Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism

During the activation of complement C4 to C4b, the exposure of its thioester domain (TED) is crucial for the attachment of C4b to activator surfaces. In the C4b crystal structure, TED forms an Arg(104)-Glu(1032) salt bridge to tether its neighbouring macroglobulin (MG1) domain. Here, we examined the C4b domain structure to test whether this salt bridge affects its conformation. Dual polarisation interferometry of C4b immobilised at a sensor surface showed that the maximum thickness of C4b increased by 0.46 nm with increase in NaCl concentration from 50 mM to 175 mM NaCl. Analytical ultracentrifugation showed that the sedimentation coefficient s20, w of monomeric C4b of 8.41 S in 50 mM NaCl buffer decreased to 7.98 S in 137 mM NaCl buffer, indicating that C4b became more extended. Small angle X-ray scattering reported similar RG values of 4.89-4.90 nm for C4b in 137-250 mM NaCl. Atomistic scattering modelling of the C4b conformation showed that TED and the MG1 domain were separated by 4.7 nm in 137-250 mM NaCl, this being greater than that of 4.0 nm in the C4b crystal structure. Our data reveal that in low NaCl concentrations, both at surfaces and in solution, C4b forms compact TED-MG1 structures. In solution, physiologically-relevant NaCl concentrations lead to the separation of the TED and MG1 domain, making C4b less able to bind to its complement regulators. These conformational changes are similar to those seen previously for complement C3b, confirming the importance of this salt bridge for regulating both C4b and C3b

The egiin davaa prehistoric rupture, central mongolia: A large magnitude normal faulting earthquake on a reactivated fault with little cumulative slip located in a slowly deforming intraplate setting

The prehistoric Egiin Davaa earthquake rupture is well-preserved in late Quaternary deposits within the Hangay Mountains of central Mongolia. The rupture is expressed by a semicontinuous 80 km-long topographic scarp. Geomorphological reconstructions reveal a relatively constant scarp height of 4-4.5 m and a NW-directed slip vector. Previous researchers have suggested that the scarp's exceptional geomorphological preservation indicates that it may correspond to an earthquake that occurred in the region c. 500 years ago. However, we constrain the last rupture to have been at least 4 ka ago from morphological dating and < 7.4 ka ago based on radiocarbon dating from one of two palaeoseismic trenches. Our study shows that discrete earthquake ruptures, along with details such as the locations of partially infilled fissures, can be preserved for periods well in excess of 1000 years in the interior of Asia, providing an archive of fault movements that can be directly read from the Earth's surface over a timescale appropriate for the study of slowly deforming continental interiors. The Egiin Davaa rupture involved c. 8 m of slip which, along with the observations that it is largely unsegmented along its length and that the ratio of cumulative slip (c. 250 m) to fault length (c. 80 km) is small, suggests relatively recent reactivation of a pre-existing geological structure

The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

Prostaglandin E2 Regulates AMPA Receptor Phosphorylation and Promotes Membrane Insertion in Preoptic Area Neurons and Glia during Sexual Differentiation

Sexual differentiation of the rodent brain is dependent upon the organizing actions of the steroid hormone, estradiol. In the preoptic area, a brain region critical for the expression of adult reproductive behavior, there are twice as many dendritic spine synapses per unit length on newborn male neurons compared to female neurons and this sex difference correlates with the expression of adult male copulatory behavior. The sex difference in the POA is achieved via estradiol's upregulation of the membrane-derived lipid signaling molecule prostaglandin E2 (PGE2); PGE2 is necessary and sufficient to masculinize both dendritic spine density and adult sexual behavior in rats. We have previously shown that PGE2 activates EP2 and EP4 receptors which increases protein kinase A (PKA) activity and that masculinized dendritic spine density and sex behavior are both dependent upon PKA as well as activation of AMPA type glutamate receptors. In the current experiments, we build upon this signaling cascade by determining that PGE2 induces phosphorylation of the AMPA receptor subunit, GluR1, which leads to increased AMPA receptor insertion at the membrane. Treating female pups on the day of birth with PGE2 induced the phosphorylation of GluR1 at the PKA-sensitive site within 2 hours of treatment, an effect that was blocked by co-administration of the PKA/AKAP inhibitor, HT31 with PGE2. Brief treatment of mixed neuronal/glial POA cultures with PGE2 or the cAMP/PKA stimulator, forskolin, increased membrane associated GluR1 in both neurons and glia. We speculate that PGE2 induced increases in AMPA receptor associated with the membrane underlies our previously observed increase in dendritic spine density and is a critical component in the masculinization of rodent sex behavior

Approaches to quality improvement in nursing homes: Lessons learned from the six-state pilot of CMS's Nursing Home Quality Initiative

BACKGROUND: In November 2002, the Centers for Medicare & Medicaid Services (CMS) launched a Nursing Home Quality Initiative that included publicly reporting a set of Quality Measures for all nursing homes in the country, and providing quality improvement assistance to nursing homes nationwide. A pilot of this initiative occurred in six states for six months prior to the launch. METHODS: Review and analysis of the lessons learned from the six Quality Improvement Organizations (QIOs) that led quality improvement efforts in nursing homes from the six pilot states. RESULTS: QIOs in the six pilot states found several key outcomes of the Nursing Home Quality Initiative that help to maximize the potential of public reporting to leverage effective improvement in nursing home quality of care. First, public reporting focuses the attention of all stakeholders in the nursing home industry on achieving good quality outcomes on a defined set of measures, and creates an incentive for partnership formation. Second, publicly reported quality measures motivate nursing home providers to improve in certain key clinical areas, and in particular to seek out new ways of changing processes of care, such as engaging physicians and the medical director more directly. Third, the lessons learned by QIOs in the pilot of this Initiative indicate that certain approaches to providing quality improvement assistance are key to guiding nursing home providers' desire and enthusiasm to improve towards a using a systematic approach to quality improvement. CONCLUSION: The Nursing Home Quality Initiative has already demonstrated the potential of public reporting to foster collaboration and coordination among nursing home stakeholders and to heighten interest of nursing homes in quality improvement techniques. The lessons learned from this pilot project have implications for any organizations or individuals planning quality improvement projects in the nursing home setting

The first determination of Generalized Polarizabilities of the proton by a Virtual Compton Scattering experiment

Absolute differential cross sections for the reaction (e+p -> e+p+gamma) have been measured at a four-momentum transfer with virtuality Q^2=0.33 GeV^2 and polarization \epsilon = 0.62 in the range 33.6 to 111.5 MeV/c for the momentum of the outgoing photon in the photon-proton center of mass frame. The experiment has been performed with the high resolution spectrometers at the Mainz Microtron MAMI. From the photon angular distributions, two structure functions which are a linear combination of the generalized polarizabilities have been determined for the first time.Comment: 4 pages, 3 figure

Carbon stable isotope analysis of cereal remains as a way to reconstruct water availability: preliminary results

Reconstructing past water availability, both as rainfall and irrigation, is important to answer questions about the way society reacts to climate and its changes and the role of irrigation in the development of social complexity. Carbon stable isotope analysis of archaeobotanical remains is a potentially valuable method for reconstructing water availability. To further define the relationship between water availability and plant carbon isotope composition and to set up baseline values for the Southern Levant, grains of experimentally grown barley and sorghum were studied. The cereal crops were grown at three stations under five different irrigation regimes in Jordan. Results indicate that a positive but weak relationship exists between irrigation regime and total water input of barley grains, but no relationship was found for sorghum. The relationship for barley is site-specific and inter-annual variation was present at Deir ‘Alla, but not at Ramtha and Khirbet as-Samra