The TLR2/6 ligand PAM2CSK4 is a Th2 polarizing adjuvant in Leishmania major and Brugia malayi murine vaccine models.

Toll-like receptors (TLRs) play an important role in the innate and adaptive immune responses to pathogens, and are the target of new vaccine adjuvants. TLR2 plays a role in parasite recognition and activation of immune responses during cutaneous leishmaniasis infection, suggesting that TLR2 could be targeted by adjuvants for use in Leishmania vaccines. We therefore explored using Pam2CSK4 (Pam2) and Pam3CSK4 (Pam3) lipopeptide adjuvants, which activate TLR2/6 and TLR2/1 heterodimers respectively, in vaccine models for parasitic infections.The use of lipopeptide adjuvants was explored using two vaccine models. For cutaneous leishmaniasis, the lipopeptide adjuvants Pam2 and Pam3 were compared to that of the Th1-driving double-stranded DNA TLR9 agonist CpG for their ability to improve the efficacy of the autoclaved Leishmania major (ALM) vaccine to protect against L. major infection. The ability of Pam2 to enhance the efficacy of a soluble Brugia malayi microfilariae extract (BmMfE) vaccine to protect against filarial infection was also assessed in a peritoneal infection model of B. malayi filariasis. Parasite antigen-specific cellular and humoral immune responses were assessed post-challenge.The use of lipopeptides in ALM-containing vaccines did not provide any protection upon infection with L. major, and Pam2 exacerbated the disease severity in vaccinated mice post-challenge. Pam2, and to a lesser extent Pam3, were able to elevate antigen-specific immune responses post-challenge in this model, but these responses displayed a skewed Th2 phenotype as characterised by elevated levels of IgG1. In the B. malayi vaccine model, the use of Pam2 as an adjuvant with BmMfE induced significant protective immunity to the same level as inclusion of an Alum adjuvant. Here, both Pam2 and Alum were found to enhance antigen-specific antibody production post-challenge, and Pam2 significantly elevated levels of antigen-specific IL-4, IL-5 and IL-13 produced by splenocytes.These data indicate that TLR2/6-targeting ligands could be considered as adjuvants for vaccines that require robust Th2 and/or antibody-dependent immunity

Ontology engineering for simulation component reuse

Commercial-off-the-shelf (COTS) simulation packages (CSPs) are widely used in industry, although they have yet to operate across organizational boundaries. Reuse across organizations is restricted by the same semantic issues that restrict the inter-organizational use of web services. The current representations of web components are predominantly syntactic in nature lacking the fundamental semantic underpinning required to support discovery on the emerging semantic web. Semantic models, in the form of ontology, utilized by web service discovery and deployment architectures provide one approach to support simulation model reuse. Semantic interoperation is achieved through the use of simulation component ontologies to identify required components at varying levels of granularity (including both abstract and specialized components). Selected simulation components are loaded into a CSP, modified according to the requirements of the new model and executed. The paper presents the development of an ontology, connector software and web service discovery architecture. The ontology is extracted from simulation scenarios involving airport, restaurant and kitchen service suppliers. The ontology engineering framework and discovery architecture provide a novel approach to inter-organizational simulation, adopting a less intrusive interface between participants. Although specific to CSPs the work has wider implications for the simulation community

Semantic web services for simulation component reuse and interoperability: An ontology approach

Commercial-off-the-shelf (COTS) Simulation Packages (CSPs) are widely used in industry primarily due to economic factors associated with developing proprietary software platforms. Regardless of their widespread use, CSPs have yet to operate across organizational boundaries. The limited reuse and interoperability of CSPs are affected by the same semantic issues that restrict the inter-organizational use of software components and web services. The current representations of Web components are predominantly syntactic in nature lacking the fundamental semantic underpinning required to support discovery on the emerging Semantic Web. The authors present new research that partially alleviates the problem of limited semantic reuse and interoperability of simulation components in CSPs. Semantic models, in the form of ontologies, utilized by the authors’ Web service discovery and deployment architecture provide one approach to support simulation model reuse. Semantic interoperation is achieved through a simulation component ontology that is used to identify required components at varying levels of granularity (i.e. including both abstract and specialized components). Selected simulation components are loaded into a CSP, modified according to the requirements of the new model and executed. The research presented here is based on the development of an ontology, connector software, and a Web service discovery architecture. The ontology is extracted from simulation scenarios involving airport, restaurant and kitchen service suppliers. The ontology engineering framework and discovery architecture provide a novel approach to inter-organizational simulation, by adopting a less intrusive interface between participants Although specific to CSPs this work has wider implications for the simulation community. The reason being that the community as a whole stands to benefit through from an increased awareness of the state-of-the-art in Software Engineering (for example, ontology-supported component discovery and reuse, and service-oriented computing), and it is expected that this will eventually lead to the development of a unique Software Engineering-inspired methodology to build simulations in future

Surgical vs Conservative Treatments for Adolescent Shoulder Instability

Shoulder instability following an anterior shoulder dislocation is common in active adolescent populations and can have negative long-term impacts on activities of daily living and competitive physical activities. Historically, shoulder instability following anterior shoulder dislocation is treated surgically due to the high risk of recurrent instability. However, conservative treatments may be appropriate in certain adolescent populations due to skeletal immaturity. This article investigates the effectiveness of conservative therapy compared to surgical repair in the adolescent population with shoulder instability following anterior shoulder dislocation

Determining the possible application value of diatoms as indicators of general water quality: a comparison with SASS 5

The applicability of a European numerical diatom index, the Specific Pollution sensitivity Index (SPI), was tested in a river system where the SPI scores were compared both to chemical water quality and to scores yielded using a macro-invertebrate index of riverine health namely the South African Scoring System (SASS 5). This investigation showed that the SPI reflects certain elements of water quality with a high degree of accuracy. Due to the broad species base of SPI, few problems were encountered when using this system in the Southern Hemisphere. The conclusion is that SPI or a similar diatom index will provide a valuable addition to the suite of biomonitoring tools currently in use in South Africa. WaterSA Vol.30 (3) 2004: 325-33

Calcitization of aragonitic bryozoans in Cenozoic tropical carbonates from East Kalimantan, Indonesia

© The Author(s) 2016. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The file attached is the published version of the article

Neural Signatures of Prediction Errors in a Decision-Making Task are Modulated by Action Execution Failures

Decisions must be implemented through actions, and actions are prone to error. As such, when an expected outcome is not obtained, an individual should be sensitive to not only whether the choice itself was suboptimal but also whether the action required to indicate that choice was executed successfully. The intelligent assignment of credit to action execution versus action selection has clear ecological utility for the learner. To explore this, we used a modified version of a classic reinforcement learning task in which feedback indicated whether negative prediction errors were, or were not, associated with execution errors. Using fMRI, we asked if prediction error computations in the human striatum, a key substrate in reinforcement learning and decision making, are modulated when a failure in action execution results in the negative outcome. Participants were more tolerant of non-rewarded outcomes when these resulted from execution errors versus when execution was successful, but reward was withheld. Consistent with this behavior, a model-driven analysis of neural activity revealed an attenuation of the signal associated with negative reward prediction errors in the striatum following execution failures. These results converge with other lines of evidence suggesting that prediction errors in the mesostriatal dopamine system integrate high-level information during the evaluation of instantaneous reward outcomes

Pregnancy is associated with elevation of liver enzymes in HIV-positive women on antiretroviral therapy.

The objective of this study is to assess whether pregnancy is associated with an increased risk of liver enzyme elevation (LEE) and severe LEE in HIV-positive women on antiretroviral therapy (ART)

Duration of ruptured membranes and mother-to-child HIV transmission: a prospective population-based surveillance study

OBJECTIVE: To investigate the association between duration of rupture of membranes (ROM) and mother-to-child HIV transmission (MTCT) rates in the era of combination antiretroviral therapy (cART). DESIGN: The National Study of HIV in Pregnancy and Childhood (NSHPC) undertakes comprehensive population-based surveillance of HIV in pregnant women and children. SETTING: UK and Ireland. POPULATION: A cohort of 2398 singleton pregnancies delivered vaginally, or by emergency caesarean section, in women on cART in pregnancy during the period 2007-2012 with information on duration of ROM; HIV infection status was available for 1898 infants. METHODS: Descriptive analysis of NSHPC data. MAIN OUTCOME MEASURES: Rates of MTCT. RESULTS: In 2116 pregnancies delivered at term, the median duration of ROM was 3 hours 30 minutes (interquartile range, IQR 1-8 hours). The overall MTCT rate for women delivering at term with duration of ROM ≥4 hours was 0.64% compared with 0.34% for ROM <4 hours, with no significant difference between the groups (OR 1.90, 95% CI 0.45-7.97). In women delivering at term with a viral load of <50 copies/ml, there was no evidence of a difference in MTCT rates with duration of ROM ≥4 hours, compared with <4 hours (0.14% for ≥4 hours versus 0.12% for <4 hour; OR 1.14, 95% CI 0.07-18.27). Among infants born preterm with infection status available, there were no transmissions in 163 deliveries where the maternal viral load was <50 copies/ml. CONCLUSIONS: No association was found between duration of ROM and MTCT in women taking cART. TWEETABLE ABSTRACT: Rupture of membranes of more than 4 hours is not associated with MTCT of HIV in women on effective ART delivering at term