Dalevilhelmsen8086

Another haplotype at the locus may reflect a secondary selection signal, although its functional impact is unknown. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median 4.1 months) versus placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤ 22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of mCRPC. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target/immunizing antigens PAP and/or PA2024; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (i.e. increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus has limited response to immune checkpoint inhibitors. Since sipuleucel-T is able to traffic T-cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email journals.permissions@oup.com.Salmonella enterica serovar Infantis (S. Infantis) is one of the dominant serovars of the bacterial pathogen Salmonella enterica. In recent years, the number of human infections caused by S. Infantis has been increasing in many countries, and often the emerging population harbors a unique virulence-resistant megaplasmid called pESI. Here, we report the complete gap-free genome sequence of the S. Infantis Israeli emerging clone and compare its chromosome and pESI sequences with other complete S. Infantis genomes. We show a conserved presence of the Salmonella pathogenicity islands 1-6, 9, 11, 12 and CS54 and a common integration of five bacteriophages in the S. Infantis chromosome. In contrast, we found variable presence of additionally three chromosomally integrated phages and eight modular regions in pESI, which contribute to the genetic and phenotypic diversity (including antimicrobial resistance) of this ubiquitous foodborne pathogen. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.Large (>10kb), nearly-identical (>99% nucleotide identity), palindromic sequences are enriched on mammalian sex chromosomes. Primate Y-palindromes undergo high rates of arm-to-arm gene conversion, a proposed mechanism for maintaining their sequence integrity in the absence of X-Y recombination. It is unclear whether X-palindromes, which can freely recombine in females, undergo arm-to-arm gene conversion and, if so, at what rate. We generated high-quality sequence assemblies of Mus molossinus and Mus spretus X-palindromic regions and compared them to orthologous Mus musculus X-palindromes. Our evolutionary sequence comparisons find evidence of X-palindrome arm-to-arm gene conversion at rates comparable to autosomal allelic gene conversion rates in mice. Mus X-palindromes also carry more derived than ancestral variants between species, suggesting their sequence is rapidly diverging. We speculate that in addition to maintaining genes' sequence integrity via sequence homogenization, palindrome arm-to-arm gene conversion may also facilitate rapid sequence divergence. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.MOTIVATION Therapeutic peptides failing at clinical trials could be attributed to their toxicity profiles like hemolytic activity, which hamper further progress of peptides as drug candidates. The accurate prediction of hemolytic peptides (HLPs) and its activity from the given peptides is one of the challenging tasks in immunoinformatics, which is essential for drug development and basic research. Although, there are a few computational methods that have been proposed for this aspect, none of them are able to identify hemolytic peptides and their activities simultaneously. RESULTS In this study, we proposed a two-layer prediction framework, called HLPpred-Fuse, that can accurately and automatically predict both hemolytic peptides (HLPs or non-HLPs) as well as HLPs activity (high and low). More specifically, feature representation learning scheme was utilized to generate 54 probabilistic features by integrating six different machine-learning classifiers and nine different sequence-based encodings. Consequently, the 54 probabilistic features were fused to provide sufficiently converged sequence information which was used as an input to extremely randomized tree for the development of two final prediction models which independently identify hemolytic peptide and its activity. Performance comparisons over empirical cross-validation analysis, independent test, and case study against state-of-the-art methods demonstrate that HLPpred-Fuse consistently outperformed these methods in the identification of hemolytic activity. AVAILABILITY For the convenience of experimental scientists, a web-based tool has been established at http//thegleelab.org/HLPpred-Fuse. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online. © The Author(s) (2020). Published by Oxford University Press. All rights reserved. this website For Permissions, please email journals.permissions@oup.com.