Identification of Interdependent Variables that Influence Coreceptor Switch in R5 SHIVSF162P3N_{SF162P3N}-Infected Macaques

Background: We previously reported that adoption of an “open” envelope glycoprotein (Env) to expose the CD4 binding site for efficient receptor binding and infection of cell targets such as macrophages that express low levels of the receptor represents an early event in the process of coreceptor switch in two rapidly progressing (RP) R5 SHIV$_{SF162P3N}$-infected rhesus macaques, releasing or reducing Env structural constraints that have been suggested to limit the pathways available for a change in coreceptor preference. Here we extended these studies to two additional RP monkeys with coreceptor switch and three without to confirm and identify additional factors that facilitated the process of phenotypic conversion. Results: We found that regardless of coreceptor switching, R5 viruses in SHIV$_{SF162P3N}$-infected RP macaques evolved over time to infect macrophages more efficiently; this was accompanied by increased sCD4 sensitivity, with structural changes in the CD4 binding site, the V3 loop and/or the fusion domain of their Envs that are suggestive of better CD4 contact, CCR5 usage and/or virus fusion. However, sCD4-sensitive variants with improved CD4 binding were observed only in RPs with coreceptor switch. Furthermore, cumulative viral load was higher in RPs with than in those without phenotypic switch, with the latter maintaining a longer period of seroconversion. Conclusions: Our data suggest that the increased virus replication in the RPs with R5-to-X4 conversion increased the rate of virus evolution and reduction in the availability of target cells with optimal CD4 expression heightened the competition for binding to the receptor. In the absence of immunological restrictions, variants that adopt an “open” Env to expose the CD4 binding site for better CD4 use are selected, allowing structural changes that confer CXCR4-use to be manifested. Viral load, change in target cell population during the course of infection and host immune response therefore are interdependent variables that influence R5 virus evolution and coreceptor switch in SHIV$_{SF162P3N}$-infected rhesus macaques. Because an "open" Env conformation also renders the virus more susceptible to antibody neutralization, our findings help to explain the infrequent and late appearance of X4 virus in HIV-1 infection when the immune system deteriorates

Sarcopenia; Aging-related loss of muscle mass and function

Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and extended rehabilitation. This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of -motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates. Loss of muscle mass with aging, which is largely due to the progressive loss of motoneurons, is associated with reduced muscle fiber number and size. Muscle function progressively declines because motoneuron loss is not adequately compensated by reinnervation of muscle fibers by the remaining motoneurons. At the intracellular level, key factors are qualitative changes in posttranslational modifications of muscle proteins and the loss of coordinated control between contractile, mitochondrial, and sarcoplasmic reticulum protein expression. Quantitative and qualitative changes in skeletal muscle during the process of aging also have been implicated in the pathogenesis of acquired and hereditary neuromuscular disorders. In experimental models, specific intervention strategies have shown encouraging results on limiting deterioration of motor unit structure and function under conditions of impaired innervation. Translated to the clinic, if these or similar interventions, by saving muscle and improving mobility, could help alleviate sarcopenia in the elderly, there would be both great humanitarian benefits and large cost savings for health care systems

Human Security, Peacebuilding, and the Hazara Minority of Afghanistan: A study of the importance of improving the community security of marginalized groups in peacebuilding efforts in non-Western Societies

This thesis is focused on the lack of investment in the human security of the marginalized Hazara minority of Afghanistan. Human security is a relatively new concept over which there is considerable debate and this thesis presents a discussion of various debates regarding human security and peacekeeping before taking a firm stance in the debates, emphasizing the importance of investing in the human security of marginalized groups in non-Western societies. The case of the human security of the Hazara has never been researched before and this thesis therefore represents a unique case study. This thesis finds that there are four clearly identifiable factors which have led to a lack of investment in the Hazara, namely: the inaccessibility of their native region, the Hazarajat, continued discrimination against them, the militarization of aid, and the top-down, donor-driven nature of aid in Afghanistan. The effects of this lack of investment manifest themselves both domestically within Afghanistan and internationally, with thousands of Hazaras emigrating to other countries, which emphasize the importance of a bottom-up human security approach to peacebuilding which involves an understanding of the socio-political situation on the ground

Supporting Streaming Updates in an Active Data Warehouse

Active Data Warehousing has emerged as an alternative to conventional warehousing practices in order to meet the high demand of applications for up-to-date information. In a nutshell, an active warehouse is refreshed on-line and thus achieves a higher consistency between the stored information and the latest data updates. The need for on-line warehouse refreshment introduces several challenges in the implementation of data warehouse transformations, with respect to their execution time and their overhead to the warehouse processes. In this paper, we focus on a frequently encountered operation in this context, namely, the join of a fast stream S of source updates with a disk-based relation R, under the constraint of limited memory. This operation lies at the core of several common transformations, such as, surrogate key assignment, duplicate detection or identification of newly inserted tuples. We propose a specialized join algorithm, termed mesh join (MESHJOIN), that compensates for the difference in the access cost of the two join inputs by (a) relying entirely on fast sequential scans of R, and (b) sharing the I/O cost of accessing R across multiple tuples of S. We detail the MESHJOIN algorithm and develop a systematic cost model that enables the tuning of MESHJOIN for two objectives: maximizing throughput under a specific memory budget or minimizing memory consumption for a specific throughput. We present an experimental study that validates the performance of MESHJOIN on synthetic and real-life data. Our results verify the scalability of MESH-JOIN to fast streams and large relations, and demonstrate its numerous advantages over existing join algorithms. 1