HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy

The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02+ healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02− HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

The load dependence of kinesin’s mechanical cycle

Kinesin is a dimeric motor protein that transports organelles in a stepwise manner toward the plus-end of microtubules by converting the energy of ATP hydrolysis into mechanical work. External forces can influence the behavior of kinesin, and force-velocity curves have shown that the motor will slow down and eventually stall under opposing loads of ≈5 pN. Using an in vitro motility assay in conjunction with a high-resolution optical trapping microscope, we have examined the behavior of individual kinesin molecules under two previously unexplored loading regimes: super-stall loads (>5 pN) and forward (plus-end directed) loads. Whereas some theories of kinesin function predict a reversal of directionality under high loads, we found that kinesin does not walk backwards under loads of up to 13 pN, probably because of an irreversible transition in the mechanical cycle. We also found that this cycle can be significantly accelerated by forward loads under a wide range of ATP concentrations. Finally, we noted an increase in kinesin’s rate of dissociation from the microtubule with increasing load, which is consistent with a load dependent partitioning between two recently described kinetic pathways: a coordinated-head pathway (which leads to stepping) and an independent-head pathway (which is static).

The roles of prefrontal brain regions in components of working memory: Effects of memory load and individual differences

Using an event-related functional MRI design, we explored the relative roles of dorsal and ventral prefrontal cortex (PFC) regions during specific components (Encoding, Delay, Response) of a working memory task under different memory-load conditions. In a group analysis, effects of increased memory load were observed only in dorsal PFC in the encoding period. Activity was lateralized to the right hemisphere in the high but not the low memory-load condition. Individual analyses revealed variability in activation patterns across subjects. Regression analyses indicated that one source of variability was subjects’ memory retrieval rate. It was observed that dorsal PFC plays a differentially greater role in information retrieval for slower subjects, possibly because of inefficient retrieval processes or a reduced quality of mnemonic representations. This study supports the idea that dorsal and ventral PFC play different roles in component processes of working memory.

Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging

Allostatic load (AL) has been proposed as a new conceptualization of cumulative biological burden exacted on the body through attempts to adapt to life's demands. Using a multisystem summary measure of AL, we evaluated its capacity to predict four categories of health outcomes, 7 years after a baseline survey of 1,189 men and women age 70–79. Higher baseline AL scores were associated with significantly increased risk for 7-year mortality as well as declines in cognitive and physical functioning and were marginally associated with incident cardiovascular disease events, independent of standard socio-demographic characteristics and baseline health status. The summary AL measure was based on 10 parameters of biological functioning, four of which are primary mediators in the cascade from perceived challenges to downstream health outcomes. Six of the components are secondary mediators reflecting primarily components of the metabolic syndrome (syndrome X). AL was a better predictor of mortality and decline in physical functioning than either the syndrome X or primary mediator components alone. The findings support the concept of AL as a measure of cumulative biological burden.

Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine.

The association between human immunodeficiency virus type I (HIV-1) RNA load changes and the emergence of resistant virus variants was investigated in 24 HIV-1-infected asymptomatic persons during 2 years of treatment with zidovudine by sequentially measuring serum HIV-1 RNA load and the relative amounts of HIV-1 RNA containing mutations at reverse transcriptase (RT) codons 70 (K-->R), 41 (M-->L), and 215 (T-->Y/F). A mean maximum decline in RNA load occurred during the first month, followed by a resurgence between 1 and 3 months, which appeared independent of drug-resistance. Mathematical modeling suggests that this resurgence is caused by host-parasite dynamics, and thus reflects infection of the transiently increased numbers of CD4+ lymphocytes. Between 3 and 6 months of treatment, the RNA load returned to baseline values, which was associated with the emergence of virus containing a single lysine to arginine amino acid change at RT codon 70, only conferring an 8-fold reduction in susceptibility. Despite the relative loss of RNA load suppression, selection toward mutations at RT codons 215 and 41 continued. Identical patterns were observed in the mathematical model. While host-parasite dynamics and outgrowth of low-level resistant virus thus appear responsible for the loss of HIV-1 RNA load suppression, zidovudine continues to select for alternative mutations, conferring increasing levels of resistance.

Estimating and forecasting generalized fractional Long memory stochastic volatility models

In recent years fractionally differenced processes have received a great deal of attention due to its flexibility in financial applications with long memory. This paper considers a class of models generated by Gegenbauer polynomials, incorporating the long memory in stochastic volatility (SV) components in order to develop the General Long Memory SV (GLMSV) model. We examine the statistical properties of the new model, suggest using the spectral likelihood estimation for long memory processes, and investigate the finite sample properties via Monte Carlo experiments. We apply the model to three exchange rate return series. Overall, the results of the out-of-sample forecasts show the adequacy of the new GLMSV model.

Nutrient Load Reduction: Challenges facing the Chesapeake 2000 Agreement

The Chesapeake Bay is the largest estuary in the United States supporting a complex ecosystem that sustains many habitats and the organisms that depend on them. The bay also supports economic, recreational, and cultural activities to over 16 million people residing in the watershed. Changes within the watershed have caused excessive levels of nutrients, mainly nitrogen and phosphorous, to pollute the bay. The Chesapeake Bay Program, guided by a complex agreement, was created to address these and other issues and oversee the restoration of the bay. The most recent version of this agreement, the Chesapeake 2000, declares its continued commitment to restore the bay with over 100 goals to be met by the year 2010. Reports show that although intensive efforts have been made to promote nutrient reduction, very little reduction has actually resulted. This project described these efforts. The final results reveal obstacles affecting progress, shortcomings to current approaches and possible solutions for future implementation.

Forecasting Elections with High Volatility

This article uses data from the social survey Allbus 1998 to introduce a method of forecasting elections in a context of electoral volatility. The approach models the processes of change in electoral behaviour, exploring patterns in order to model the volatility expressed by voters. The forecast is based on the matrix of transition probabilities, following the logic of Markov chains. The power of the matrix, and the use of the mover-stayer model, is debated for alternative forecasts. As an example of high volatility, the model uses data from the German general election of 1998. The unification of two German states in 1990 caused the incorporation of around 15 million new voters from East Germany who had limited familiarity and no direct experience of the political culture in West Germany. Under these circumstances, voters were expected to show high volatility.

Forecasting migration between the EU, V4 and Eastern Europe. Impact of visa abolition. OSW Report, July 2014

This book is the result of one year of solid work among a multinational research team assembled from seven states (Poland, Czechia, Hungary, Slovakia, Ukraine, Belarus and Moldova). It aims at a detailed analysis of migration patterns and migration forecasts from Ukraine, Belarus and Moldova to the EU/V4. In particular, the nexus between EU visa policy and migration dynamics as well as the impact of economic, political and institutional factors on migration from Eastern Europe have been investigated. The importance of migration policy must be stressed here. Together with demand for the foreign labour force (labour market needs, level of wages, existing work opportunities) and migration networks (including ethnic links), migration policy has a powerful influence on the scale, directions and characteristics of human flows.