The Effects of Cellulase on Cell Wall Structure and the Rumen Digestion of Alfalfa Silage

First- and second-cut alfalfa (Medicago sativa) was ensiled with no additive, microbial (Lactobacillus casei) inoculant, cellulase derived from Acremonium celluloytics Y-94, co-addition of inoculant and cellulase, and formic acid. The resultant silages were digested in the rumen of a dairy cow. The alfalfa and the silages were then examined with scanning electron microscope (SEM) and their chemical characteristics analyzed to evaluate the effects of cellulase on the quality of alfalfa silage and its cell wall structure. The addition of cellulase lend to both a greater loss of parenchymal tissue and decrease in digestibility during rumen degradation than did the other additives moreover, photos taken during SEM examination also showed that cellulase affected cell wall decomposition. The results of this study may suggest that the addition of cellulase affects fiber digestion by ruminant animals

The Effect of Cellulase on Cell Wall Structure and the Rumen Digestion of Timothy Silage

The objective of this study was to determine the effect of additives on the structure changes of related tissues during the ensiling process and the rumen digestion of timothy. In the first cut-timothy, the addition of LC+AC improved the fermentation qualities of the silage. Addition of cellulase resulted in significant decreases in NDF, ADF, cellulose, and hemicellulose content. SEM examination of the samples suggests that the degradation of parenchymal tissues was enhanced by the cellulase, but no significant differences were observed among the additives in the rumen digestion. The NDF and cellulose digestibility of the AC- and LC+AC-treated silages were lower than those of the other silages. In the second one, after digestion in the rumen, there was a marked loss of inner parenchymal tissues in AC and LC+AC-treated silages

Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis : Results from Greater Than 17,000 Patient-Years of Exposure

Altres ajuts: The studies described herein and the Rapid Service Fee were funded by Eli Lilly and Company.Long-term safety data are critical for evaluating therapies for psoriasis. Ixekizumab has demonstrated efficacy and is well tolerated for the treatment of moderate-to-severe plaque psoriasis. We examined the safety and tolerability of up to 5 years of ixekizumab therapy in patients with psoriasis. Integrated safety data were analyzed from 13 ixekizumab clinical studies. Rates of treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and AEs of special interest were analyzed for the 12-week induction period in the combined pivotal studies, and for all pooled studies by year(s) of therapy and overall, reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (p-y) and/or frequencies. Total ixekizumab exposure was 17,003.4 p-y (N = 5898); 2749 patients had ≥ 4 years of exposure. When compared across years of exposure, rates for AEs remained largely stable or declined, including TEAEs leading to discontinuation (3.8/100 p-y in year 1, declining to 2.0/100 p-y in year 5); SAEs (range 6.2-7.0/100 p-y); serious infections (range 1.3-1.7/100 p-y); nonmelanoma skin cancer (ranging from 0.5/100 p-y in year 1 to 0.2/100 p-y in years 4-5); other malignancies (range 0.4-0.6/100 p-y); inflammatory bowel disease including ulcerative colitis and Crohn's disease (IR 0.2/100 p-y); and major adverse cardiovascular events (MACE) (range 0.3-0.7/100 p-y). Candidiasis was reported in 327 patients (IR 1.9/100 p-y), with the majority identified as mucocutaneous. The rate of injection site reactions was 15.5/100 p-y during year 1 and 2.0-2.3/100 p-y by years 3-5. The decrease in rates of TEAEs and the stable rates of SAEs, other malignancies and MACE during up to 5 years of ixekizumab dosing are consistent with previous reports describing a favorable safety profile of ixekizumab following shorter durations of exposure. Eli Lilly and Company

Combining Effects and Coeffects via Grading

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by the Association for Computing Machinery.$\textit{Effects}$ and $\textit{coeffects}$ are two general, complementary aspects of program behaviour. They roughly correspond to computations which change the execution context (effects) versus computations which make demands on the context (coeffects). Effectful features include partiality, non-determinism, input-output, state, and exceptions. Coeffectful features include resource demands, variable access, notions of linearity, and data input requirements. The effectful or coeffectful behaviour of a program can be captured and described via type-based analyses, with fine grained information provided by monoidal effect annotations and semiring coeffects. Various recent work has proposed models for such typed calculi in terms of $\textit{graded (strong) monads}$ for effects and $\textit{graded (monoidal) comonads}$ for coeffects. Effects and coeffects have been studied separately so far, but in practice many computations are both effectful and coeffectful, e.g., possibly throwing exceptions but with resource requirements. To remedy this, we introduce a new general calculus with a combined $\textit{effect-coeffect system}$. This can describe both the $\textit{changes}$ and $\textit{requirements}$ that a program has on its context, as well as interactions between these effectful and coeffectful features of computation. The effect-coeffect system has a denotational model in terms of effect-graded monads and coeffect-graded comonads where interaction is expressed via the novel concept of $\textit{graded distributive laws}$. This graded semantics unifies the syntactic type theory with the denotational model. We show that our calculus can be instantiated to describe in a natural way various different kinds of interaction between a program and its evaluation context.Orchard was supported by EPSRC grant EP/M026124/1 and EP/K011715/1 (whilst previously at Imperial College London), Katsumata by JSPS KAKENHI grant JP15K00014, Uustalu by Estonian Min. of Educ. and Res. grant IUT33-13 and Estonian Sci. Found. grant 9475. Gaboardi’s work was done in part while at the University of Dundee, UK supported by EPSRC grant EP/M022358/1

Measured and projected beam backgrounds in the Belle II experiment at the SuperKEKB collider

The Belle II experiment at the SuperKEKB electron-positron collider aims to collect an unprecedented data set of $50~{\rm ab}^{-1}$ to study $CP$-violation in the $B$-meson system and to search for Physics beyond the Standard Model. SuperKEKB is already the world's highest-luminosity collider. In order to collect the planned data set within approximately one decade, the target is to reach a peak luminosity of $\rm 6 \times 10^{35}~cm^{-2}s^{-1}$ by further increasing the beam currents and reducing the beam size at the interaction point by squeezing the betatron function down to $\beta^{*}_{\rm y}=\rm 0.3~mm$. To ensure detector longevity and maintain good reconstruction performance, beam backgrounds must remain well controlled. We report on current background rates in Belle II and compare these against simulation. We find that a number of recent refinements have significantly improved the background simulation accuracy. Finally, we estimate the safety margins going forward. We predict that backgrounds should remain high but acceptable until a luminosity of at least $\rm 2.8 \times 10^{35}~cm^{-2}s^{-1}$ is reached for $\beta^{*}_{\rm y}=\rm 0.6~mm$. At this point, the most vulnerable Belle II detectors, the Time-of-Propagation (TOP) particle identification system and the Central Drift Chamber (CDC), have predicted background hit rates from single-beam and luminosity backgrounds that add up to approximately half of the maximum acceptable rates.Comment: 28 pages, 17 figures, 9 tables (revised

Polyamines Are Required for Virulence in Salmonella enterica Serovar Typhimurium

Sensing and responding to environmental cues is a fundamental characteristic of bacterial physiology and virulence. Here we identify polyamines as novel environmental signals essential for virulence of Salmonella enterica serovar Typhimurium, a major intracellular pathogen and a model organism for studying typhoid fever. Central to its virulence are two major virulence loci Salmonella Pathogenicity Island 1 and 2 (SPI1 and SPI2). SPI1 promotes invasion of epithelial cells, whereas SPI2 enables S. Typhimurium to survive and proliferate within specialized compartments inside host cells. In this study, we show that an S. Typhimurium polyamine mutant is defective for invasion, intracellular survival, killing of the nematode Caenorhabditis elegans and systemic infection of the mouse model of typhoid fever. Virulence of the mutant could be restored by genetic complementation, and invasion and intracellular survival could, as well, be complemented by the addition of exogenous putrescine and spermidine to the bacterial cultures prior to infection. Interestingly, intracellular survival of the polyamine mutant was significantly enhanced above the wild type level by the addition of exogenous putrescine and spermidine to the bacterial cultures prior to infection, indicating that these polyamines function as an environmental signal that primes S. Typhimurium for intracellular survival. Accordingly, experiments addressed at elucidating the roles of these polyamines in infection revealed that expression of genes from both of the major virulence loci SPI1 and SPI2 responded to exogenous polyamines and was reduced in the polyamine mutant. Together our data demonstrate that putrescine and spermidine play a critical role in controlling virulence in S. Typhimurium most likely through stimulation of expression of essential virulence loci. Moreover, our data implicate these polyamines as key signals in S. Typhimurium virulence

Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era

Abstract Background Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings. Methods We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding. Results Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4. Conclusions These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci.http://deepblue.lib.umich.edu/bitstream/2027.42/109537/1/12920_2013_Article_485.pd

Oncogenic KRAS sensitises colorectal tumour cells to chemotherapy by p53-dependent induction of Noxa

BACKGROUND: Oxaliplatin and 5-fluorouracil (5-FU) currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumour responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that oncogenic KRAS in colorectal tumour cells sensitises these cells to chemotherapy. METHODS: FACS analysis was used to determine cell-cycle distribution and the percentage of apoptotic and mitotic cells. A multiplexed RT-PCR assay was used to identify KRAS-controlled apoptosis regulators after exposure to 5-FU or oxaliplatin. Lentiviral expression of short-hairpin RNAs was used to suppress p53 or Noxa. RESULTS: Oncogenic KRAS sensitised colorectal tumour cells to oxaliplatin and 5-FU in a p53-dependent manner and promoted p53 phosphorylation at Ser37 and Ser392, without affecting p53 stabilisation, p21 induction, or cell-cycle arrest. Chemotherapy-induced expression of the p53 target gene Noxa was selectively enhanced by oncogenic KRAS. Suppression of Noxa did not affect p21 induction or cell-cycle arrest, but reduced KRAS/p53-dependent apoptosis after exposure to chemotherapy in vitro and in tumour xenografts. Noxa suppression did not affect tumour growth per se, but strongly reduced the response of these tumours to chemotherapy. CONCLUSION: Oncogenic KRAS determines the cellular response to p53 activation by oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa. British Journal of Cancer (2010) 102, 1254-1264. doi: 10.1038/sj.bjc.6605633 www.bjcancer.com Published online 30 March 2010 (C) 2010 Cancer Research U

Stat1 Phosphorylation Determines Ras Oncogenicity by Regulating p27Kip1

Inactivation of p27Kip1 is implicated in tumorigenesis and has both prognostic and treatment-predictive values for many types of human cancer. The transcription factor Stat1 is essential for innate immunity and tumor immunosurveillance through its ability to act downstream of interferons. Herein, we demonstrate that Stat1 functions as a suppressor of Ras transformation independently of an interferon response. Inhibition of Ras transformation and tumorigenesis requires the phosphorylation of Stat1 at tyrosine 701 but is independent of Stat1 phosphorylation at serine 727. Stat1 induces p27Kip1 expression in Ras transformed cells at the transcriptional level through mechanisms that depend on Stat1 phosphorylation at tyrosine 701 and activation of Stat3. The tumor suppressor properties of Stat1 in Ras transformation are reversed by the inactivation of p27Kip1. Our work reveals a novel functional link between Stat1 and p27Kip1, which act in coordination to suppress the oncogenic properties of activated Ras. It also supports the notion that evaluation of Stat1 phosphorylation in human tumors may prove a reliable prognostic factor for patient outcome and a predictor of treatment response to anticancer therapies aimed at activating Stat1 and its downstream effectors