In Vivo validation of a bioinformatics based tool to identify reduced replication capacity in HIV-1.

Although antiretroviral drug resistance is common in treated HIV infected individuals, it is not a consistent indicator of HIV morbidity and mortality. To the contrary, HIV resistance-associated mutations may lead to changes in viral fitness that are beneficial to infected individuals. Using a bioinformatics-based model to assess the effects of numerous drug resistance mutations, we determined that the D30N mutation in HIV-1 protease had the largest decrease in replication capacity among known protease resistance mutations. To test this in silico result in an in vivo environment, we constructed several drug-resistant mutant HIV-1 strains and compared their relative fitness utilizing the SCID-hu mouse model. We found HIV-1 containing the D30N mutation had a significant defect in vivo, showing impaired replication kinetics and a decreased ability to deplete CD4+ thymocytes, compared to the wild-type or virus without the D30N mutation. In comparison, virus containing the M184V mutation in reverse transcriptase, which shows decreased replication capacity in vitro, did not have an effect on viral fitness in vivo. Thus, in this study we have verified an in silico bioinformatics result with a biological assessment to identify a unique mutation in HIV-1 that has a significant fitness defect in vivo

The Good Flow: How Happiness Emerges from the Skillful Enactment of Morality

In this paper, I will argue that 'being good' positively correlates to 'being happy.' First, I will clarify how I’ll be using the word ‘morality’ and the phrase ‘being good’. Second, I will claim that moral goodness is developed and exercised as a kind of practical skill. This will allow me to propose that ‘being good’ – like other complex and engaging skills – entails the elicitation of a kind of flow experience. Third, I will propose that ‘being good’ involves achieving what I'll call ‘vertical coherency’ within one’s life and that this provides sustained engagement (‘flow’) and meaning while exercising moral goodness. Lastly, I will show why the kind of happiness that we truly want for ourselves and those we care about emerges from a moral engagement – a ‘good flow’ – of the sort described

Observed Relationships Between Economic And Technical Receipts Revisions In Federal Budget Projections

This paper presents results illustrating a close relationship between economic and technical errors in receipts projections made by the OMB and the CBO. The specific source appears to be the relationship between economic and technical errors for personal income tax receipts. Receipts projections generally are efficient in the use of prior information, although some evidence exists to suggest that OMB economic receipts revisions are related to prior economic information. The results indicate a greater sensitivity of changes in receipts projections to changes in the performance of the economy than typically realized.Tax receipts; forecasts; budget

Evaluation of curriculum online: report of the follow up survey of schools

This report contains the findings of the second survey of schools carried out as part of the evaluation of curriculum online. One questionnaire collected school-level information for each school and additional questionnaires collected data for selected subject areas

Stem-cell-based gene therapy for HIV infection.

Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells

Koszul duality and mixed Hodge modules

We prove that on a certain class of smooth complex varieties (those with "affine even stratifications"), the category of mixed Hodge modules is "almost" Koszul: it becomes Koszul after a few unwanted extensions are eliminated. We also give an equivalence between perverse sheaves on such a variety and modules for a certain graded ring, obtaining a formality result as a corollary. For flag varieties, these results were proved earlier by Beilinson-Ginzburg-Soergel using a rather different construction.Comment: 26 pages. v4: added Proposition 3.9; streamlined Section 4; other minor correction

The limits of mean-field heterozygosity estimates under spatial extension in simulated plant populations

Computational models of evolutionary processes are increasingly required to incorporate multiple and diverse sources of data. A popular feature to include in population genetics models is spatial extension, which reflects more accurately natural populations than does a mean field approach. However, such models necessarily violate the mean field assumptions of classical population genetics, as do natural populations in the real world. Recently, it has been questioned whether classical approaches are truly applicable to the real world. Individual based models (IBM) are a powerful and versatile approach to achieve integration in models. In this study an IBM was used to examine how populations of plants deviate from classical expectations under spatial extension. Populations of plants that used three different mating strategies were placed in a range of arena sizes giving crowded to sparse occupation densities. Using a measure of population density, the pollen communication distance (Pcd), the deviation exhibited by outbreeding populations differed from classical mean field expectations by less than 5% when Pcd was less than 1, and over this threshold value the deviation significantly increased. Populations with an intermediate mating strategy did not have such a threshold and deviated directly with increasing isolation between individuals. Populations with a selfing strategy were influenced more by the mating strategy than by increased isolation. In all cases pollen dispersal was more influential than seed dispersal. The IBM model showed that mean field calculations can be reasonably applied to natural outbreeding plant populations that occur at a density in which individuals are less than the average pollen dispersal distance from their neighbors