The deleted in brachydactyly B domain of ROR2 is required for receptor activation by recruitment of Src

The transmembrane receptor 'ROR2' resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its' signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach, that ROR2 exhibits dimerisation-induced tyrosine kinase activity and the ROR2 C-terminal domain, which is deleted in BDB, is required for recruitment and activation of the non-receptor tyrosine kinase Src. Native ROR2 phosphorylation is induced by the ligand Wnt5a and is blocked by pharmacological inhibition of Src kinase activity. Eight sites of Src-mediated ROR2 phosphorylation have been identified by mass spectrometry. Activation via tyrosine phosphorylation of ROR2 receptor leads to its internalisation into Rab5 positive endosomes. These findings show that BDB mutant receptors are defective in kinase activation as a result of failure to recruit Src

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Regulation of the JNK3 signaling pathway during islet isolation: JNK3 and c-fos as new markers of islet quality for transplantation.

Stress conditions generated throughout pancreatic islet processing initiate the activation of pro-inflammatory pathways and beta-cell destruction. Our goal is to identify relevant and preferably beta-specific markers to assess the activation of beta-cell stress and apoptotic mechanisms, and therefore the general quality of the islet preparation prior to transplantation. Protein expression and activation were analyzed by Western blotting and kinase assays. ATP measurements were performed by a luminescence-based assay. Oxygen consumption rate (OCR) was measured based on standard protocols using fiber optic sensors. Total RNA was used for gene expression analyzes. Our results indicate that pancreas digestion initiates a potent stress response in the islets by activating two stress kinases, c-Jun N-terminal Kinase (JNK) and p38. JNK1 protein levels remained unchanged between different islet preparations and following culture. In contrast, levels of JNK3 increased after islet culture, but varied markedly, with a subset of preparations bearing low JNK3 expression. The observed changes in JNK3 protein content strongly correlated with OCR measurements as determined by the Spearman's rank correlation coefficient rho [Formula: see text] in the matching islet samples, while inversely correlating with c-fos mRNA expression [Formula: see text]. In conclusion, pancreas digestion recruits JNK and p38 kinases that are known to participate to beta-cell apoptosis. Concomitantly, the islet isolation alters JNK3 and c-fos expression, both strongly correlating with OCR. Thus, a comparative analysis of JNK3 and c-fos expression before and after culture may provide for novel markers to assess islet quality prior to transplantation. JNK3 has the advantage over all other proposed markers to be islet-specific, and thus to provide for a marker independent of non-beta cell contamination

Assessment of risk of insect-resistant transgenic crops to nontarget arthropods

An international initiative is developing a scientifically rigorous approach to evaluate the potential risks to nontarget arthropods (NTAs) posed by insect-resistant, genetically modified (IRGM) crops. It adapts the tiered approach to risk assessment that is used internationally within regulatory toxicology and environmental sciences. The approach focuses on the formulation and testing of clearly stated risk hypotheses, making maximum use of available data and using formal decision guidelines to progress between testing stages (or tiers). It is intended to provide guidance to regulatory agencies that are currently developing their own NTA risk assessment guidelines for IRGM crops and to help harmonize regulatory requirements between different countries and different regions of the world

The Late Pleistocene Po River lowstand wedge in the Adriatic Sea: Controls on architecture variability and sediment partitioning

Although facies and stratal geometries of continental margin successions can be defined in detail based on subsurface and outcrop studies, most studies lack the high-resolution age control needed to constrain the time scale of formation of such successions and infer their external forcing mechanisms. Our work on the Po River Lowstand Wedge (PRLW) indicates that deposition rates are surprisingly high with the entire 350-m-thick succession being deposited in less than 17,000 years, and with individual clinothems recording time periods ranging from 400 to 4700 years. The PRLW preserves a high-resolution record of stacked, deltaic shelf-edge clinothems deposited during the Last Glacial Maximum (31.8–14.4 ky BP) in the Adriatic basin (Mediterranean Sea). We investigated clinothem internal geometry, stacking patterns, and facies distributions to infer the main controls on their growth by integrating seismic reflection data with seismic facies attributes and paleoenvironmental proxies. The stratigraphic framework of the shelf-edge clinothems was then related to major paleoenvironmental shifts during the last glacial cycle and driven by eustatic and climatic changes. Within the PRLW, we recognized three distinctive types of 100's-m-high shelf-edge clinothems, type A, type B and type C, each with diagnostic topset geometries, shelf-edge trajectories, and associated distal basin-fill deposits. These elemental clinothem types stack into two Clinothem Sets. Clinothem Set 1, with essentially flat to slightly descending shelf-edge trajectory, is composed of stacked types A and B clinothems, and records the direct influence of river flux leading to dysoxic conditions on the bottom of the basin. In particular, clinothem accumulation rates were as much as 200 km3/ky in some of the type B clinothems. Clinothem Set 2, showing ascending shelf-edge trajectory, records an aggradational stacking coupled with a retreat of the river-entry points with benthic fauna assemblages that reflect the influence of peaks in freshwater discharge. Whereas Clinothem Set 1 developed under perturbations of river supply linked to the multi-scale waxing and waning of glaciers during an interval dominated by eustatic fall, Clinothem Set 2 reflects the main thawing of glaciers concomitant to the first phase of the eustatic rise. From a sequence stratigraphic perspective, Clinothem Set 1 is interpreted as staked high-frequency sequences, while Clinothem Set 2 represents a stack of high-frequency parasequences. The high-resolution age control from boreholes and seismic data enabled us to relate stratal character to independently constrained environmental proxies: this revealed how the evolution of a shelf-edge system intricately convolves the influences of both global (eustacy) and regional (climate-driven supply fluctuations) controls, both at sub-Milankovitch scales. Finally, the thickness, geometry, and stacking patterns of the centennial to millennial clinothems of the PRLW vary in systematic ways resulting in geometries that closely resemble those of ancient shelf-edge systems, and offering the PRLW as a sub-modern analogue. Our observations also reinforce the focus of the classic sequence-stratigraphic approach on analyzing surfaces and their geometric relations and not on time duration or formation mechanisms

The International Law of Secession and the Protection of the Human Rights of Oppressed Sub-State Groups: Yesterday, Today and Tomorrow

This paper focuses on significant patterns/features in the historical development of the international law of secession and its contribution over time (or the lack thereof) to the struggle to afford greater protection to oppressed sub-state groups the world over. It was Crawford Young who once observed that “the state as an analytical quarry is an elusive and complex prey.” With the necessary modifications, this observation applies with almost equal force to the international law of secession. Complexity and confusion loom too large in this area of international law. For example, there is, at best, little clarity in the literature of the discipline of international law and in related fields of study regarding the existence or otherwise of an international legal entitlement to secession in favor of even the most highly oppressed and subjugated sub-state groups

The Role of Neutrophils during Mild and Severe Influenza Virus Infections of Mice

Neutrophils have been implicated in both protective and pathological responses following influenza virus infections. We have used mAb 1A8 (anti-Ly6G) to specifically deplete LyG6high neutrophils and induce neutropenia in mice infected with virus strains known to differ in virulence. Mice were also treated with mAb RB6-8C5 (anti-Ly6C/G or anti-Gr-1), a mAb widely used to investigate the role of neutrophils in mice that has been shown to bind and deplete additional leukocyte subsets. Using mAb 1A8, we confirm the beneficial role of neutrophils in mice infected with virus strains of intermediate (HKx31; H3N2) or high (PR8; H1N1) virulence whereas treatment of mice infected with an avirulent strain (BJx109; H3N2) did not affect disease or virus replication. Treatment of BJx109-infected mice with mAb RB6-8C5 was, however, associated with significant weight loss and enhanced virus replication indicating that other Gr-1+ cells, not neutrophils, limit disease severity during mild influenza infections

The role of neutrophils in the upper and lower respiratory tract during influenza virus infection of mice

BACKGROUND: Neutrophils have been shown to play a role in host defence against highly virulent and mouse-adapted strains of influenza virus, however it is not clear if an effective neutrophil response is an important factor moderating disease severity during infection with other virus strains. In this study, we have examined the role of neutrophils during infection of mice with influenza virus strain HKx31, a virus strain of the H3N2 subtype and of moderate virulence for mice, to determine the role of neutrophils in the early phase of infection and in clearance of influenza virus from the respiratory tract during the later phase of infection. METHODS: The anti-Gr-1 monoclonal antibody (mAb) RB6-8C5 was used to (i) identify neutrophils in the upper (nasal tissues) and lower (lung) respiratory tract of uninfected and influenza virus-infected mice, and (ii) deplete neutrophils prior to and during influenza virus infection of mice. RESULTS: Neutrophils were rapidly recruited to the upper and lower airways following influenza virus infection. We demonstrated that use of mAb RB6-8C5 to deplete C57BL/6 (B6) mice of neutrophils is complicated by the ability of this mAb to bind directly to virus-specific CD8+ T cells. Thus, we investigated the role of neutrophils in both the early and later phases of infection using CD8+ T cell-deficient B6.TAP-/- mice. Infection of B6.TAP-/- mice with a low dose of influenza virus did not induce clinical disease in control animals, however RB6-8C5 treatment led to profound weight loss, severe clinical disease and enhanced virus replication throughout the respiratory tract. CONCLUSION: Neutrophils play a critical role in limiting influenza virus replication during the early and later phases of infection. Furthermore, a virus strain of moderate virulence can induce severe clinical disease in the absence of an effective neutrophil response

Near-identical star formation rate densities from Hα and FUV at redshift zero

For the first time both H$\alpha$ and far-ultraviolet (FUV) observations from an HI-selected sample are used to determine the dust-corrected star formation rate density (SFRD: $\dot{\rho}$) in the local Universe. Applying the two star formation rate indicators on 294 local galaxies we determine log($\dot{\rho}$$_{H\alpha}) = -1.68~^{+0.13}_{-0.05}$ [M$_{\odot}$ yr$^{-1}$ Mpc$^{-3}]$ and log($\dot{\rho}_{FUV}$) $= -1.71~^{+0.12}_{-0.13}$ [M$_\odot$ yr$^{-1}$ Mpc$^{-3}]$. These values are derived from scaling H$\alpha$ and FUV observations to the HI mass function. Galaxies were selected to uniformly sample the full HI mass (M$_{HI}$) range of the HI Parkes All-Sky Survey (M$_{HI} \sim10^{7}$ to $\sim10^{10.7}$ M$_{\odot}$). The approach leads to relatively larger sampling of dwarf galaxies compared to optically-selected surveys. The low HI mass, low luminosity and low surface brightness galaxy populations have, on average, lower H$\alpha$/FUV flux ratios than the remaining galaxy populations, consistent with the earlier results of Meurer. The near-identical H$\alpha$- and FUV-derived SFRD values arise with the low H$\alpha$/FUV flux ratios of some galaxies being offset by enhanced H$\alpha$ from the brightest and high mass galaxy populations. Our findings confirm the necessity to fully sample the HI mass range for a complete census of local star formation to include lower stellar mass galaxies which dominate the local Universe.Partial funding for the SINGG and SUNGG surveys came from NASA grants NAG5-13083 (LTSA program), GALEX GI04- 0105-0009 (NASA GALEX Guest Investigator grant) and NNX09AF85G (GALEX archival grant) to G.R. Meurer. FAR acknowledges partial funding from the Department of Physics, University of Western Australia. This research has made use of the NASA/IPAC Extragalactic Database (NED), which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration

General beliefs about medicines among doctors and nurses in out-patient care: a cross-sectional study

Background: Doctors and nurses are two natural partners in the healthcare team, but they usually differ in their perspectives on how to work for increased health. These professions may also have different beliefs about medicines, a factor important for adherence to medicines. The aim was to explore general beliefs about medicines among doctors and nurses.Methods: Questionnaires were sent to 306 private practitioners (PPs), 298 general practitioners (GPs) and 303 nurses in the county of Västra Götaland, Sweden. The questionnaire included sociodemographic questions and the general part of the Beliefs about Medicines Questionnaire (BMQ), which measures the beliefs people have about medicines in general. General beliefs about medicines in relation to background variables were explored with independent t-tests and ANOVA analyses. Differences between occupations and influences of interaction variables were analysed with multiple linear regression models for general beliefs about medicines.  Results: The data collection resulted in 616 questionnaires (62.1% PPs; 61.6% GPs; 80.5% nurses). The majority of the PPs and 40% of the GPs were male but most of the nurses were female. The GPs' mean age was 47 years, PPs' 60 years and nurses' 52 years. Few nurses originated from non-Nordic countries while 15% of the PPs and 25% of the GPs did. Nurses saw medicines as more harmful and less beneficial than did PPs and GPs. These differences could not be explained by the included interaction variables. GPs with a Nordic background saw medicines as more beneficial and less harmful than did GPs with a non-Nordic background. Furthermore, GPs of non-Nordic origin were most likely to believe that medicines were  overprescribed by doctors.Conclusion: Doctors were more positive about medicines than nurses. The differences in beliefs about medicines found between doctors and nurses could not be explained by any of the included interaction variables. These differences in beliefs may be useful in discussions among future and practising doctors and nurses to enhance understanding of each other's profession and teamwork. </p