Security governance and networks: New theoretical perspectives in transatlantic security

The end of the Cold War has not only witnessed the rise of new transnational threats such as terrorism, crime, proliferation and civil war; it has also seen the growing role of non-state actors in the provision of security in Europe and North America. Two concepts in particular have been used to describe these transformations: security governance and networks. However, the differences and potential theoretical utility of these two concepts for the study of contemporary security have so far been under-examined. This article seeks to address this gap. It proposes that security governance can help to explain the transformation of Cold War security structures, whereas network analysis is particularly useful for understanding the relations and interactions between public and private actors in the making and implementation of national and international security policies

Computational Modelling of Genome-Side Transcription Assembly Networks Using a Fluidics Analogy

Understanding how a myriad of transcription regulators work to modulate mRNA output at thousands of genes remains a fundamental challenge in molecular biology. Here we develop a computational tool to aid in assessing the plausibility of gene regulatory models derived from genome-wide expression profiling of cells mutant for transcription regulators. mRNA output is modelled as fluid flow in a pipe lattice, with assembly of the transcription machinery represented by the effect of valves. Transcriptional regulators are represented as external pressure heads that determine flow rate. Modelling mutations in regulatory proteins is achieved by adjusting valves' on/off settings. The topology of the lattice is designed by the experimentalist to resemble the expected interconnection between the modelled agents and their influence on mRNA expression. Users can compare multiple lattice configurations so as to find the one that minimizes the error with experimental data. This computational model provides a means to test the plausibility of transcription regulation models derived from large genomic data sets

Access to Reliable Information about Long-Term Prognosis Influences Clinical Opinion on Use of Lifesaving Intervention

Background: Decompressive craniectomy has been traditionally used as a lifesaving rescue treatment in severe traumatic brain injury (TBI). This study assessed whether objective information on long-term prognosis would influence healthcare workers ’ opinion about using decompressive craniectomy as a lifesaving procedure for patients with severe TBI. Method: A two-part structured interview was used to assess the participants ’ opinion to perform decompressive craniectomy for three patients who had very severe TBI. Their opinion was assessed before and after knowing the predicted and observed risks of an unfavourable long-term neurological outcome in various scenarios. Results: Five hundred healthcare workers with a wide variety of clinical backgrounds participated. The participants were significantly more likely to recommend decompressive craniectomy for their patients than for themselves (mean difference in visual analogue scale [VAS] 21.5, 95 % confidence interval 21.3 to 21.6), especially when the next of kin of the patients requested intervention. Patients ’ preferences were more similar to patients who had advance directives. The participants’ preferences to perform the procedure for themselves and their patients both significantly reduced after knowing the predicted risks of unfavourable outcomes, and the changes in attitude were consistent across different specialties, amount of experience in caring for similar patients, religious backgrounds, and positions in the specialty of the participants. Conclusions: Access to objective information on risk of an unfavourable long-term outcome influenced healthcare workers

Crystal Structure and Functional Analysis of the SARS-Coronavirus RNA Cap 2′-O-Methyltransferase nsp10/nsp16 Complex

Cellular and viral S-adenosylmethionine-dependent methyltransferases are involved in many regulated processes such as metabolism, detoxification, signal transduction, chromatin remodeling, nucleic acid processing, and mRNA capping. The Severe Acute Respiratory Syndrome coronavirus nsp16 protein is a S-adenosylmethionine-dependent (nucleoside-2′-O)-methyltransferase only active in the presence of its activating partner nsp10. We report the nsp10/nsp16 complex structure at 2.0 Å resolution, which shows nsp10 bound to nsp16 through a ∼930 Å2 surface area in nsp10. Functional assays identify key residues involved in nsp10/nsp16 association, and in RNA binding or catalysis, the latter likely through a SN2-like mechanism. We present two other crystal structures, the inhibitor Sinefungin bound in the S-adenosylmethionine binding pocket and the tighter complex nsp10(Y96F)/nsp16, providing the first structural insight into the regulation of RNA capping enzymes in (+)RNA viruses

Determinants of synaptic integration and heterogeneity in rebound firing explored with data-driven models of deep cerebellar nucleus cells

Significant inroads have been made to understand cerebellar cortical processing but neural coding at the output stage of the cerebellum in the deep cerebellar nuclei (DCN) remains poorly understood. The DCN are unlikely to just present a relay nucleus because Purkinje cell inhibition has to be turned into an excitatory output signal, and DCN neurons exhibit complex intrinsic properties. In particular, DCN neurons exhibit a range of rebound spiking properties following hyperpolarizing current injection, raising the question how this could contribute to signal processing in behaving animals. Computer modeling presents an ideal tool to investigate how intrinsic voltage-gated conductances in DCN neurons could generate the heterogeneous firing behavior observed, and what input conditions could result in rebound responses. To enable such an investigation we built a compartmental DCN neuron model with a full dendritic morphology and appropriate active conductances. We generated a good match of our simulations with DCN current clamp data we recorded in acute slices, including the heterogeneity in the rebound responses. We then examined how inhibitory and excitatory synaptic input interacted with these intrinsic conductances to control DCN firing. We found that the output spiking of the model reflected the ongoing balance of excitatory and inhibitory input rates and that changing the level of inhibition performed an additive operation. Rebound firing following strong Purkinje cell input bursts was also possible, but only if the chloride reversal potential was more negative than −70 mV to allow de-inactivation of rebound currents. Fast rebound bursts due to T-type calcium current and slow rebounds due to persistent sodium current could be differentially regulated by synaptic input, and the pattern of these rebounds was further influenced by HCN current. Our findings suggest that active properties of DCN neurons could play a crucial role for signal processing in the cerebellum

Are we under-utilizing the talents of primary care personnel? A job analytic examination

BACKGROUND: Primary care staffing decisions are often made unsystematically, potentially leading to increased costs, dissatisfaction, turnover, and reduced quality of care. This article aims to (1) catalogue the domain of primary care tasks, (2) explore the complexity associated with these tasks, and (3) examine how tasks performed by different job titles differ in function and complexity, using Functional Job Analysis to develop a new tool for making evidence-based staffing decisions. METHODS: Seventy-seven primary care personnel from six US Department of Veterans Affairs (VA) Medical Centers, representing six job titles, participated in two-day focus groups to generate 243 unique task statements describing the content of VA primary care. Certified job analysts rated tasks on ten dimensions representing task complexity, skills, autonomy, and error consequence. Two hundred and twenty-four primary care personnel from the same clinics then completed a survey indicating whether they performed each task. Tasks were catalogued using an adaptation of an existing classification scheme; complexity differences were tested via analysis of variance. RESULTS: Objective one: Task statements were categorized into four functions: service delivery (65%), administrative duties (15%), logistic support (9%), and workforce management (11%). Objective two: Consistent with expectations, 80% of tasks received ratings at or below the mid-scale value on all ten scales. Objective three: Service delivery and workforce management tasks received higher ratings on eight of ten scales (multiple functional complexity dimensions, autonomy, human error consequence) than administrative and logistic support tasks. Similarly, tasks performed by more highly trained job titles received higher ratings on six of ten scales than tasks performed by lower trained job titles. Contrary to expectations, the distribution of tasks across functions did not significantly vary by job title. CONCLUSION: Primary care personnel are not being utilized to the extent of their training; most personnel perform many tasks that could reasonably be performed by personnel with less training. Primary care clinics should use evidence-based information to optimize job-person fit, adjusting clinic staff mix and allocation of work across staff to enhance efficiency and effectiveness

Catalytic living ring-opening metathesis polymerization

In living ring-opening metathesis polymerization (ROMP), a transition-metal–carbene complex polymerizes ring-strained olefins with very good control of the molecular weight of the resulting polymers. Because one molecule of the initiator is required for each polymer chain, however, this type of polymerization is expensive for widespread use. We have now designed a chain-transfer agent (CTA) capable of reducing the required amount of metal complex while still maintaining full control over the living polymerization process. This new method introduces a degenerative transfer process to ROMP. We demonstrate that substituted cyclohexene rings are good CTAs, and thereby preserve the ‘living’ character of the polymerization using catalytic quantities of the metal complex. The resulting polymers show characteristics of a living polymerization, namely narrow molecular-weight distribution, controlled molecular weights and block copolymer formation. This new technique provides access to well- defined polymers for industrial, biomedical and academic use at a fraction of the current costs and significantly reduced levels of residual ruthenium catalyst

Role of cAMP in the promotion of colorectal cancer cell growth by Prostaglandin E2

<p>Abstract</p> <p>Background</p> <p>Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) reaction, stimulates the growth of colonic epithelial cells. It is inferred that the abrogation of prostaglandins' growth-promoting effects as a result of COX inhibition underlies the advantageous effects of non-steroidal anti-inflammatory drugs in colorectal carcinoma (CRC). Despite this appreciation, the underlying molecular mechanisms remain obscure since cell culture studies have yielded discrepant results regarding PGE2's mitogenicity.</p> <p>Methods</p> <p>We have employed several alternative approaches to score cell proliferation and apoptosis of 4 CRC cell lines exposed to PGE2 under various conditions. To investigate the role of cAMP in PGE2's functions, activation of the cAMP pathway was assessed at different levels (changes in cAMP levels and PKA activity) in cells subjected to specific manipulations including the use of specific inhibitors or prostanoid receptor-selective agonists/antagonists.</p> <p>Results</p> <p>Our data document that the dose-response curve to PGE2 is 'bell-shaped', with nano molar concentrations of PGE2 being more mitogenic than micro molar doses. Remarkably, mitogenicity inversely correlates with the ability of PGE2 doses to raise cAMP levels. Consistent with a major role for cAMP, cAMP raising agents and pertussis toxin revert the mitogenic response to PGE2. Accordingly, use of prostanoid receptor-selective agonists argues for the involvement of the EP3 receptor and serum deprivation of HT29 CRC cells specifically raises the levels of Gi-coupled EP3 splice variants.</p> <p>Conclusion</p> <p>The present data indicate that the mitogenic action of low PGE2 doses in CRC cells is mediated via Gi-proteins, most likely through the EP3 receptor subtype, and is superimposed by a second, cAMP-dependent anti-proliferative effect at higher PGE2 doses. We discuss how these findings contribute to rationalize conflictive literature data on the proliferative action of PGE2.</p