A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis

A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.     

The gateway pDEST17 expression vector encodes a -1 ribosomal frameshifting sequence

The attB1 site in the Gateway (Invitrogen) bacterial expression vector pDEST17, necessary for in vitro site-specific recombination, contains the sequence AAA-AAA. The sequence A-AAA-AAG within the Escherichia coli dnaX gene is recognized as ‘slippery’ and promotes −1 translational frameshifting. We show here, by expressing in E. coli several plant cDNAs with and without single nucleotide deletions close to the translation initiation codons, that pDEST17 is intrinsically susceptible to −1 ribosomal frameshifting at the sequence C-AAA-AAA. The deletion mutants produce correct-sized, active enzymes with a good correlation between enzyme amount and activity. We demonstrate unambiguously the frameshift through a combination of Edman degradation, MALDI-ToF mass fingerprint analysis of tryptic peptides and MALDI-ToF reflectron in-source decay (rISD) sequencing. The degree of frameshifting depends on the nature of the sequence being expressed and ranged from 25 to 60%. These findings suggest that caution should be exercised when employing pDEST17 for high-level protein expression and that the attB1 site has some potential as a tool for studying −1 frameshifting.     

The Angiosperm Gibberellin-GID1-DELLA Growth Regulatory Mechanism: How an “Inhibitor of an Inhibitor” Enables Flexible Response to Fluctuating Environments

The phytohormone gibberellin (GA) has long been known to regulate the growth, development, and life cycle progression of flowering plants. However, the molecular GA-GID1-DELLA mechanism that enables plants to respond to GA has only recently been discovered. In addition, studies published in the last few years have highlighted previously unsuspected roles for the GA-GID1-DELLA mechanism in regulating growth response to environmental variables. Here, we review these advances within a general plant biology context and speculate on the answers to some remaining questions. We also discuss the hypothesis that the GA-GID1-DELLA mechanism enables flowering plants to maintain transient growth arrest, giving them the flexibility to survive periods of adversity.     

Molecular evidence places the swallow bug genus Oeciacus Stål within the bat and bed bug genus Cimex Linnaeus (Heteroptera: Cimicidae)

The genera Cimex Linnaeus and Oeciacus Stål (Heteroptera: Cimicidae) are common haematophagous ectoparasites of bats or birds in the Holarctic region. Both their phylogenetic relationship and the systematics of the entire family previously were based on data from morphology and host relationships. Relationships among nine species of the genus Cimex and three species of the genus Oeciacus were analysed here using two mitochondrial and three nuclear genes. Cimex was shown to be paraphyletic with respect to Oeciacus. Oeciacus is thus proposed as a synonym of Cimex. The characteristic phenotype of Oeciacus results from the specific host association with different species of swallows (Hirundinidae). The morphological characters that have been used as diagnostic for the genera were shown to be valid and can be further used for determination at species level. The present analyses recovered the four traditional morphologically defined species groups of the genus Cimex. However, their relationships were poorly resolved – only the C. hemipterus group showed a well‐supported relationship to the C. pipistrelli group. The molecular differentiation within the Palaearctic C. pipistrelli and the Nearctic C. pilosellus species groups correlates with their karyotype differentiation. Furthermore, the analyses suggest poly‐ or paraphyly of the former genus Oeciacus. Either way this indicates there is a large amount of host‐associated phenotypic convergence in either bat‐ or bird‐associated groups of species. The probability of host choice and subsequent switch in Cimicidae are discussed and possible scenarios of the evolution of host association in species of Cimex are suggested.     

Early education and health outcomes of a 2001 U.S. Birth Cohort

This paper looks at health outcomes, health behaviors, and health screening with respect to participation in Early Childhood Care and Education. With information on health status at multiple periods in time, we are able to look at whether healthier children select into early childhood education (as measured by center-based preschool care and Head Start), as well as whether early childhood education has immediate and near-term effects on a range of health status measures. There is some evidence that child obesity is ameliorated by participation in center-based preschool or Head Start and this finding is supported by clear evidence of improved nutrition and increased levels of health screening. Effects on other health outcomes such as asthma, ear infections, and respiratory problems may be partially masked by unobserved heterogeneity.