Interleukin-1 Receptor–Associated Kinase M–Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia

Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL-1R)–associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M^−/−) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M^−/− alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M^−/− mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M^−/− mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen.     

Phosphorylation-dependent structural changes in the regulatory light chain domain of smooth muscle heavy meromyosin.

Smooth muscle heavy meromyosin, a double-headed proteolytic fragment of myosin lacking the COOH-terminal two-thirds of the tail, has been shown previously to be regulated by phosphorylation. To examine phosphorylation-dependent structural changes near the head-tail junction, we prepared five well regulated heavy meromyosins containing single-cysteine mutants of the human smooth muscle regulatory light chain labeled with the photocross-linking reagent, benzophenone-iodoacetamide. For those mutants that generated cross-links, only one type of cross-linked species was observed, a regulatory light chain dimer. Irradiated mutants fell into two classes. First, for Q15C, A23C, and wild type (Cys-108), a regulatory light chain dimer was formed for dephosphorylated but not thiophosphorylated heavy meromyosin. These data provide direct chemical evidence that in the dephosphorylated state, Gln-15, Ala-23, and Cys-108 on one head are positioned near (within 8.9 A) the regulatory light chain of the partner head and that thiophosphorylation abolishes proximity. This behavior was also observed for the Q15C mutant on a truncated heavy meromyosin lacking both catalytic domains. For the actin-heavy meromyosin complex, cross-links were formed in both de- and thiophosphorylated states. S59C and T134C mutants were in a second mutant class, where regulatory light chain dimers were not detected in dephosphorylated or thiophosphorylated heavy meromyosin, suggesting positions outside the region of interaction of the regulatory light chains.     

Oral histories and the impact of archaeological fieldwork in contact encounters: meeting Socrates on the Omo

Whilst there is growing concern within archaeology about the wider impact of archaeological research in general, only limited attention has so far been paid to the impact fieldwork has on local communities. Here, using examples from fieldwork with an agro‐pastoral Mursi community in Ethiopia's Lower Omo Valley, we present a case in which local oral traditions are modified in response to archaeological discoveries. This illustrates a particular example of the impact of fieldwork during and after its completion; and the enduring traces of contact upon fieldwork participants. We argue that in employing an attitude of impact practice within fieldwork that foregrounds the Socratic notion of dialogue, the resulting focus highlights the value and significance of archaeology to local communities.     

Citrullination, a possible functional link between susceptibility genes and rheumatoid arthritis

Antibodies directed to citrullinated proteins (anti-cyclic citrullinated peptide) are highly specific for rheumatoid arthritis (RA). Recent data suggest that the antibodies may be involved in the disease process of RA and that several RA-associated genetic factors might be functionally linked to RA via modulation of the production of anti-cyclic citrullinated peptide antibodies or citrullinated antigens.     

Signaling activities among the Arabidopsis phyB/D/E-type phytochromes: a major role for the central region of the apoprotein

The Arabidopsis phyB, phyD, and phyE phytochromes regulate plant developmental and growth responses to continuous red light (R) and to the ratio of R to far-red (FR) light. The activities of these three photoreceptors in the control of seedling growth have been compared using a transgenic assay based upon induction of R-hypersensitivity of hypocotyl elongation by overexpression of the apoproteins from the 35S promoter. 35S-phyB, 35S-phyD, and 35S-phyE lines expressing similar levels of the respective phytochromes were isolated. Under pulses of R, phyB is very active in inducing a dwarf hypocotyl phenotype, whereas phyD and phyE are inactive. Under high-fluence continuous R, phyD shows a gain in activity whereas phyE does not. These results demonstrate significant differences in the inherent regulatory activities of these receptor apoproteins. To localize the sequence determinants of these functional differences, chimeric proteins were constructed by shuffling amino-terminal, central, and carboxy-terminal regions of phyB and phyD. Overexpression analysis of the phyB/D chimeras shows that it is the central region of these proteins that is most critical in determining their respective activities.