Predicting Transcriptional Activity of Multiple Site p53 Mutants Based on Hybrid Properties

As an important tumor suppressor protein, reactivate mutated p53 was found in many kinds of human cancers and that restoring active p53 would lead to tumor regression. In this work, we developed a new computational method to predict the transcriptional activity for one-, two-, three- and four-site p53 mutants, respectively. With the approach from the general form of pseudo amino acid composition, we used eight types of features to represent the mutation and then selected the optimal prediction features based on the maximum relevance, minimum redundancy, and incremental feature selection methods. The Mathew's correlation coefficients (MCC) obtained by using nearest neighbor algorithm and jackknife cross validation for one-, two-, three- and four-site p53 mutants were 0.678, 0.314, 0.705, and 0.907, respectively. It was revealed by the further optimal feature set analysis that the 2D (two-dimensional) structure features composed the largest part of the optimal feature set and maybe played the most important roles in all four types of p53 mutant active status prediction. It was also demonstrated by the optimal feature sets, especially those at the top level, that the 3D structure features, conservation, physicochemical and biochemical properties of amino acid near the mutation site, also played quite important roles for p53 mutant active status prediction. Our study has provided a new and promising approach for finding functionally important sites and the relevant features for in-depth study of p53 protein and its action mechanism

The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

<p>Abstract</p> <p>Background</p> <p>CD4⁺CD25^highregulatory T (T_Reg) cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of T_Regcell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of T_Regcells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP) patients, and to correlate with measures of T cell activation.</p> <p>Results</p> <p>We were able to confirm that HTLV-I drives activation, spontaneous IFNγ production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4⁺T_Regcells (CD4⁺CD25^highT cells) in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4⁺T_Regcells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127^lowT_Regcells in healthy control subjects. Finally, the proportion of CD127^lowT_Regcells correlated inversely with HTLV-1 proviral load.</p> <p>Conclusion</p> <p>Taken together, the results suggest that T_Regcells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4⁺T cells, in particular those expressing the CD25^highCD127^lowphenotype. T_Regcells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.</p

A Pilot Study with a Novel Setup for Collaborative Play of the Humanoid Robot KASPAR with children with autism

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.This article describes a pilot study in which a novel experimental setup, involving an autonomous humanoid robot, KASPAR, participating in a collaborative, dyadic video game, was implemented and tested with children with autism, all of whom had impairments in playing socially and communicating with others. The children alternated between playing the collaborative video game with a neurotypical adult and playing the same game with the humanoid robot, being exposed to each condition twice. The equipment and experimental setup were designed to observe whether the children would engage in more collaborative behaviours while playing the video game and interacting with the adult than performing the same activities with the humanoid robot. The article describes the development of the experimental setup and its first evaluation in a small-scale exploratory pilot study. The purpose of the study was to gain experience with the operational limits of the robot as well as the dyadic video game, to determine what changes should be made to the systems, and to gain experience with analyzing the data from this study in order to conduct a more extensive evaluation in the future. Based on our observations of the childrens’ experiences in playing the cooperative game, we determined that while the children enjoyed both playing the game and interacting with the robot, the game should be made simpler to play as well as more explicitly collaborative in its mechanics. Also, the robot should be more explicit in its speech as well as more structured in its interactions. Results show that the children found the activity to be more entertaining, appeared more engaged in playing, and displayed better collaborative behaviours with their partners (For the purposes of this article, ‘partner’ refers to the human/robotic agent which interacts with the children with autism. We are not using the term’s other meanings that refer to specific relationships or emotional involvement between two individuals.) in the second sessions of playing with human adults than during their first sessions. One way of explaining these findings is that the children’s intermediary play session with the humanoid robot impacted their subsequent play session with the human adult. However, another longer and more thorough study would have to be conducted in order to better re-interpret these findings. Furthermore, although the children with autism were more interested in and entertained by the robotic partner, the children showed more examples of collaborative play and cooperation while playing with the human adult.Peer reviewe

What About Interaction Geography to Evaluate Physical Learning Spaces?

This paper reviews and explores how interaction geography, a new approach to visualize people’s interaction over space and time, extends current approaches to evaluate physical learning spaces. This chapter begins by reviewing representations produced using interaction geography to study visitor engagement and learning in a museum. In particular, this review illustrates Mondrian Transcription, a method to map people’s movement and conversation over space and time, and the Interaction Geography Slicer (IGS), a dynamic visualisation tool that supports new forms of interaction and multi-modal analysis. Subsequently, this chapter explores how interaction geography may advance the evaluation of physical learning spaces by providing dynamic information visualisation methods that support more expansive views of learning and the evaluation of the alignment between space and pedagogy. This chapter concludes by outlining significant limitations and next steps to expand interaction geography to evaluate physical learning spaces

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Enrichment analysis of Alu elements with different spatial chromatin proximity in the human genome

Transposable elements (TEs) have no longer been totally considered as “junk DNA” for quite a time since the continual discoveries of their multifunctional roles in eukaryote genomes. As one of the most important and abundant TEs that still active in human genome, Alu, a SINE family, has demonstrated its indispensable regulatory functions at sequence level, but its spatial roles are still unclear. Technologies based on 3C(chromosomeconformation capture) have revealed the mysterious three-dimensional structure of chromatin, and make it possible to study the distal chromatin interaction in the genome. To find the role TE playing in distal regulation in human genome, we compiled the new released Hi-C data, TE annotation, histone marker annotations, and the genome-wide methylation data to operate correlation analysis, and found that the density of Alu elements showed a strong positive correlation with the level of chromatin interactions (hESC: r=0.9, P<2.2×1016; IMR90 fibroblasts: r = 0.94, P < 2.2 × 1016) and also have a significant positive correlation withsomeremote functional DNA elements like enhancers and promoters (Enhancer: hESC: r=0.997, P=2.3×10−4; IMR90: r=0.934, P=2×10−2; Promoter: hESC: r = 0.995, P = 3.8 × 10−4; IMR90: r = 0.996, P = 3.2 × 10−4). Further investigation involving GC content and methylation status showed the GC content of Alu covered sequences shared a similar pattern with that of the overall sequence, suggesting that Alu elements also function as the GC nucleotide and CpG site provider. In all, our results suggest that the Alu elements may act as an alternative parameter to evaluate the Hi-C data, which is confirmed by the correlation analysis of Alu elements and histone markers. Moreover, the GC-rich Alu sequence can bring high GC content and methylation flexibility to the regions with more distal chromatin contact, regulating the transcription of tissue-specific genes

Protocol for investigating genetic determinants of posttraumatic stress disorder in women from the Nurses' Health Study II

<p>Abstract</p> <p>Background</p> <p>One in nine American women will meet criteria for the diagnosis of posttraumatic stress disorder (PTSD) in their lifetime. Although twin studies suggest genetic influences account for substantial variance in PTSD risk, little progress has been made in identifying variants in specific genes that influence liability to this common, debilitating disorder.</p> <p>Methods and design</p> <p>We are using the unique resource of the Nurses Health Study II, a prospective epidemiologic cohort of 68,518 women, to conduct what promises to be the largest candidate gene association study of PTSD to date. The entire cohort will be screened for trauma exposure and PTSD; 3,000 women will be selected for PTSD diagnostic interviews based on the screening data. Our nested case-control study will genotype1000 women who developed PTSD following a history of trauma exposure; 1000 controls will be selected from women who experienced similar traumas but did not develop PTSD.</p> <p>The primary aim of this study is to detect genetic variants that predict the development of PTSD following trauma. We posit inherited vulnerability to PTSD is mediated by genetic variation in three specific neurobiological systems whose alterations are implicated in PTSD etiology: the hypothalamic-pituitary-adrenal axis, the locus coeruleus/noradrenergic system, and the limbic-frontal neuro-circuitry of fear. The secondary, exploratory aim of this study is to dissect genetic influences on PTSD in the broader genetic and environmental context for the candidate genes that show significant association with PTSD in detection analyses. This will involve: conducting conditional tests to identify the causal genetic variant among multiple correlated signals; testing whether the effect of PTSD genetic risk variants is moderated by age of first trauma, trauma type, and trauma severity; and exploring gene-gene interactions using a novel gene-based statistical approach.</p> <p>Discussion</p> <p>Identification of liability genes for PTSD would represent a major advance in understanding the pathophysiology of the disorder. Such understanding could advance the development of new pharmacological agents for PTSD treatment and prevention. Moreover, the addition of PTSD assessment data will make the NHSII cohort an unparalleled resource for future genetic studies of PTSD as well as provide the unique opportunity for the prospective examination of PTSD-disease associations.</p

Risk of Parkinson's disease after tamoxifen treatment

<p>Abstract</p> <p>Background</p> <p>Women have a reduced risk of developing Parkinson's disease (PD) compared with age-matched men. Neuro-protective effects of estrogen potentially explain this difference. Tamoxifen, commonly used in breast cancer treatment, may interfere with the protective effects of estrogen and increase risk of PD. We compared the rate of PD in Danish breast cancer patients treated with tamoxifen to the rate among those not treated with tamoxifen.</p> <p>Methods</p> <p>A cohort of 15,419 breast cancer patients identified from the Danish Breast Cancer Collaborative Group database was linked to the National Registry of Patients to identify PD diagnoses. Overall risk and rate of PD following identification into the study was compared between patients treated with tamoxifen as adjuvant hormonal therapy and patients not receiving tamoxifen. Time-dependent effects of tamoxifen treatment on PD rate were examined to estimate the likely induction period for tamoxifen.</p> <p>Results</p> <p>In total, 35 cases of PD were identified among the 15,419 breast cancer patients. No overall effect of tamoxifen on rate of PD was observed (HR = 1.3, 95% CI: 0.64-2.5), but a PD hazard ratio of 5.1 (95% CI: 1.0-25) was seen four to six years following initiation of tamoxifen treatment.</p> <p>Conclusions</p> <p>These results provide evidence that the neuro-protective properties of estrogen against PD occurrence may be disrupted by tamoxifen therapy. Tamoxifen treatments may be associated with an increased rate of PD; however these effects act after four years, are of limited duration, and the adverse effect is overwhelmed by the protection against breast recurrence conferred by tamoxifen therapy.</p