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Psoriasis is present in all racial groups, but in varying frequencies and severity. Considering that small plaque psoriasis is specific to the Asian population and severe psoriasis is more predominant in the Western population, we defined Asian small and intermediate plaque psoriasis as psoriasis subtypes and compared their molecular signatures with the classic subtype of Western large plaque psoriasis. Two different characteristics of psoriatic spreading-vertical growth and radial expansion-were contrasted between subtypes, and genomic data were correlated to histologic and clinical measurements. Compared with Western large plaque psoriasis, Asian small plaque psoriasis revealed limited psoriasis spreading, but IL-17A and IL-17-regulated proinflammatory cytokines were highly expressed. Paradoxically, IL-17A and IL-17-regulated proinflammatory cytokines were lower in Western large plaque psoriasis, whereas T cells and dendritic cells in total psoriatic skin area were exponentially increased. Negative immune regulators, such as CD69 and FAS, were decreased in both Western large plaque psoriasis and psoriasis with accompanying arthritis or obesity, and their expression was correlated with psoriasis severity index. Based on the disease subtype comparisons, we propose that dysregulation of T-cell expansion enabled by downregulation of immune negative regulators is the main mechanism for development of large plaque psoriasis subtypes.

A search is presented for a singly produced excited bottom quark (b*) decaying to a top quark and a W boson in the all-hadronic, lepton+jets, and dilepton final states in proton-proton collisions at root s = 8 TeV recorded by the CMS experiment at the CERN LHC. Data corresponding to an integrated luminosity of 19.7 fb(-1) are used. No significant excess of events is observed with respect to standard model expectations. We set limits at 95% confidence on the product of the b* quark production cross section and its branching fraction to tW. The cross section limits are interpreted for scenarios including left-handed, right-handed, and vector-like couplings of the b* quark and are presented in the two-dimensional coupling plane based on the production and decay coupling constants. The masses of the left-handed, right-handed, and vector-like b* quark states are excluded at 95% confidence below 1390, 1430, and 1530 GeV, respectively, for benchmark couplings. This analysis gives the most stringent limits on the mass of the b* quark to date.

Classical republicanism and classical liberalism divide on the understanding of freedom, the one taking it as non-domination, the other as non-interference. And essentially the same division survives today, with serious policy implications, between neo-republicanism and neo-liberalism.

I applaud Morsella et al.'s approach to investigate consciousness in terms of behavioral control. After all, the function of the brain is to control behavior, and consciousness contributes to the function of the brain. However, I question whether conscious content is available only to the skeletal muscle system, as the principle of parallel responses into skeletal muscle (PRISM) (Morsella 2005) proposes.

Background Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1. Patients and Methods A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model. Results None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50-3.70], P = 2x10(-4)). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82-8.92], P = 8x10(-4)). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10(-5)). Conclusion Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir-or boceprevir-based therapy.

Stevia (Stevia rebaudiana) produces not only a group of diterpenoid glycosides known as steviol glycosides (SGs), but also other labdane-type diterpenoids that may be spatially separated from SGs. However, their biosynthetic routes and spatial distribution in leaf tissues have not yet been elucidated. Here, we integrate metabolome and transcriptome analyses of Stevia to explore the biosynthetic capacity of leaf tissues for diterpenoid metabolism. Tissue-specific chemical analyses confirmed that SGs were accumulated in leaf cells but not in trichomes. On the other hand, Stevia leaf trichomes stored other labdane-type diterpenoids such as oxomanoyl oxide and agatholic acid. RNA sequencing analyses from two different tissues of Stevia provided a comprehensive overview of dynamic metabolic activities in trichomes and leaf without trichomes. These metabolite-guided transcriptomics and phylogenetic and gene expression analyses clearly identified specific gene members encoding enzymes involved in the 2-C-methyl-D-erythritol 4-phosphate pathway and the biosynthesis of steviol or other labdane-type diterpenoids. Additionally, our RNA sequencing analysis uncovered copalyl diphosphate synthase (SrCPS) and kaurene synthase1 (SrKS1) homologs, SrCPS2 and KS-like (SrKSL), which were specifically expressed in trichomes. In vitro and in planta assays showed that unlike SrCPS and SrKS1, SrCPS2 synthesized labda-13-cn-8-ol diphosphate and successively catalyzed the formation of manoyl oxide and epi-manoyl oxide in combination with SrKSL. Our findings suggest that Stevia may have evolved to use distinct metabolic pathways to avoid metabolic interferences in leaf tissues for efficient production of diverse secondary metabolites.

Objectives: To measure plasma nucleosome levels and expression of toll-like receptors (TLRs) in a pilot cohort of patients with severe acute kidney injury (AKI) within a randomised controlled trial of continuous venovenous haemofiltration with high cut-off filters (CVVH-HCO) v standard filters (CVVH-std). Methods: We measured plasma nucleosome levels using the Cell Death Detection ELISA PLUS (10X) assay kit. We analysed plasma levels for correlation with disease severity and compared the effects of CVVH-HCO and CVVH-std on plasma nucleosome levels over the first 72 hours. We studied cell surface TLR expression on CD14-positive monocytes in a subcohort of CVVH-HCO patients. Results: We did not detect nucleosomes in normal human plasma, but found elevated nucleosome levels in patients with severe AKI. Nucleosome levels at randomisation correlated weakly with Acute Physiology and Chronic Health Evaluation Ill scores (Pearson rho =0.475, P=0.016). Treatment with CVVH-HCO or CVVH-std had no effect on nucleosome levels over 72 hours. The mean fluorescence intensity (MFI) ratios of TLR2 and TLR4 expression were elevated throughout the 72-hour period (range for TLR2, 0.97-3.98; range for TLR4, 0.91-10.18) and did not appear to decrease as a result of treatment with CVVH-HCO. Conclusions: Nucleosome concentration was elevated in the plasma of patients with severe AKI and mildly correlated with disease severity, but was not affected by treatment with CVVH-HCO or CVVH-std. Similarly, levels of TLR2 and TLR4 expression did not decrease over time during CVVH-HCO treatment.

As a consequence of excessive antibiotic therapies in hospitalized patients, Clostridium difficile, a Gram-positive anaerobic spore-forming intestinal pathogen, is the leading cause of hospital-acquired diarrhea and colitis. Drug treatments for these diseases are often complicated by antibiotic-resistant strains and a high frequency of treatment failures and relapse; therefore, novel nonantibiotic approaches may prove to be more effective. In this study, we recombinantly expressed a prophage lysin identified from a C. difficile strain, CD630, which we named PlyCD. PlyCD was found to have lytic activity against specific C. difficile strains. However, the recombinantly expressed catalytic domain of this protein, PlyCD(1-174), displayed significantly greater lytic activity (>4-log kill) and a broader lytic spectrum against C. difficile strains while still retaining a high degree of specificity toward C. difficile versus commensal clostridia and other bacterial species. Our data also indicated that noneffective doses of vancomycin and PlyCD(1-174) when combined in vitro could be significantly more bactericidal against C. difficile. In an ex vivo treatment model of mouse colon infection, we found that PlyCD(1-174) functioned in the presence of intestinal contents, significantly decreasing colonizing C. difficile compared to controls. Together, these data suggest that PlyCD(1-174) has potential as a novel therapeutic for clinical application against C. difficile infection, either alone or in combination with other preexisting treatments to improve their efficacy.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.