.4, the resolutions are approximately 2.8% in p(T), and respectively, 10 m m and 30 mu m in the transverse and longitudinal impact parameters. The position resolution achieved for reconstructed primary vertices that correspond to interesting pp collisions is 10-12 mu m in each of the three spatial dimensions. The tracking and vertexing software is fast and flexible, and easily adaptable to other functions, such as fast tracking for the trigger, or dedicated tracking for electrons that takes into account bremsstrahlung.

The implicit goal of functional magnetic resonance imaging is to infer local neural activity. There is considerable debate, however, as to whether imaging correlates most linearly with local spiking or some local field potential (LFP) measurement. Through simultaneous neuroimaging (intrinsic-signal optical imaging) and electrode recordings from alert, task-engaged macaque monkeys, we showed previously that local electrophysiology correlates with only a specific stimulus-related imaging component. Here we show that this stimulus-related component-obtained by subtracting a substantial task-related component-is particularly linear with local spiking over a comprehensive range of response strengths. Matches to concurrent LFP measurements are, to varying degrees, poorer. As a control, we also tried matching the full imaging signal to local electrophysiology without subtracting task-related components. These control matches were consistently worse; they were, however, slightly better for gamma LFP than spiking, potentially resolving discrepancies between our findings and earlier reports favoring LFP.

We report that mice with closed-head multiple traumatic brain injury (TBI) show a decrease in the motoric aspects of generalized arousal, as measured by automated, quantitative behavioral assays. Further, we found that temporally-patterned deep brain stimulation (DBS) can increase generalized arousal and spontaneous motor activity in this mouse model of TBI. This arousal increase is input-pattern-dependent, as changing the temporal pattern of DBS can modulate its effect on motor activity. Finally, an extensive examination of mouse behavioral capacities, looking for deficits in this model of TBI, suggest that the strongest effects of TBI in this model are found in the initiation of any kind of movement. (C) 2014 Elsevier B.V. All rights reserved.

Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming.

A search for neutral Higgs bosons in the minimal supersymmetric extension of the standard model (MSSM) decaying to tau-lepton pairs in pp collisions is performed, using events recorded by the CMS experiment at the LHC. The dataset corresponds to an integrated luminosity of 24.6 fb(-1), with 4.9 fb(-1) at 7TeV and 19.7 fb(-1) at 8TeV. To enhance the sensitivity to neutral MSSM Higgs bosons, the search includes the case where the Higgs boson is produced in association with a b-quark jet. No excess is observed in the tau-lepton-pair invariant mass spectrum. Exclusion limits are presented in the MSSM parameter space for different benchmark scenarios, m(h)(max), m(h)(mod+), m(h)(mod-), light-stop, light-stau, T-phobic, and low-m(H). Upper limits on the cross section times branching fraction for gluon fusion and b-quark associated Higgs boson production are also given.

Monocyte chemoattractant protein 1 (MCP1) is an important chemoattractant for microglia. Rodent MCP1 carries a heavily glycosylated C-terminus, which has been predicted to increase local MCP1 concentration, promote MCP1 dimerization/oligomerization, and facilitate receptor engagement. Previous studies have shown that MCP1 mutant lacking the glycosylated C-terminus cannot dimerize/oligomerize, but has higher chemotactic potency than the wild-type (full-length) MCP1, suggesting that rodent MCP1 may function as a monomer. Although many groups support this hypothesis, there is no direct evidence on whether rodent MCP1 dimer is functional. In this paper, using forced recombinant dimeric MCP1 proteins we show that mouse MCP1 dimer is unable to activate Rac1, promote protrusion of lamellipodia, or induce microglial migration, although it can bind to CCR2 and mediate its internalization. These results support the idea that signaling events mediated by MCP1 require the presence of the monomeric form of this chemokine. (C) 2014 Elsevier Ltd. All rights reserved.

Membrane phospholipids can function as potent regulators of ion channel function. This study uncovers and investigates the effect of phosphatidic acid on Kv channel gating. Using the method of reconstitution into planar lipid bilayers, in which protein and lipid components are defined and controlled, we characterize two effects of phosphatidic acid. The first is a non-specific electrostatic influence on activation mediated by electric charge density on the extracellular and intracellular membrane surfaces. The second is specific to the presence of a primary phosphate group, acts only through the intracellular membrane leaflet and depends on the presence of a particular arginine residue in the voltage sensor. Intracellular phosphatidic acid accounts for a nearly 50 mV shift in the midpoint of the activation curve in a direction consistent with stabilization of the voltage sensor's closed conformation. These findings support a novel mechanism of voltage sensor regulation by the signaling lipid phosphatidic acid.

DNA replication in eukaryotes is asymmetric, with separate DNA polymerases (Pol) dedicated to bulk synthesis of the leading and lagging strands. Pol alpha/primase initiates primers on both strands that are extended by Pol epsilon on the leading strand and by Pol delta on the lagging strand. The CMG (Cdc45-MCM-GINS) helicase surrounds the leading strand and is proposed to recruit Pol epsilon for leading-strand synthesis, but to date a direct interaction between CMG and Pol epsilon has not been demonstrated. While purifying CMG helicase over-expressed in yeast, we detected a functional complex between CMG and native Pol epsilon. Using pure CMG and Pol epsilon, we reconstituted a stable 15-subunitCMG-Pol epsilon complex and showed that it is a functional polymerase-helicase on a model replication fork in vitro. On its own, the Pol2 catalytic subunit of Pol epsilon is inefficient in CMG-dependent replication, but addition of the Dpb2 protein subunit of Pol epsilon, known to bind the Psf1 protein subunit of CMG, allows stable synthesis with CMG. Dpb2 does not affect Pol delta function with CMG, and thus we propose that the connection between Dpb2 andCMGhelps to stabilize Pol epsilon on the leading strand as part of a 15-subunit leading- strand holoenzyme we refer to as CMGE. Direct binding between Pol epsilon and CMG provides an explanation for specific targeting of Pol epsilon to the leading strand and provides clear mechanistic evidence for how strand asymmetry is maintained in eukaryotes.

Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T(-)B(+)NK(+)severe combined immunodeficiency (SCID). Only two other CORO1A-kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A-kindred. We captured a 10-year analysis of the immune-clinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings. We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA(+) (na < ve) T and memory B cells, low NK cells and abnormally increased double-negative (DN) I'delta T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations. We reveal the third CORO1A-mutated kindred, with the immune phenotype of abnormal na < ve CD4 and DN T-cells and newfound characteristics of a late/hypomorphic-like SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A-SCID-CID spectrum.