Bistability through triadic closure

We propose and analyse a class of evolving network models suitable for describing a dynamic topological structure. Applications include telecommunication, on-line social behaviour and information processing in neuroscience. We model the evolving network as a discrete time Markov chain, and study a very general framework where, conditioned on the current state, edges appear or disappear independently at the next timestep. We show how to exploit symmetries in the microscopic, localized rules in order to obtain conjugate classes of random graphs that simplify analysis and calibration of a model. Further, we develop a mean field theory for describing network evolution. For a simple but realistic scenario incorporating the triadic closure effect that has been empirically observed by social scientists (friends of friends tend to become friends), the mean field theory predicts bistable dynamics, and computational results confirm this prediction. We also discuss the calibration issue for a set of real cell phone data, and find support for a stratified model, where individuals are assigned to one of two distinct groups having different within-group and across-group dynamics.

Sexuality in older age: essential considerations for healthcare professionals

This review describes the fact that many elderly people enjoy an active sex life and examines the evidence against the general perception of an 'asexual' old age. It offers an overview of the evidence for healthcare professionals who had not previously considered the sexuality of their older patients. It also describes some of the sexual problems faced by older people, especially the difficulties experienced in disclosing such problems to healthcare professionals. It examines why healthcare professionals routinely avoid discussing sexual problems with older patients, and how this can be improved. It also offers some recommendations for future research in the area, as well as a word of caution regarding the temptation of over-sexualising the ageing process.

The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen.

Activation of mouse platelets by collagen is associated with tyrosine phosphorylation of multiple proteins including the Fc receptor gamma-chain, the tyrosine kinase Syk and phospholipase Cgamma2, suggesting that collagen signals in a manner similar to that of immune receptors. This hypothesis has been tested using platelets from mice lacking the Fc receptor gamma-chain or Syk. Tyrosine phosphorylation of Syk and phospholipase Cgamma2 by collagen stimulation is absent in mice lacking the Fc receptor gamma-chain. Tyrosine phosphorylation of phospholipase Cgamma2 by collagen stimulation is also absent in mice platelets which lack Syk, although phosphorylation of the Fc receptor gamma-chain is maintained. In contrast, tyrosine phosphorylation of platelet proteins by the G protein-coupled receptor agonist thrombin is maintained in mouse platelets deficient in Fc receptor gamma-chain or Syk. The absence of Fc receptor gamma-chain or Syk is accompanied by a loss of secretion and aggregation responses in collagen- but not thrombin-stimulated platelets. These observations provide the first direct evidence of an essential role for the immunoreceptor tyrosine-based activation motif (ITAM) in signalling by a non-immune receptor stimulus.

Essential selfadjointness of singular magnetic Schrödinger operators on Riemannian manifolds

In this paper we extend the well-known Leinfelder–Simader theorem on the essential selfadjointness of singular Schrödinger operators to arbitrary complete Riemannian manifolds. This improves some earlier results of Shubin, Milatovic and others.

SEF17 fimbriae are essential for the convoluted colonial morphology of Salmonella enteritidis

Salmonella enteritidis isolated from poultry infections generated a convoluted colonial morphology after 48 h growth on colonisation factor antigen (CFA) agar at 25 degrees C. A mutant S. enteritidis defective for the elaboration of the SEF17 fimbrial antigen, in which the agf gene cluster was inactivated by insertion of an ampicillin resistance gene cassette, and other wild-type S. enteritidis transduced to this genotype failed to produce convoluted colonies. However, growth of SEF17(-) mutans at 25 degrees C on CFA agar supplemented with 0.001% Congo red resulted in partial recovery of the phenotype. Immunoelectron microscopy demonstrated that copious amounts of the SEF17 fimbrial antigen were present in the extracellular matrix of convoluted colonies of wild-type virulent S. enteritidis isolates. Bacteria were often hyperflagellated also. Immunoelectron microscopy of SEF17(-) mutants grown on CFA agar+0.001% Congo red demonstrated the elaboration of an as yet undefined fimbrial structure. Isolates of S. enteritidis which were described previously as avirulent and sensitive to environmental stress failed to express SEF17 or produce convoluted colonies. These data indicate an essential role for SEF17, and possibly for another fimbria and flagella, in the generation of the convoluted colonial phenotype. The relationship between virulence and colonial phenotype is discussed.

Platelet protein disulfide isomerase is required for thrombus formation but not essential for hemostasis in mice

Protein disulfide isomerase (PDI) derived from intravascular cells is required for thrombus formation. However, it remains unclear whether platelet PDI contributes to the process. Using platelet-specific PDI-deficient mice, we demonstrate that PDI-null platelets have defects in aggregation and ATP secretion induced by thrombin, collagen, and ADP. Such defects were rescued by exogenously-added wild-type but not mutant PDI, indicating that the isomerase activity of platelet surface PDI is critical for the regulatory effect. PDI-deficient platelets expressed increased levels of intracellular ERp57 and ERp72. Platelet PDI regulated αIIbβ3 integrin activation but not P-selectin exposure, Ca2+ mobilization, β3-talin interaction, and platelet spreading on immobilized fibrinogen. Inhibition of ERp57 further diminished αIIbβ3 integrin activation, aggregation and ATP secretion of activated PDI-deficient platelets, suggesting distinct roles of PDI and ERp57 in platelet functions. We found that platelet PDI is important for thrombus formation on collagen-coated surfaces under arteriolar shear. Intravital microscopy demonstrates that platelet PDI is important for platelet accumulation but not initial adhesion and fibrin generation following laser-induced arteriolar injury. Tail bleeding time and blood loss in platelet-specific PDI-deficient mice were not significantly increased. Our results provide important evidence that platelet PDI is essential for thrombus formation but not for hemostasis in mice.

A defined intestinal colonization microbiota for gnotobiotic pigs

Maximising the ability of piglets to survive exposure to pathogens is essential to reduce early piglet mortality, an important factor in efficient commercial pig production. Mortality rates can be influenced by many factors, including early colonization by microbial commensals. Here we describe the development of an intestinal microbiota, the Bristol microbiota, for use in gnotobiotic pigs and its influence on synthesis of systemic immunoglobulins. Such a microbiota will be of value in studies of the consequences of early microbial colonization on development of the intestinal immune system and subsequent susceptibility to disease. Gnotobiotic pig studies lack a well-established intestinal microbiota. The use of the Altered Schaedler Flora (ASF), a murine intestinal microbiota, to colonize the intestines of Caesarean-derived, gnotobiotic pigs prior to gut closure, resulted in unreliable colonization with most (but not all) strains of the ASF. Subsequently, a novel, simpler porcine microbiota was developed. The novel microbiota reliably colonized the length of the intestinal tract when administered to gnotobiotic piglets. No health problems were observed, and the novel microbiota induced a systemic increase in serum immunoglobulins, in particular IgA and IgM. The Bristol microbiota will be of value for highly controlled, reproducible experiments of the consequences of early microbial colonization on susceptibility to disease in neonatal piglets, and as a biomedical model for the impact of microbial colonization on development of the intestinal mucosa and immune system in neonates.

3D cloud reconstructions: evaluation of scanning radar scan strategy with a view to surface shortwave radiation closure

The ability of six scanning cloud radar scan strategies to reconstruct cumulus cloud fields for radiation study is assessed. Utilizing snapshots of clean and polluted cloud fields from large eddy simulations, an analysis is undertaken of error in both the liquid water path and monochromatic downwelling surface irradiance at 870 nm of the reconstructed cloud fields. Error introduced by radar sensitivity, choice of radar scan strategy, retrieval of liquid water content (LWC), and reconstruction scheme is explored. Given an in␣nitely sensitive radar and perfect LWC retrieval, domain average surface irradiance biases are typically less than 3 W m␣2 ␣m␣1, corresponding to 5–10% of the cloud radiative effect (CRE). However, when using a realistic radar sensitivity of ␣37.5 dBZ at 1 km, optically thin areas and edges of clouds are dif␣cult to detect due to their low radar re-ectivity; in clean conditions, overestimates are of order 10 W m␣2 ␣m␣1 (~20% of the CRE), but in polluted conditions, where the droplets are smaller, this increases to 10–26 W m␣2 ␣m␣1 (~40–100% of the CRE). Drizzle drops are also problematic; if treated as cloud droplets, reconstructions are poor, leading to large underestimates of 20–46 W m␣2 ␣m␣1 in domain average surface irradiance (~40–80% of the CRE). Nevertheless, a synergistic retrieval approach combining the detailed cloud structure obtained from scanning radar with the droplet-size information and location of cloud base gained from other instruments would potentially make accurate solar radiative transfer calculations in broken cloud possible for the first time.

The ESA climate change initiative: satellite data records for essential climate variables

Observations of Earth from space have been made for over 40 years and have contributed to advances in many aspects of climate science. However, attempts to exploit this wealth of data are often hampered by a lack of homogeneity and continuity and by insufficient understanding of the products and their uncertainties. There is, therefore, a need to reassess and reprocess satellite datasets to maximize their usefulness for climate science. The European Space Agency has responded to this need by establishing the Climate Change Initiative (CCI). The CCI will create new climate data records for (currently) 13 essential climate variables (ECVs) and make these open and easily accessible to all. Each ECV project works closely with users to produce time series from the available satellite observations relevant to users' needs. A climate modeling users' group provides a climate system perspective and a forum to bring the data and modeling communities together. This paper presents the CCI program. It outlines its benefit and presents approaches and challenges for each ECV project, covering clouds, aerosols, ozone, greenhouse gases, sea surface temperature, ocean color, sea level, sea ice, land cover, fire, glaciers, soil moisture, and ice sheets. It also discusses how the CCI approach may contribute to defining and shaping future developments in Earth observation for climate science.

The dermomyotome ventrolateral lip is essential for the hypaxial myotome formation

Background The myotome is the primitive skeletal muscle that forms within the embryonic metameric body wall. It can be subdivided into an epaxial and hypaxial domain. It has been shown that the formation of the epaxial myotome requires the dorsomedial lip of the dermomyotome (DML). Although the ventrolateral lip (VLL) of the dermomyotome is believed to be required for the formation of the hypaxial myotome, experimentally evidence for this statement still needs to be provided. Provision of such data would enable the resolution of a debate regarding the formation of the hypaxial dermomyotome. Two mechanisms have been proposed for this tissue. The first proposes that the intermediate dermomyotome undergoes cellular expansion thereby pushing the ventral lateral lip in a lateral direction (translocation). In contrast, the alternative view holds that the ventral lateral lip grows laterally. Results Using time lapse confocal microscopy, we observed that the GFP-labelled ventrolateral lip (VLL) of the dermomyotome grows rather than translocates in a lateral direction. The necessity of the VLL for lateral extension of the myotome was addressed by ablation studies. We found that the hypaxial myotome did not form after VLL ablation. In contrast, the removal of an intermediate portion of the dermomyotome had very little effect of the hypaxial myotome. These results demonstrate that the VLL is required for the formation of the hypaxial myotome. Conclusion Our study demonstrates that the dermomyotome ventrolateral lip is essential for the hypaxial myotome formation and supports the lip extension model. Therefore, despite being under independent signalling controls, both the dorsomedial and ventrolateral lip fulfil the same function, i.e. they extend into adjacent regions permitting the growth of the myotome.

Integrin-linked kinase regulates the rate of platelet activation and is essential for the formation of stable thrombi

BACKGROUND: Integrin-linked kinase (ILK) and its associated complex of proteins are involved in many cellular activation processes, including cell adhesion and integrin signaling. We have previously demonstrated that mice with induced platelet ILK deficiency show reduced platelet activation and aggregation, but only a minor bleeding defect. Here, we explore this apparent disparity between the cellular and hemostatic phenotypes. METHODS: The impact of ILK inhibition on integrin αII b β3 activation and degranulation was assessed with the ILK-specific inhibitor QLT0267, and a conditional ILK-deficient mouse model was used to assess the impact of ILK deficiency on in vivo platelet aggregation and thrombus formation. RESULTS: Inhibition of ILK reduced the rate of both fibrinogen binding and α-granule secretion, but was accompanied by only a moderate reduction in the maximum extent of platelet activation or aggregation in vitro. The reduction in the rate of fibrinogen binding occurred prior to degranulation or translocation of αII b β3 to the platelet surface. The change in the rate of platelet activation in the absence of functional ILK led to a reduction in platelet aggregation in vivo, but did not change the size of thrombi formed following laser injury of the cremaster arteriole wall in ILK-deficient mice. It did, however, result in a marked decrease in the stability of thrombi formed in ILK-deficient mice. CONCLUSION: Taken together, the findings of this study indicate that, although ILK is not essential for platelet activation, it plays a critical role in facilitating rapid platelet activation, which is essential for stable thrombus formation.

Reconfiguration and closure of lobe flux by reconnection during northward IMF: possible evidence for signatures in cusp/cleft auroral emissions

Observations are presented of the response of the dayside cusp/cleft aurora to changes in both the clock and elevation angles of the interplanetary magnetic field (IMF) vector, as monitored by the WIND spacecraft. The auroral observations are made in 630 nm light at the winter solstice near magnetic noon, using an all-sky camera and a meridian-scanning photometer on the island of Spitsbergen. The dominant change was the response to a northward turning of the IMF which caused a poleward retreat of the dayside aurora. A second, higher-latitude band of aurora was seen to form following the northward turning, which is interpreted as the effect of lobe reconnection which reconfigures open flux. We suggest that this was made possible in the winter hemisphere, despite the effect of the Earth's dipole tilt, by a relatively large negative X component of the IMF. A series of five events then formed in the poleward band and these propagated in a southwestward direction and faded at the equatorward edge of the lower-latitude band as it migrated poleward. It is shown that the auroral observations are consistent with overdraped lobe flux being generated by lobe reconnection in the winter hemisphere and subsequently being re-closed by lobe reconnection in the summer hemisphere. We propose that the balance between the reconnection rates at these two sites is modulated by the IMF elevation angle, such that when the IMF points more directly northward, the summer lobe reconnection site dominates, re-closing all overdraped lobe flux and eventually becoming disconnected from the Northern Hemisphere.

Nicked-site substrates for a serine recombinase reveal enzyme–DNA communications and an essential tethering role of covalent enzyme–DNA linkages

To analyse the mechanism and kinetics of DNA strand cleavages catalysed by the serine recombinase Tn3 resolvase, we made modified recombination sites with a single-strand nick in one of the two DNA strands. Resolvase acting on these sites cleaves the intact strand very rapidly, giving an abnormal half-site product which accumulates. We propose that these reactions mimic second-strand cleavage of an unmodified site. Cleavage occurs in a synapse of two sites, held together by a resolvase tetramer; cleavage at one site stimulates cleavage at the partner site. After cleavage of a nicked-site substrate, the half-site that is not covalently linked to a resolvase subunit dissociates rapidly from the synapse, destabilizing the entire complex. The covalent resolvase–DNA linkages in the natural reaction intermediate thus perform an essential DNA-tethering function. Chemical modifications of a nicked-site substrate at the positions of the scissile phosphodiesters result in abolition or inhibition of resolvase-mediated cleavage and effects on resolvase binding and synapsis, providing insight into the serine recombinase catalytic mechanism and how resolvase interacts with the substrate DNA.