Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate

The activity of the p53 gene product is regulated by a plethora of posttranslational modifications. An open question is whether such posttranslational changes act redundantly or dependently upon one another. We show that a functional interference between specific acetylated and phosphorylated residues of p53 influences cell fate. Acetylation of lysine 320 (K320) prevents phosphorylation of crucial serines in the NH2-terminal region of p53; only allows activation of genes containing high-affinity p53 binding sites, such as p21/WAF; and promotes cell survival after DNA damage. In contrast, acetylation of K373 leads to hyperphosphorylation of p53 NH2-terminal residues and enhances the interaction with promoters for which p53 possesses low DNA binding affinity, such as those contained in proapoptotic genes, leading to cell death. Further, acetylation of each of these two lysine clusters differentially regulates the interaction of p53 with coactivators and corepressors and produces distinct gene-expression profiles. By analogy with the “histone code” hypothesis, we propose that the multiple biological activities of p53 are orchestrated and deciphered by different “p53 cassettes,” each containing combination patterns of posttranslational modifications and protein–protein interactions

Electronic gaming machine characteristics: it's the little things that count

A range of gamblers, from low-frequency social gamblers through to problem gamblers in treatment, participated in focus groups discussing the characteristics of Electronic Gaming Machines (EGMs) that they found attractive. Analyses of the resulting transcripts resulted in two groups of EGM characteristics being identified as important, one group associated with winning and one with betting. Overall, free spin features were identified in all groups as the most attractive characteristic of EGMS. Beyond that it was smaller win-related characteristics, and low-denomination machines with multiple playable lines that were associated with increased duration and intensity of gambling behaviour. The important characteristics were consistent across different levels of gamblers, with the key behavioural difference being a self-reported ‘expertise’, and ‘strategic’ approach to gambling amongst higher-frequency gamblers and problem gamblers in treatment. The key characteristics all occur frequently and result in more wins and extended gambling sessions. The patterns identified resonated with established behavioural principles, and with models describing the development of problem gambling and addictions more generally

Psychometric Curve and Behavioral Strategies for Whisker-Based Texture Discrimination in Rats

The rodent whisker system is a major model for understanding neural mechanisms for tactile sensation of surface texture (roughness). Rats discriminate surface texture using the whiskers, and several theories exist for how texture information is physically sensed by the long, moveable macrovibrissae and encoded in spiking of neurons in somatosensory cortex. However, evaluating these theories requires a psychometric curve for texture discrimination, which is lacking. Here we trained rats to discriminate rough vs. fine sandpapers and grooved vs. smooth surfaces. Rats intermixed trials at macrovibrissa contact distance (nose >2 mm from surface) with trials at shorter distance (nose <2 mm from surface). Macrovibrissae were required for distant contact trials, while microvibrissae and non-whisker tactile cues were used for short distance trials. A psychometric curve was measured for macrovibrissa-based sandpaper texture discrimination. Rats discriminated rough P150 from smoother P180, P280, and P400 sandpaper (100, 82, 52, and 35 µm mean grit size, respectively). Use of olfactory, visual, and auditory cues was ruled out. This is the highest reported resolution for rodent texture discrimination, and constrains models of neural coding of texture information

Infectivity in Skeletal Muscle of Cattle with Atypical Bovine Spongiform Encephalopathy

The amyloidotic form of bovine spongiform encephalopathy (BSE) termed BASE is caused by a prion strain whose biological properties differ from those of typical BSE, resulting in a clinically and pathologically distinct phenotype. Whether peripheral tissues of BASE-affected cattle contain infectivity is unknown. This is a critical issue since the BASE prion is readily transmissible to a variety of hosts including primates, suggesting that humans may be susceptible. We carried out bioassays in transgenic mice overexpressing bovine PrP (Tgbov XV) and found infectivity in a variety of skeletal muscles from cattle with natural and experimental BASE. Noteworthy, all BASE muscles used for inoculation transmitted disease, although the attack rate differed between experimental and natural cases (∼70% versus ∼10%, respectively). This difference was likely related to different prion titers, possibly due to different stages of disease in the two conditions, i.e. terminal stage in experimental BASE and pre-symptomatic stage in natural BASE. The neuropathological phenotype and PrPres type were consistent in all affected mice and matched those of Tgbov XV mice infected with brain homogenate from natural BASE. The immunohistochemical analysis of skeletal muscles from cattle with natural and experimental BASE showed the presence of abnormal prion protein deposits within muscle fibers. Conversely, Tgbov XV mice challenged with lymphoid tissue and kidney from natural and experimental BASE did not develop disease. The novel information on the neuromuscular tropism of the BASE strain, efficiently overcoming species barriers, underlines the relevance of maintaining an active surveillance

Changeover ratio effects on concurrent variable-interval performance

Rats' bar-pressing was maintained by concurrent variable-interval schedules of reinforcement. A fixed-ratio of pulls on a chain (the changeover ratio) was required for switching between schedules. The first experiment employed equal variable-interval schedules and symmetrical changeover ratios. Increasing these ratios resulted in a decrease in the rate of switching between schedules and an increase in local response rate. In the second experiment, a range of asymmetrical changeover ratios was used with equal variable-interval schedules, and a preference was found for the schedule associated with the larger switching-into ratio. Both the distributions of responses and time between the two schedules deviated from those expected on the basis of obtained reinforcers. In the third experiment, the switching-out-of ratio was dependent on the amount of time spent in a variable-interval 2-minute schedule; a constant ratio permitted switching out of the alternative variable-interval 1-minute schedule. A strong preference was shown for the variable-interval 2-minute schedule. The fourth experiment used equal variable-interval schedules; one changeover ratio was varied while the second remained constant. The results failed to show systematic differences in local response rates immediately after a changeover

Generating Variable and Random Schedules of Reinforcement Using Microsoft Excel Macros

Variable reinforcement schedules are used to arrange the availability of reinforcement following varying response ratios or intervals of time. Random reinforcement schedules are subtypes of variable reinforcement schedules that can be used to arrange the availability of reinforcement at a constant probability across number of responses or time. Generating schedule values for variable and random reinforcement schedules can be difficult. The present article describes the steps necessary to write macros in Microsoft Excel that will generate variable-ratio, variable-interval, variable-time, random-ratio, random-interval, and random-time reinforcement schedule values

HIV Testing Rates and Factors Associated With Recent HIV Testing Among Male Couples

Little data exists on HIV testing rates among male couples. By using dyadic data from 142 male couples, we found that less than a quarter of the men had gotten tested for HIV in the previous three months. Few factors also were associated with their most recent HIV test