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The observation of a new b baryon via its strong decay into Xi(-)(b)pi(+) (plus charge conjugates) is reported. The measurement uses a data sample of pp collisions at root s = 7 TeV collected by the CMS experiment at the LHC, corresponding to an integrated luminosity of 5.3 fb(-1). The known Xi(-)(b) baryon is reconstructed via the decay chain Xi(-)(b) -> J/psi Xi(-) -> mu(+)mu(-)Lambda(0)pi(-), with Lambda(0) -> p pi(-). A peak is observed in the distribution of the difference between the mass of the Xi(-)(b)pi(+) system and the sum of the masses of the Xi(-)(b) and pi(+), with a significance exceeding 5 standard deviations. The mass difference of the peak is 14.84 +/- 0.74(stat) +/- 0.28(syst) MeV. The new state most likely corresponds to the J(P) = 3/2(+) companion of the Xi(b).

Records of excitatory postsynaptic currents (EPSCs) are often complex, with overlapping signals that display a large range of amplitudes. Statistical analysis of the kinetics and amplitudes of such complex EPSCs is nonetheless essential to the understanding of transmitter release. We therefore developed a maximum-likelihood blind deconvolution algorithm to detect exocytotic events in complex EPSC records. The algorithm is capable of characterizing the kinetics of the prototypical EPSC as well as delineating individual release events at higher temporal resolution than other extant methods. The approach also accommodates data with low signal-to-noise ratios and those with substantial overlaps between events. We demonstrated the algorithm's efficacy on paired whole-cell electrode recordings and synthetic data of high complexity. Using the algorithm to align EPSCs, we characterized their kinetics in a parameter-free way. Combining this approach with maximum-entropy deconvolution, we were able to identify independent release events in complex records at a temporal resolution of less than 250 ms. We determined that the increase in total postsynaptic current associated with depolarization of the presynaptic cell stems primarily from an increase in the rate of EPSCs rather than an increase in their amplitude. Finally, we found that fluctuations owing to postsynaptic receptor kinetics and experimental noise, as well as the model dependence of the deconvolution process, explain our inability to observe quantized peaks in histograms of EPSC amplitudes from physiological recordings.

Biology presents many examples of planar distribution and structural networks having dense sets of closed loops. An archetype of this form of network organization is the vasculature of dicotyledonous leaves, which showcases a hierarchicallynested architecture containing closed loops at many different levels. Although a number of approaches have been proposed to measure aspects of the structure of such networks, a robust metric to quantify their hierarchical organization is still lacking. We present an algorithmic framework, the hierarchical loop decomposition, that allows mapping loopy networks to binary trees, preserving in the connectivity of the trees the architecture of the original graph. We apply this framework to investigate computer generated graphs, such as artificial models and optimal distribution networks, as well as natural graphs extracted from digitized images of dicotyledonous leaves and vasculature of rat cerebral neocortex. We calculate various metrics based on the asymmetry, the cumulative size distribution and the Strahler bifurcation ratios of the corresponding trees and discuss the relationship of these quantities to the architectural organization of the original graphs. This algorithmic framework decouples the geometric information (exact location of edges and nodes) from the metric topology (connectivity and edge weight) and it ultimately allows us to perform a quantitative statistical comparison between predictions of theoretical models and naturally occurring loopy graphs.

Measurements of jet characteristics from inclusive jet production in proton-proton collisions at a centre-of-mass energy of 7 TeV are presented. The data sample was collected with the CMS detector at the LHC during 2010 and corresponds to an integrated luminosity of 36 pb(-1). The mean charged-hadron multiplicity, the differential and integral jet shape distributions, and two independent moments of the shape distributions are measured as functions of the jet transverse momentum for jets reconstructed with the anti-k(T) algorithm. The measured observables are corrected to the particle level and compared with predictions from various QCD Monte Carlo generators.

Secreted Wnt morphogens are signaling molecules essential for embryogenesis, pathogenesis, and regeneration and require distinct modifications for secretion, gradient formation, and activity. Whether Wnt proteins can be posttranslationally inactivated during development and homeostasis is unknown. Here we identify, through functional cDNA screening, a transmembrane protein Tiki1 that is expressed specifically in the dorsal Spemann-Mangold Organizer and is required for anterior development during Xenopus embryogenesis. Tiki1 antagonizes Wnt function in embryos and human cells via a TIKI homology domain that is conserved from bacteria to mammals and acts likely as a protease to cleave eight amino-terminal residues of a Wnt protein, resulting in oxidized Wnt oligomers that exhibit normal secretion but minimized receptor-binding capability. Our findings identify a Wnt-specific protease that controls head formation, reveal a mechanism for morphogen inactivation through proteolysis-induced oxidation-oligomerization, and suggest a role of the Wnt amino terminus in evasion of oxidizing inactivation. TIKI proteins may represent potential therapeutic targets.

The interferon (IFN)-induced transmembrane protein 3 (IFITM3) is a cellular restriction factor that inhibits infection by influenza virus and many other pathogenic viruses. IFITM3 prevents endocytosed virus particles from accessing the host cytoplasm although little is known regarding its regulatory mechanisms. Here we demonstrate that IFITM3 localization to and antiviral remodeling of endolysosomes is differentially regulated by S-palmitoylation and lysine ubiquitination. Although S-palmitoylation enhances IFITM3 membrane affinity and antiviral activity, ubiquitination decreases localization with endolysosomes and decreases antiviral activity. Interestingly, autophagy reportedly induced by IFITM3 expression is also negatively regulated by ubiquitination. However, the canonical ATG5-dependent autophagy pathway is not required for IFITM3 activity, indicating that virus trafficking from endolysosomes to autophagosomes is not a pre-requisite for influenza virus restriction. Our characterization of IFITM3 ubiquitination sites also challenges the dual-pass membrane topology predicted for this protein family. We thus evaluated topology by N-linked glycosylation site insertion and protein lipidation mapping in conjunction with cellular fractionation and fluorescence imaging. Based on these studies, we propose that IFITM3 is predominantly an intramembrane protein where both the N and C termini face the cytoplasm. In sum, by characterizing S-palmitoylation and ubiquitination of IFITM3, we have gained a better understanding of the trafficking, activity, and intramembrane topology of this important IFN-induced effector protein.

We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions.

Background: Two competing concepts address the development of involvement with psychoactive substances: the "gateway hypothesis" (GH) and common liability to addiction (CLA). Method: The literature on theoretical foundations and empirical findings related to both concepts is reviewed. Results: The data suggest that drug use initiation sequencing, the core GH element, is variable and opportunistic rather than uniform and developmentally deterministic. The association between risks for use of different substances, if any, can be more readily explained by common underpinnings than by specific staging. In contrast, the CLA concept is grounded in genetic theory and supported by data identifying common sources of variation in the risk for specific addictions. This commonality has identifiable neurobiological substrate and plausible evolutionary explanations. Conclusions: Whereas the "gateway" hypothesis does not specify mechanistic connections between "stages", and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, and establishes a theoretical and empirical foundation to research in etiology, quantitative risk and severity measurement, as well as targeted non-drug-specific prevention and early intervention. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Active blood-brain barrier mechanisms, such as the major efflux transporter P-glycoprotein (mdr1), modulate the in vivo/central nervous system (CNS) effects of many pharmacological agents, whether they are used for nonmedical reasons or in pharmacotherapy. The powerful, widely available hallucinogen salvinorin A (from the plant Salvia divinorum) is a high-efficacy, selective kappa-opioid agonist and displays fast-onset behavioral effects (e. g., within 1 min of administration) and relatively short duration of action. In vitro studies suggest that salvinorin A may be a P-glycoprotein substrate; thus, the functional status of P-glycoprotein may influence the behavioral effects of salvinorin A or its residence in CNS after parenteral administration. We therefore studied whether a competing P-glycoprotein substrate (the clinically available agent loperamide; 0.032-0.32 mg/kg) or a selective P-glycoprotein blocker, tariquidar (0.32-3.2 mg/kg) could enhance unconditioned behavioral effects (ptosis and facial relaxation, known to be caused by kappa-agonists in nonhuman primates) of salvinorin A, as well as its entry and residence in the CNS, as measured by cerebrospinal fluid sampling. Pretreatment with either loperamide or tariquidar dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation. In a control study, loperamide and tariquidar were inactive when given as a pretreatment to ((+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593), a kappa-agonist known to be a very poor P-glycoprotein substrate. Furthermore, pretreatment with tariquidar (3.2 mg/kg) also enhanced peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These are the first studies in vivo showing the sensitivity of salvinorin A effects to modulation by the P-glycoprotein transporter, a major functional component of the blood-brain barrier.

Genetic and biological characterization of new hepaciviruses infecting animals contributes to our understanding of the ultimate origins of hepatitis C virus (HCV) infection in humans and dramatically enhances our ability to study its pathogenesis using tractable animal models. Animal homologs of HCV include a recently discovered canine hepacivirus (CHV) and GB virus B (GBV-B), both viruses with largely undetermined natural host ranges. Here we used a versatile serology-based approach to determine the natural host of the only known nonprimate hepacivirus (NPHV), CHV, which is also the closest phylogenetic relative of HCV. Recombinant protein expressed from the helicase domain of CHV NS3 was used as antigen in the luciferase immunoprecipitation system (LIPS) assay to screen several nonprimate animal species. Thirty-six samples from 103 horses were immunoreactive, and viral genomic RNA was present in 8 of the 36 seropositive animals and none of the seronegative animals. Complete genome sequences of these 8 genetically diverse NPHVs showed 14% (range, 6.4% to 17.2%) nucleotide sequence divergence, with most changes occurring at synonymous sites. RNA secondary structure prediction of the 383-base 5' untranslated region of NPHV was refined and extended through mapping of polymorphic sites to unpaired regions or (semi)covariant pairings. Similar approaches were adopted to delineate extensive RNA secondary structures in the coding region of the genome, predicted to form 27 regularly spaced, thermodynamically stable stem-loops. Together, these findings suggest a promising new nonprimate animal model and provide a database that will aid creation of functional NPHV cDNA clones and other novel tools for hepacivirus studies.