Genome-wide mRNA expression correlates of viral control in CD4+ T-cells from HIV-1-infected individuals.

There is great interindividual variability in HIV-1 viral setpoint after seroconversion, some of which is known to be due to genetic differences among infected individuals. Here, our focus is on determining, genome-wide, the contribution of variable gene expression to viral control, and to relate it to genomic DNA polymorphism. RNA was extracted from purified CD4+ T-cells from 137 HIV-1 seroconverters, 16 elite controllers, and 3 healthy blood donors. Expression levels of more than 48,000 mRNA transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina). Genome-wide SNP data was generated from genomic DNA using the HumanHap550 Genotyping BeadChip (Illumina). We observed two distinct profiles with 260 genes differentially expressed depending on HIV-1 viral load. There was significant upregulation of expression of interferon stimulated genes with increasing viral load, including genes of the intrinsic antiretroviral defense. Upon successful antiretroviral treatment, the transcriptome profile of previously viremic individuals reverted to a pattern comparable to that of elite controllers and of uninfected individuals. Genome-wide evaluation of cis-acting SNPs identified genetic variants modulating expression of 190 genes. Those were compared to the genes whose expression was found associated with viral load: expression of one interferon stimulated gene, OAS1, was found to be regulated by a SNP (rs3177979, p = 4.9E-12); however, we could not detect an independent association of the SNP with viral setpoint. Thus, this study represents an attempt to integrate genome-wide SNP signals with genome-wide expression profiles in the search for biological correlates of HIV-1 control. It underscores the paradox of the association between increasing levels of viral load and greater expression of antiviral defense pathways. It also shows that elite controllers do not have a fully distinctive mRNA expression pattern in CD4+ T cells. Overall, changes in global RNA expression reflect responses to viral replication rather than a mechanism that might explain viral control.

Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection.

Natural killer (NK) cells play an essential role in innate immune control of poxviral infections in vivo. However, the mechanism(s) underlying NK cell activation and function in response to poxviruses remains poorly understood. In a mouse model of infection with vaccinia virus (VV), the most studied member of the poxvirus family, we identified that the Toll-like receptor (TLR) 2-myeloid differentiating factor 88 (MyD88) pathway was critical for the activation of NK cells and the control of VV infection in vivo. We further showed that TLR2 signaling on NK cells, but not on accessory cells such as dendritic cells (DCs), was necessary for NK cell activation and that this intrinsic TLR2-MyD88 signaling pathway was required for NK cell activation and played a critical role in the control of VV infection in vivo. In addition, we showed that the activating receptor NKG2D was also important for efficient NK activation and function, as well as recognition of VV-infected targets. We further demonstrated that VV could directly activate NK cells via TLR2 in the presence of cytokines in vitro and TLR2-MyD88-dependent activation of NK cells by VV was mediated through the phosphatidylinositol 3-kinase (PI3K)-extracellular signal-regulated kinase (ERK) pathway. Taken together, these results represent the first evidence that intrinsic TLR signaling is critical for NK cell activation and function in the control of a viral infection in vivo, indicate that multiple pathways are required for efficient NK cell activation and function in response to VV infection, and may provide important insights into the design of effective strategies to combat poxviral infections.

The increasing impact of human immunodeficiency virus infections, sexually transmitted diseases, and viral hepatitis in Durham County, North Carolina: a call for coordinated and integrated services.

BACKGROUND: Durham County, North Carolina, faces high rates of human immunodeficiency virus (HIV) infection (with or without progression to AIDS) and sexually transmitted diseases (STDs). We explored the use of health care services and the prevalence of coinfections, among HIV-infected residents, and we recorded community perspectives on HIV-related issues. METHODS: We evaluated data on diagnostic codes, outpatient visits, and hospitalizations for individuals with HIV infection, STDs, and/or hepatitis B or C who visited Duke University Hospital System (DUHS). Viral loads for HIV-infected patients receiving care were estimated for 2009. We conducted geospatial mapping to determine disease trends and used focus groups and key informant interviews to identify barriers and solutions to improving testing and care. RESULTS: We identified substantial increases in HIV/STDs in the southern regions of the county. During the 5-year period, 1,291 adults with HIV infection, 4,245 with STDs, and 2,182 with hepatitis B or C were evaluated at DUHS. Among HIV-infected persons, 13.9% and 21.8% were coinfected with an STD or hepatitis B or C, respectively. In 2009, 65.7% of HIV-infected persons receiving care had undetectable viral loads. Barriers to testing included stigma, fear, and denial of risk, while treatment barriers included costs, transportation, and low medical literacy. LIMITATIONS: Data for health care utilization and HIV load were available from different periods. Focus groups were conducted among a convenience sample, but they represented a diverse population. CONCLUSIONS: Durham County has experienced an increase in the number of HIV-infected persons in the county, and coinfections with STDs and hepatitis B or C are common. Multiple barriers to testing/treatment exist in the community. Coordinated care models are needed to improve access to HIV care and to reduce testing and treatment barriers.

Biomimetic engineered muscle with capacity for vascular integration and functional maturation in vivo.

Tissue-engineered skeletal muscle can serve as a physiological model of natural muscle and a potential therapeutic vehicle for rapid repair of severe muscle loss and injury. Here, we describe a platform for engineering and testing highly functional biomimetic muscle tissues with a resident satellite cell niche and capacity for robust myogenesis and self-regeneration in vitro. Using a mouse dorsal window implantation model and transduction with fluorescent intracellular calcium indicator, GCaMP3, we nondestructively monitored, in real time, vascular integration and the functional state of engineered muscle in vivo. During a 2-wk period, implanted engineered muscle exhibited a steady ingrowth of blood-perfused microvasculature along with an increase in amplitude of calcium transients and force of contraction. We also demonstrated superior structural organization, vascularization, and contractile function of fully differentiated vs. undifferentiated engineered muscle implants. The described in vitro and in vivo models of biomimetic engineered muscle represent enabling technology for novel studies of skeletal muscle function and regeneration.

Suppression of the Hepatitis C viral load by Phyllanthus niruri extracts

Gemstone Team ANTIDOTE

When a trauma becomes a key to identity: Enhanced integration of trauma memories predicts posttraumatic stress disorder symptoms

The Centrality of Event Scale (CES) measures the extent to which a traumatic memory forms a central component of personnal identity, a turning point in the life story and a reference point for everyday inferences. In two studies, we show that the CES is positively correlated with severity of PTSD symptoms, even when controlling for measures of anxiety, depression, dissociation and self-consciousness. The findings contradict the widespread view that poor integration of the traumatic memory into one's life story is a main cause of PTSD symptoms. Instead, enhanced integration appears to be a key issue. Copyright © 2006 John Wiley & Sons, Ltd.

Dispersal and Integration in Female Chimpanzees

In chimpanzees, most females disperse from the community in which they were born to reproduce in a new community, thereby eliminating the risk of inbreeding with close kin. However, across sites, some females breed in their natal community, raising questions about the flexibility of dispersal, the costs and benefits of different strategies and the mitigation of costs associated with dispersal and integration. In this dissertation I address these questions by combining long-term behavioral data and recent field observations on maturing and young adult females in Gombe National Park with an experimental manipulation of relationship formation in captive apes in the Congo.

To assess the risk of inbreeding for females who do and do not disperse, 129 chimpanzees were genotyped and relatedness between each dyad was calculated. Natal females were more closely related to adult community males than were immigrant females. By examining the parentage of 58 surviving offspring, I found that natal females were not more related to the sires of their offspring than were immigrant females, despite three instances of close inbreeding. The sires of all offspring were less related to the mothers than non-sires regardless of the mother’s residence status. These results suggest that chimpanzees are capable of detecting relatedness and that, even when remaining natal, females can largely avoid, though not eliminate, inbreeding.

Next, I examined whether dispersal was associated with energetic, social, physiological and/or reproductive costs by comparing immigrant (n=10) and natal (n=9) females of similar age using 2358 hours of observational data. Natal and immigrant females did not differ in any energetic metric. Immigrant females received aggression from resident females more frequently than natal females. Immigrants spent less time in social grooming and more time self-grooming than natal females. Immigrant females primarily associated with resident males, had more social partners and lacked close social allies. There was no difference in levels of fecal glucocorticoid metabolites in immigrant and natal females. Immigrant females gave birth 2.5 years later than natal females, though the survival of their first offspring did not differ. These results indicate that immigrant females in Gombe National Park do not face energetic deficits upon transfer, but they do enter a hostile social environment and have a delayed first birth.

Next, I examined whether chimpanzees use condition- and phenotype-dependent cues in making dispersal decisions. I examined the effect of social and environmental conditions present at the time females of known age matured (n=25) on the females’ dispersal decisions. Females were more likely to disperse if they had more male maternal relatives and thus, a high risk of inbreeding. Females with a high ranking mother and multiple maternal female kin tended to disperse less frequently, suggesting that a strong female kin network provides benefits to the maturing daughter. Females were also somewhat less likely to disperse when fewer unrelated males were present in the group. Habitat quality and intrasexual competition did not affect dispersal decisions. Using a larger sample of 62 females observed as adults in Gombe, I also detected an effect of phenotypic differences in personality on the female’s dispersal decisions; extraverted, agreeable and open females were less likely to disperse.

Natural observations show that apes use grooming and play as social currency, but no experimental manipulations have been carried out to measure the effects of these behaviors on relationship formation, an essential component of integration. Thirty chimpanzees and 25 bonobos were given a choice between an unfamiliar human who had recently groomed or played with them over one who did not. Both species showed a preference for the human that had interacted with them, though the effect was driven by males. These results support the idea that grooming and play act as social currency in great apes that can rapidly shape social relationships between unfamiliar individuals. Further investigation is needed to elucidate the use of social currency in female apes.

I conclude that dispersal in female chimpanzees is flexible and the balance of costs and benefits varies for each individual. Females likely take into account social cues present at maturity and their own phenotype in choosing a settlement path and are especially sensitive to the presence of maternal male kin. The primary cost associated with philopatry is inbreeding risk and the primary cost associated with dispersal is delay in the age at first birth, presumably resulting from intense social competition. Finally, apes may strategically make use of affiliative behavior in pursuing particular relationships, something that should be useful in the integration process.

Introduction: The apparel industry and North American economic integration

The economic and social consequences of international trade agreements have become a major area of inquiry in development studies in recent years. As evidenced by the energetic protests surrounding the Seattle meeting of the World Trade Organization (WTO) in December 1999 and the controversy about China's admission to the WTO, such agreements have also become a focus of political conflict in both the developed and developing countries. At issue are questions of job gains and job losses in different regions, prices paid by consumers, acceptable standards for wages and working conditions in transnational manufacturing industries, and the quality of the environment. All these concerns have arisen with regard to the North American Free Trade Agreement (NAFTA) and can be addressed through an examination of changes in the dynamics of the apparel industry in the post-NAFTA period.1 In this book, we examine the evolution of the apparel industry in North America in order to address some of these questions as they pertain to North America, with an eye toward the broader implications of our findings. We also consider the countries of the Caribbean Basin and Central America, whose textile and apparel goods are now allowed to enter the U.S. market on the same basis as those from Canada and Mexico (Odessey 2000). © 2009 by Temple University Press. All rights reserved.

Performance evaluation of the register insertion protocol for voice-data integration

The performance of the register insertion protocol for mixed voice-data traffic is investigated by simulation. The simulation model incorporates a common insertion buffer for station and ring packets. Bandwidth allocation is achieved by imposing a queue limit at each node. A simple priority scheme is introduced by allowing the queue limit to vary from node to node. This enables voice traffic to be given priority over data. The effect on performance of various operational and design parameters such as ratio of voice to data traffic, queue limit and voice packet size is investigated. Comparisons are made where possible with related work on other protocols proposed for voice-data integration. The main conclusions are: (a) there is a general degradation of performance as the ratio of voice traffic to data traffic increases, (b) substantial improvement in performance can be achieved by restricting the queue length at data nodes and (c) for a given ring utilisation, smaller voice packets result in lower delays for both voice and data traffic.

The integration of an intelligent knowledge-based system into engineering software using the blackboard structure

Over recent years there has been an increase in the use of generic Computational Fluid Dynamics (CFD) software packages spread across various application fields. This has created the need for the integration of expertise into CFD software. Expertise can be integrated into CFD software in the form of an Intelligent Knowledge-Based System (IKBS). The advantages of integrating intelligence into generic engineering software are discussed with a special view to software engineering considerations. The software modelling cycle of a typical engineering problem is identified and the respective expertise and user control needed for each modelling phase is shown. The requirements of an IKBS for CFD software are discussed and compared to current practice. The blackboard software architecture is presented. This is shown to be appropriate for the integration of an IKBS into an engineering software package. This is demonstrated through the presentation of the prototype CFD software package FLOWES.

Towards the design of a portal framework for web services integration

Web services based systems have recently found their way into many applications such as e-commerce, corporate integration and e-learning. Construction of new services or introducing new functions to existing services requires composition of web services. Current approaches to service composition often require major programming effort; this is time consuming and requires considerable developer expertise. In this paper, we explore the real and rich scenarios found in e-learning where education services are offered through the Internet by networked universities to potentially millions in the world. These services are derived from existing/emerging business operation processes and commonly offered through a web interface, combined with other services such as email and ftp services, to support partial/full business processes. We identify the requirements for a generic portal framework for easy integration of existing expertise and services of individual institutions (enterprises). We examine the existing technologies and standards, and point out the gaps to be filled in designing the architecture of the framework

Policy-centric integration and dynamic composition of autonomic computing techniques

This paper presents innovative work in the development of policy-based autonomic computing. The core of the work is a powerful and flexible policy-expression language AGILE, which facilitates run-time adaptable policy configuration of autonomic systems. AGILE also serves as an integrating platform for other self-management technologies including signal processing, automated trend analysis and utility functions. Each of these technologies has specific advantages and applicability to different types of dynamic adaptation. The AGILE platform enables seamless interoperability of the different technologies to each perform various aspects of self-management within a single application. The various technologies are implemented as object components. Self-management behaviour is specified using the policy language semantics to bind the various components together as required. Since the policy semantics support run-time re-configuration, the self-management architecture is dynamically composable. Additional benefits include the standardisation of the application programmer interface, terminology and semantics, and only a single point of embedding is required.

Semi-Lagrange time integration for PDE models of asian options

Semi-Lagrange time integration is used with the finite difference method to provide accurate stable prices for Asian options, with or without early exercise. These are combined with coordinate transformations for computational efficiency and compared with published results