Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homology modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives.     

Accumulation of oxidatively generated DNA damage in the brain: a mechanism of neurotoxicity

Unrepaired or erroneously repaired DNA lesions drive genomic instability and contribute to cellular and organ decline. Since delayed neuropathologies are common in survivors of smoke inhalation injuries, we asked whether the integrity of brain DNA might be compromised by acute exposure to combustion smoke. Although many studies demonstrate that the brain is equipped to repair oxidatively damaged DNA, to date, the capacity for accurate DNA repair under conditions of disrupted oxygenation and oxidative stress has not been defined. We show that DNA adducts detectable by their ability to block PCR amplification form in the rat hippocampus after acute exposure to smoke. To identify the different types of adducts and to dissect their temporal formation and repair profiles in vivo in the brain, we used DNA-modifying enzymes to convert specific adducts into strand breaks prior to PCR amplification. Using this strategy, we detected formation of oxidative DNA adducts early on after smoke inhalation, while mismatched bases emerged at the later recovery times, potentially due to an erroneous DNA repair process. Erroneous repair can be mutagenic and because the initial smoke-induced oxidative damage to DNA is extensive, compromised fidelity of DNA repair may underlie neurotoxicity and contribute to delayed death of hippocampal neurons.     

Mitochondrial diversification of the Peromyscus mexicanus species group in Nuclear Central America: biogeographic and taxonomic implications

The mountain mice of the Peromyscus mexicanus group currently encompass six known species; however, the limits between species remain uncertain, with two considered monotypic and the other four having multiple associated subspecific names. Based on the most comprehensive sampling of the group throughout its distribution in Nuclear Central America, we used data of the mitochondrial cytochrome b gene to assess its genetic diversity, phylogeny, and main biogeographic and diversification patterns. Our mitochondrial phylogeny only partially reflects the current taxonomy of the group, in agreement with some of the taxonomically recognized species. Specifically, our phylogenetic results show that the group is highly structured, including four main clades with genetic distances ranging from 11 to 8.6%. A remarkable level of differentiation is found at a more local level, defined as 15 different lineages with high nucleotide and haplotype diversity (π = 0.068, h = 0.99), and with divergence and genetic distance values (p‐uncorrected = 9.9–2.4%; K2P = 10.8–3.0%) similar to values observed between species within Peromyscus. Accordingly, we propose that the reference name P. mexicanus is polyphyletic and should be restricted to the mountains of central Mexico west of the Isthmus of Tehuantepec. We suggest to limit the other five recognized specific names to equal number of lineages, as monophyletic, and to revalidate three junior synonyms: Peromyscus salvadorensis, P. nicaraguae and P. tropicalis. The Isthmus of Tehuantepec, the Motagua‐Polochic‐Jocotán fault system, the Maya Highlands and the Honduras Depression are examples of geographic features that are likely associated with the differentiation of main lineages. Some other lineages may represent candidate species, hence the need to review the taxonomic status of the entire P. mexicanus group.     

A vestige of a prebiotic bonding machine is functioning within the contemporary ribosome

Based on the presumed capability of a prebiotic pocket-like entity to accommodate substrates whose stereochemistry enables the creation of chemical bonds, it is suggested that a universal symmetrical region identified within all contemporary ribosomes originated from an entity that we term the 'proto-ribosome'. This 'proto-ribosome' could have evolved from an earlier machine that was capable of performing essential tasks in the RNA world, called here the 'pre-proto-ribosome', which was adapted for producing proteins.     

Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.     

Abundance of archaeal and bacterial ammonia oxidizers – Possible bioindicator for soil monitoring

Many soil functions are driven by soil microorganisms and they have therefore been identified as appropriate indicators for monitoring of soil status. Genetic profiling of the bacterial ammonia oxidizing community was recently top-scored as soil biological indicator (Ritz et al., 2009). However, ammonia oxidation is not only performed by bacteria, but also ammonia oxidizing archaea. Based on the suggested niche differentiation between these two groups and findings that they are susceptible to environmental change in soil ecosystems at varying scales, we suggest that the abundance of these two communities rather than community profiling of the ammonia oxidizing bacteria could serve as a relevant and cost-effective bioindicator for soil monitoring.     

Do Stress Responses Promote Leukemia Progression? An Animal Study Suggesting a Role for Epinephrine and Prostaglandin-E2 through Reduced NK Activity

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E(2) or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.     

Antimicrobial peptides important in innate immunity

Antimicrobial peptides are present in all walks of life, from plants to animals, and they are considered to be endogenous antibiotics. In general, antimicrobial peptides are determinants of the composition of the microbiota and they function to fend off microbes and prevent infections. Antimicrobial peptides eliminate micro-organisms through disruption of their cell membranes. Their importance in human immunity, and in health as well as disease, has only recently been appreciated. The present review provides an introduction to the field of antimicrobial peptides in general and discusses two of the major classes of mammalian antimicrobial peptides: the defensins and the cathelicidins. The review focuses on their structures, their main modes of action and their regulation.     

Solvent isotope effects in intramolecular catalysis: Acyl transfer reactions of 4-nitrophenyl 5-nitrosalicylate in aqueous tris buffer

A kinetic study of the reactions of 4-nitrophenyl 5-nitrosalicylate in aqueous Tris buffer at 25°C has revealed three kinetically significant reactions: Tris aminolysis of the un-ionized substrate, Tris aminolysis of the ionized substrate, and spontaneous hydrolysis of the ionized substrate. Solvent isotope effects have been measured for all three reactions. Mechanisms are discussed, and the conclusion is reached that intramolecular catalysis is operating in only the spontaneous hydrolysis.