6′′‐Thioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91322/1/ange_201200761_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/91322/2/5750_ftp.pd

Personality Traits and Personal Values:A Meta-Analysis

Personality traits and personal values are important psychological characteristics, serving as important predictors of many outcomes. Yet, they are frequently studied separately, leaving the field with a limited understanding of their relationships. We review existing perspectives regarding the nature of the relationships between traits and values and provide a conceptual underpinning for understanding the strength of these relationships. Using 60 studies, we present a meta-analysis of the relationships between the Five-Factor Model (FFM) of personality traits and the Schwartz values, and demonstrate consistent and theoretically meaningful relationships. However, these relationships were not generally large, demonstrating that traits and values are distinct constructs. We find support for our premise that more cognitively based traits are more strongly related to values and more emotionally based traits are less strongly related to values. Findings also suggest that controlling for personal scale-use tendencies in values is advisable

Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1

Crystal structure of the VP4 protease from infectious pancreatic necrosis virus reveals the acyl-enzyme complex for an intermolecular self-cleavage reaction

Infectious pancreatic necrosis virus (IPNV), an aquatic birnavirus that infects salmonid fish, encodes a large polyprotein (NH2-pVP2-VP4-VP3-COOH) that is processed through the proteolytic activity of its own protease, VP4, to release the proteins pVP2 and VP3. pVP2 is further processed to give rise to the capsid protein VP2 and three peptides that are incorporated into the virion. Reported here are two crystal structures of the IPNV VP4 protease solved from two different crystal symmetries. The electron density at the active site in the triclinic crystal form, refined to 2.2-A˚ resolution, reveals the acyl-enzyme complex formed with an internalVP4cleavage site. The complex was generated using a truncated enzyme in which the general base lysine was substituted. Inside the complex, the nucleophilic Ser633O_ forms an ester bond with the main-chain carbonyl of the C-terminal residue, Ala716, of a neighboring VP4. The structure of this substrate-VP4 complex allows us to identify the S1, S3, S5, and S6 substrate binding pockets as well as other substrate- VP4 interactions and therefore provides structural insights into the substrate specificity of this enzyme. The structure from the hexagonal crystal form, refined to 2.3-A˚ resolution, reveals the free-binding site of the protease. Three-dimensional alignment with the VP4 of blotched snakehead virus, another birnavirus, shows that the overall structure of VP4 is conserved despite a low level of sequence identity (_19%). The structure determinations of IPNV VP4, the first of an acyl-enzyme complex for a Ser/Lys dyad protease, provide insights into the catalytic mechanism and substrate recognition of this type of protease

Expression, purification and crystallization of a birnavirus-encoded protease, VP4, from blotched snakehead virus (BSNV)

The expression, purification and crystallization of a viral protease from the blotched snakehead virus (BSNV) are described and the diffraction data collected to 2.5 Å from two different crystal forms are reported

Crystal structure of a novel viral protease with a serine/lysine catalytic dyad mechanism

International audienceThe blotched snakehead virus (BSNV), an aquatic birnavirus, encodes a polyprotein (NH2-pVP2-X-VP4-VP3-COOH) that is processed through the proteolytic activity of its own protease (VP4) to liberate itself and the viral proteins pVP2, X and VP3. The protein pVP2 is further processed by VP4 to give rise to the capsid protein VP2 and four structural peptides. We report here the crystal structure of a VP4 protease from BSNV, which displays a catalytic serine/lysine dyad in its active site. This is the first crystal structure of a birnavirus protease and the first crystal structure of a viral protease that utilizes a lysine general base in its catalytic mechanism. The topology of the VP4 substrate binding site is consistent with the enzymes substrate specificity and a nucleophilic attack from the si-face of the substrates scissile bond. Despite low levels of sequence identity, VP4 shows similarities in its active site to other characterized Ser/Lys proteases such as signal peptidase, LexA protease and Lon protease. Together, the structure of VP4 provides insights into the mechanism of a recently characterized clan of serine proteases that utilize a lysine general base and reveals the structure of potential targets for antiviral therapy, especially for other related and economically important viruses, such as infectious bursal disease virus in poultry and infectious pancreatic necrosis virus in aquaculture

Purification, crystallization and preliminary X-ray analysis of truncated and mutant forms of VP4 protease from infectious pancreatic necrosis virus

Various truncated and mutant forms of the protease VP4 from infectious pancreatic necrosis virus were used to generate two different crystal forms of VP4 which diffracted to beyond 2.4 Å resolution

Data from: Coral snakes predict the evolution of mimicry across New World snakes

Batesian mimicry, in which harmless species (mimics) deter predators by deceitfully imitating the warning signals of noxious species (models), generates striking cases of phenotypic convergence that are classic examples of evolution by natural selection. However, mimicry of venomous coral snakes has remained controversial because of unresolved conflict between the predictions of mimicry theory and empirical patterns in the distribution and abundance of snakes. Here we integrate distributional, phenotypic and phylogenetic data across all New World snake species to demonstrate that shifts to mimetic coloration in nonvenomous snakes are highly correlated with coral snakes in both space and time, providing overwhelming support for Batesian mimicry. We also find that bidirectional transitions between mimetic and cryptic coloration are unexpectedly frequent over both long- and short-time scales, challenging traditional views of mimicry as a stable evolutionary ‘end point’ and suggesting that insect and snake mimicry may have different evolutionary dynamics

Inside Cover: 6′′‐Thioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes (Angew. Chem. Int. Ed. 23/2012)

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Innentitelbild: 6′′‐Thioether Tobramycin Analogues: Towards Selective Targeting of Bacterial Membranes (Angew. Chem. 23/2012)

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