The kinase VRK1 is required for normal meiotic progression in mammalian oogenesis

The kinase VRK1 has been implicated in mitotic and meiotic progression in invertebrate species, but whether it mediates these events during mammalian gametogenesis is not completely understood. Previous work has demonstrated a role for mammalian VRK1 in proliferation of male spermatogonia, yet whether VRK1 plays a role in meiotic progression, as seen in Drosophila, has not been determined. Here, we have established a mouse strain bearing a gene trap insertion in the VRK1 locus that disrupts Vrk1 expression. In addition to the male proliferation defects, we find that reduction of VRK1 activity causes a delay in meiotic progression during oogenesis, results in the presence of lagging chromosomes during formation of the metaphase plate, and ultimately leads to the failure of oocytes to be fertilized. The activity of at least one phosphorylation substrate of VRK1, p53, is not required for these defects. These results are consistent with previously defined functions of VRK1 in meiotic progression in Drosophila oogenesis, and indicate a conserved role for VRK1 in coordinating proper chromosomal configuration in female meiosis.     

7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site

Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice.     

Cutaneous malignancies: melanoma and nonmelanoma types

This article reviews melanoma and nonmelanoma cutaneous malignancies.     

Analyzing nested experimental designs—A user-friendly resampling method to determine experimental significance

While hierarchical experimental designs are near-ubiquitous in neuroscience and biomedical research, researchers often do not take the structure of their datasets into account while performing statistical hypothesis tests. Resampling-based methods are a flexible strategy for performing these analyses but are difficult due to the lack of open-source software to automate test construction and execution. To address this, we present Hierarch, a Python package to perform hypothesis tests and compute confidence intervals on hierarchical experimental designs. Using a combination of permutation resampling and bootstrap aggregation, Hierarch can be used to perform hypothesis tests that maintain nominal Type I error rates and generate confidence intervals that maintain the nominal coverage probability without making distributional assumptions about the dataset of interest. Hierarch makes use of the Numba JIT compiler to reduce p-value computation times to under one second for typical datasets in biomedical research. Hierarch also enables researchers to construct user-defined resampling plans that take advantage of Hierarch’s Numba-accelerated functions.     

Protein synthesis as an early response to fertilization of the sea urchin egg: A model

We have developed a quantitative computer model which simulates the rise in protein synthesis resulting from the fertilization of the sea urchin egg. The model predicts the kinetics of incorporation of radioactively labeled amino acids into proteins for the experimental situation in which the amino acid pool is labeled prior to fertilization. The computer model is used to examine the impact of changes in the values of major parameters such as the time of initiation of protein synthesis, the rate at which mRNA is unmasked, the ribosome transit time, and the rate of depletion of the labeled amino acid pool on the kinetics of amino acid incorporation. When experimentally determined values for these parameters are used the model predicts kinetics which closely approximate the kinetics actually observed in newly fertilized eggs. We suggest that the rate at which mRNA is made available for translation and a change in the elongation rate following fertilization control the rise in protein synthesis, and that both of these processes are initiated within 0–2 min following the initial fertilization event.     

Unraveling the Role of the C-terminal Helix Turn Helix of the Coat-binding Domain of Bacteriophage P22 Scaffolding Protein

Many viruses encode scaffolding and coat proteins that co-assemble to form procapsids, which are transient precursor structures leading to progeny virions. In bacteriophage P22, the association of scaffolding and coat proteins is mediated mainly by ionic interactions. The coat protein-binding domain of scaffolding protein is a helix turn helix structure near the C terminus with a high number of charged surface residues. Residues Arg-293 and Lys-296 are particularly important for coat protein binding. The two helices contact each other through hydrophobic side chains. In this study, substitution of the residues of the interface between the helices, and the residues in the β-turn, by aspartic acid was used examine the importance of the conformation of the domain in coat binding. These replacements strongly affected the ability of the scaffolding protein to interact with coat protein. The severity of the defect in the association of scaffolding protein to coat protein was dependent on location, with substitutions at residues in the turn and helix 2 causing the most significant effects. Substituting aspartic acid for hydrophobic interface residues dramatically perturbs the stability of the structure, but similar substitutions in the turn had much less effect on the integrity of this domain, as determined by circular dichroism. We propose that the binding of scaffolding protein to coat protein is dependent on angle of the β-turn and the orientation of the charged surface on helix 2. Surprisingly, formation of the highly complex procapsid structure depends on a relatively simple interaction.     

Associations between stress reactivity and sexual and nonsexual risk taking in young adult human males

Release of the hormone cortisol represents a distress response to novel or stressful situations. Individual differences in such reactivity have been conceptualized as representing a relatively enduring, generalizable trait. In this study, cortisol responses to two experimentally manipulated "sexual" and "nonsexual" stressors were used to examine whether stress reactivity is related to sexual and nonsexual risk behavior in young adult males. Analyses were based on 150 males 18 to 25 years old; risk behavior was assessed in confidential, self-administered questionnaires. Analyses indicated that both stressors effectively elicited cortisol increases. Generalized reactivity, defined as a cortisol response to both stressors, was inversely associated with deviance (e.g., theft, substance use) and with two indicators of sexual risk taking (lifetime number of intercourse partners and frequency of condom use). Findings are discussed in terms of cross-situational consistency of stress responses, the utility of stress reactivity for understanding individual differences in risk taking, and the interpretive limitations imposed by study design.