Dynamic removal of replication protein A by Dna2 facilitates primer cleavage during Okazaki fragment processing in Saccharomyces cerevisiae

Eukaryotic Okazaki fragments are initiated by an RNA/DNA primer, which is removed before the fragments are joined. Polymerase d displaces the primer into a flap for processing. Dna2 nuclease/helicase and flap endonuclease 1 (FEN1) are proposed to cleave the flap. The single-stranded DNA binding protein, replication protein A (RPA), governs cleavage activity. Flap-bound RPA inhibits FEN1. This necessitates cleavage by Dna2, which is stimulated by RPA. FEN1 then cuts the remaining RPA-free flap to create a nick for ligation. Cleavage by Dna2 requires that it enter the 5'-end and track down the flap. Since Dna2 cleaves the RPA-bound flap, we investigated the mechanism by which Dna2 accesses the protein-coated flap for cleavage. Using a nuclease-defective Dna2 mutant, we showed that just binding of Dna2 dissociates the flap-bound RPA. Facile dissociation is specific to substrates with a genuine flap, and will not occur with an RPA-coated single strand. We also compared the cleavage patterns of Dna2 with and without RPA to better define RPA stimulation of Dna2. Stimulation derived from removal of DNA folding in the flap. Apparently, coordinated with its dissociation, RPA relinquishes the flap to Dna2 for tracking in a way that does not allow flap structure to reform. We also found that RPA strand melting activity promotes excessive flap elongation, but it is suppressed by Dna2-promoted RPA dissociation. Overall, results indicate that Dna2 and RPA coordinate their functions for efficient flap cleavage and preparation for FEN1

Living with HIV after Release from Prison: An Evaluation of the Long-term Health of Formerly Incarcerated Individuals who used Michigan’s Community Reentry Service

In 2003, Michigan implemented a reentry service to assist HIV-infected people incarcerated in state prisons in linking to HIV medical care immediately upon their release. We examined whether formerly incarcerated people were linked to care successfully, remained in care, and were in good health 3 years after their date of release. In all, 190 people used the service over the 5 years following its inception. Only a minority of those who were alive and not reincarcerated at the time of the evaluation engaged consistently with medical care. Unsurprisingly given low rates of engagement in care, 3 years after their release only 27% had achieved viral suppression. Concerted efforts to support formerly incarcerated HIV-infected individuals’ engagement in care over the long term are urgently needed

A Function-to-Task Process Model for Adaptive Automation System Design

Adaptive automation systems allow the user to complete a task seamlessly with a computer performing tasks at which the human operator struggles. Unlike traditional systems that allocate functions to either the human or the machine, adaptive automation varies the allocation of functions during system operation. Creating these systems requires designers to consider issues not present during static system development. To assist in adaptive automation system design, this paper presents the concept of inherent tasks and takes advantage of this concept to create the function-to-task design process model. This process model helps the designer determine how to allocate functions to the human, machine, or dynamically between the two. An illustration of the process demonstrates the potential complexity within adaptive automation systems and how the process model aids in understanding this complexity during early stage design

Clustering-Based Online Player Modeling

Being able to imitate individual players in a game can benefit game development by providing a means to create a variety of autonomous agents and aid understanding of which aspects of game states influence game-play. This paper presents a clustering and locally weighted regression method for modeling and imitating individual players. The algorithm first learns a generic player cluster model that is updated online to capture an individual’s game-play tendencies. The models can then be used to play the game or for analysis to identify how different players react to separate aspects of game states. The method is demonstrated on a tablet-based trajectory generation game called Space Navigator

Acceleration of energetic particles by large-scale compressible magnetohydrodynamic turbulence

Fast particles diffusing along magnetic field lines in a turbulent plasma can diffuse through and then return to the same eddy many times before the eddy is randomized in the turbulent flow. This leads to an enhancement of particle acceleration by large-scale compressible turbulence relative to previous estimates in which isotropic particle diffusion is assumed.Comment: 13 pages, 3 figures, accepted for publication in Ap

A Comparison of Fish Populations in Shallow Coastal Lagoons with Contrasting Shoalgrass (Halodule wrightii) Cover in the Northcentral Gulf of Mexico

A number of studies have examined the effects of reduced seagrass cover on local fish populations (e.g., Heck et al. 1989, Ferrell and Bell 1991, Hughes et al. 2002 and more), but few of those studies have focused on shoalgrass (e.g., Tolan et al. 1997, Rydene and Matheson 2003). We present a preliminary comparison of fish populations in three shallow coastal lagoons in the northcentral GOM that have varying levels of shoalgrass cover. Namely, we compare (1) abundances of individual species and the entire fish population, (2) fish population diversity, and (3) length-frequency distributions of the most abundant species

Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy.

BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy

The effect of exercise intensity on cognitive performance during short duration treadmill running

This study examined the effect of short duration, moderate and high-intensity exercise on a Go/NoGo task. Fifteen, habitually active (9 females and 6 males aged 28 ± 5 years) agreed to participate in the study and cognitive performance was measured in three sessions lasting 10 min each, performed at three different exercise intensities: rest, moderate and high. Results indicated significant exercise intensity main effects for reaction time (RT) (p = 0.01), the omission error rate (p = 0.027) and the decision error rate (p = 0.011), with significantly longer RTs during high intensity exercise compared to moderate intensity exercise (p = 0.039) and rest (p = 0.023). Mean ± SE of RT (ms) was 395.8 ± 9.1, 396.3 ± 9.1 and 433.5 ± 16.1 for rest, moderate and high intensity exercise, respectively. This pattern was replicated for the error rate with a significantly higher omission error and decision error rate during high intensity exercise compared to moderate intensity exercise (p = 0.003) and rest (p = 0.001). Mean ± SE of omission errors (%) was 0.88 ± 0.23, 0.8 ± 0.23 and 1.8 ± 0.46% for rest, moderate and high intensity exercise, respectively. Likewise, mean ± SE of decision errors (%) was 0.73 ± 0.24, 0.73 ± 0.21 and 1.8 ± 0.31 for rest, moderate and high intensity exercise, respectively. The present study’s results suggest that 10 min workout at high intensity impairs RT performances in habitually active adults compared to rest or moderate intensity exercise