An investigation of herpes simplex virus promoter activity compatible with latency establishment reveals VP16-independent activation of immediate-early promoters in sensory neurones

Herpes simplex virus (HSV) type-1 establishes lifelong latency in sensory neurones and it is widely assumed that latency is the consequence of a failure to initiate virus immediate-early (IE) gene expression. However, using a Ore reporter mouse system in conjunction with Ore-expressing HSV-1 recombinants we have previously shown that activation of the IE ICPO promoter can precede latency establishment in at least 30 % of latently infected cells. During productive infection of non-neuronal cells, IE promoter activation is largely dependent on the transactivator VP16 a late structural component of the virion. Of significance, VP16 has recently been shown to exhibit altered regulation in neurones; where its de novo synthesis is necessary for IE gene expression during both lytic infection and reactivation from latency. In the current study, we utilized the Ore reporter mouse model system to characterize the full extent of viral promoter activity compatible with cell survival and latency establishment. In contrast to the high frequency activation of representative IE promoters prior to latency establishment, cell marking using a virus recombinant expressing Ore under VP16 promoter control was very inefficient. Furthermore, infection of neuronal cultures with VP16 mutants reveals a strong VP16 requirement for IE promoter activity in non-neuronal cells, but not sensory neurones. We conclude that only IE promoter activation can efficiently precede latency establishment and that this activation is likely to occur through a VP16-independent mechanism

When Are Two Workflows the Same?

In the area of workflow management, one is confronted with a large number of competing languages and the relations between them (e.g. relative expressiveness) are usually not clear. Moreover, even within the same language it is generally possible to express the same workflow in different ways, a feature known as variability. This paper aims at providing some of the formal groundwork for studying relative expressiveness and variability by defining notions of equivalence capturing different views on how workflow systems operate. Firstly, a notion of observational equivalence in the absence of silent steps is defined and related to classical bisimulation. Secondly, a number of equivalence notions in the presence of silent steps are defined. A distinction is made between the case where silent steps are visible (but not controllable) by the environment and the case where silent steps are not visible, i.e., there is an alternation between system events and environment interactions. It is shown that these notions of equivalence are different and do not coincide with classical notions of bisimulation with silent steps (e.g. weak and branching)

Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of α motoneurons in the spinal cord. SMA is caused by low levels of the ubiquitously expressed survival motor neuron (Smn) protein. As it is unclear how low levels of Smn specifically affect motoneurons, we have modeled SMA in zebrafish, a vertebrate model organism with well-characterized motoneuron development. Using antisense morpholinos to reduce Smn levels throughout the entire embryo, we found motor axon–specific pathfinding defects. Reduction of Smn in individual motoneurons revealed that smn is acting cell autonomously. These results show for the first time, in vivo, that Smn functions in motor axon development and suggest that these early developmental defects may lead to subsequent motoneuron loss

New findings from the time trade-off for income approach to elicit willingness to pay for a quality adjusted life year

In this paper we empirically investigate how to appropriately model utility of wealth and health. We use a recently proposed alternative approach to value willingness to pay (WTP) for health, making use of trade-offs between income and life years or quality of life, which we extend to allow for a more realistic multiplicative utility function over health and money. Moreover, we show how reference-dependency can be incorporated into this model and derive its predictions for WTP elicitation. We propose three experimental elicitation procedures and test these in a feasibility study, analysing the responses under different assumptions about the discount rate. Several interesting results are reported: first, the data are highly skewed, but if we trim the 5% lowest and highest values, we obtain plausible WTP estimates. Second, the results differ considerably between procedures, indicating that WTP estimates are sensitive to the assumed utility function. Third, respondents appear to be loss averse for both health and money, which is consistent with assumptions from prospect theory. Finally, our results also indicate that respondents are more willing to trade quality of life than life years

Hereditary haemorrhagic telangiectasia, an inherited vascular disorder in need of improved evidence-based pharmaceutical interventions

Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies

Patterns-based Evaluation of Open Source BPM Systems: The Cases of jBPM, OpenWFE, and Enhydra Shark

In keeping with the proliferation of free software development initiatives and the increased interest in the business process management domain, many open source workflow and business process management systems have appeared during the last few years and are now under active development. This upsurge gives rise to two important questions: what are the capabilities of these systems? and how do they compare to each other and to their closed source counterparts? i.e. in other words what is the state-of-the-art in the area?. To gain an insight into the area, we have conducted an in-depth analysis of three of the major open source workflow management systems - jBPM, OpenWFE and Enhydra Shark, the results of which are reported here. This analysis is based on the workflow patterns framework and provides a continuation of the series of evaluations performed using the same framework on closed source systems, business process modeling languages and web-service composition standards. The results from evaluations of the three open source systems are compared with each other and also with the results from evaluations of three representative closed source systems - Staffware, WebSphere MQ and Oracle BPEL PM, documented in earlier works. The overall conclusion is that open source systems are targeted more toward developers rather than business analysts. They generally provide less support for the patterns than closed source systems, particularly with respect to the resource perspective which describes the various ways in which work is distributed amongst business users and managed through to completion

Ultrafast extrinsic spin-Hall currents

We consider the possibility of ultrafast extrinsic spin-Hall currents, generated by skew scattering following the optical injection of charge or pure spin currents. We propose a phenomenological model for this effect in quantum well structures. An injected charge current leads to a spin-Hall-induced pure spin current, and an injected pure spin current leads to a spin-Hall-induced charge current. The resulting spin or charge accumulation can be measured optically.Comment: 18 pages, 3 figure

Flux Stabilization in 6 Dimensions: D-terms and Loop Corrections

We analyse D-terms induced by gauge theory fluxes in the context of 6-dimensional supergravity models. On the one hand, this is arguably the simplest concrete setting in which the controversial idea of `D-term uplifts' can be investigated. On the other hand, it is a very plausible intermediate step on the way from a 10d string theory model to 4d phenomenology. Our specific results include the flux-induced one-loop correction to the scalar potential coming from charged hypermultiplets. Furthermore, we comment on the interplay of gauge theory fluxes and gaugino condensation in the present context, demonstrate explicitly how the D-term arises from the gauging of one of the compactification moduli, and briefly discuss further ingredients that may be required for the construction of a phenomenologically viable model. In particular, we show how the 6d dilaton and volume moduli can be simultaneously stabilized, in the spirit of KKLT, by the combination of an R symmetry twist, a gaugino condensate, and a flux-induced D-term.Comment: 24 pages, 1 figure v2:minor correction

Contextualized Drug–Drug Interaction Management Improves Clinical Utility Compared With Basic Drug–Drug Interaction Management in Hospitalized Patients

Drug–drug interactions (DDIs) frequently trigger adverse drug events or reduced efficacy. Most DDI alerts, however, are overridden because of irrelevance for the specific patient. Basic DDI clinical decision support (CDS) systems offer limited possibilities for decreasing the number of irrelevant DDI alerts without missing relevant ones. Computerized decision tree rules were designed to context-dependently suppress irrelevant DDI alerts. A crossover study was performed to compare the clinical utility of contextualized and basic DDI management in hospitalized patients. First, a basic DDI-CDS system was used in clinical practice while contextualized DDI alerts were collected in the background. Next, this process was reversed. All medication orders (MOs) from hospitalized patients with at least one DDI alert were included. The following outcome measures were used to assess clinical utility: positive predictive value (PPV), negative predictive value (NPV), number of pharmacy interventions (PIs)/1,000 MOs, and the median time spent on DDI management/1,000 MOs. During the basic DDI management phase 1,919 MOs/day were included, triggering 220 DDI alerts/1,000 MOs; showing 57 basic DDI alerts/1,000 MOs to pharmacy staff; PPV was 2.8% with 1.6 PIs/1,000 MOs costing 37.2 minutes/1,000 MOs. No DDIs were missed by the contextualized CDS system (NPV 100%). During the contextualized DDI management phase 1,853 MOs/day were included, triggering 244 basic DDI alerts/1,000 MOs, showing 9.6 contextualized DDIs/1,000 MOs to pharmacy staff; PPV was 41.4% (P &lt; 0.01), with 4.0 PIs/1,000 MOs (P &lt; 0.01) and 13.7 minutes/1,000 MOs. The clinical utility of contextualized DDI management exceeds that of basic DDI management.</p