Reduced Retinal Microvascular Density, Improved Forepaw Reach, Comparative Microarray and Gene Set Enrichment Analysis with c-jun Targeting DNA Enzyme

Retinal neovascularization is a critical component in the pathogenesis of common ocular disorders that cause blindness, and treatment options are limited. We evaluated the therapeutic effect of a DNA enzyme targeting c-jun mRNA in mice with pre-existing retinal neovascularization. A single injection of Dz13 in a lipid formulation containing N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine inhibited c-Jun expression and reduced retinal microvascular density. The DNAzyme inhibited retinal microvascular density as effectively as VEGF-A antibodies. Comparative microarray and gene expression analysis determined that Dz13 suppressed not only c-jun but a range of growth factors and matrix-degrading enzymes. Dz13 in this formulation inhibited microvascular endothelial cell proliferation, migration and tubule formation in vitro. Moreover, animals treated with Dz13 sensed the top of the cage in a modified forepaw reach model, unlike mice given a DNAzyme with scrambled RNA-binding arms that did not affect c-Jun expression. These findings demonstrate reduction of microvascular density and improvement in forepaw reach in mice administered catalytic DNA.This work was supported by grants from Cancer Institute NSW and the National Health and Medical Research Council (NHMRC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Iranian Hostage Crisis and the Iran-U.S. Claims Tribunal: Implications for International Dispute Resolution and Diplomacy

This is the twenty-fifth anniversary of what has become known as the Iranian Hostage Crisis. We shall look back on those events in order to point to possible issues, lessons and solutions for the future

A Practical Model of Student Engagement While Programming

We consider the question of how to predict whether a student is on or off task while working on a computer programming assignment using elapsed time since the last keystroke as the single independent variable. In this paper we report results of an empirical study in which we intermittently prompted CS1 students working on a programming assignment to self-report whether they were engaged in the assignment at that moment. Our regression model derived from the results of the study shows power-law decay in the engagement rate of students with increasing time of keyboard inactivity ranging from a nearly 80% engagement rate after 45 seconds to 30% after 32 minutes of inactivity. We find that students remain engaged in programming for a median of about 8 minutes before going off task, and when they do go off task, they most often return after 1 to 4 minutes of disengagement. Our model has application in estimating the amount of engaged time students take to complete programming assignments, identifying students in need of intervention, and understanding the effects of different engagement behaviors

Accurate Estimation of Time-on-Task While Programming

In a recent study, students were periodically prompted to self-report engagement while working on computer programming assignments in a CS1 course. A regression model predicting time-on-task was proposed. While it was a significant improvement over ad-hoc estimation techniques, the study nevertheless suffered from lack of error analysis, lack of comparison with existing methods, subtle complications in prompting students, and small sample size. In this paper we report results from a study with an increased number of student participants and modified prompting scheme intended to better capture natural student behavior. Furthermore, we perform a cross-validation analysis on our refined regression model and present the resulting error bounds. We compare with threshold approaches and find that, in at least one context, a simple 5-minute threshold of inactivity is a reasonable estimate for whether a student is on-task or not. We show that our approach to modeling student engagement while programming is robust and suitable for identification of students in need of intervention, understanding engagement behavior, and estimating time taken on programming assignments

One Love: Explicit Monogamy Agreements among Heterosexual Young Adult Couples at Increased Risk of Sexually Transmitted Infections

HIV prevention strategies among couples include condom use, mutual monogamy, and HIV testing. Research suggests that condom use is more likely with new or casual partners, and tends to decline as relationships become steady over time. Little is known, however, about explicit mutual monogamy agreements and HIV testing within heterosexual couples. This study used data from 434 young heterosexual couples at increased risk of HIV and sexually transmitted infections (STIs) to assess (a) couple concordance on perceptions of a monogamy agreement, sustained monogamy, and HIV testing; and (b) the associations of relationship and demographic factors with monogamy agreement, sustained monogamy, and HIV testing. Results indicated only slight to fair agreement within couples on measures of monogamy agreement and sustained monogamy. Overall, 227 couples (52%) concurred that they had an explicit agreement to be monogamous; of those, 162 (71%) had sustained the agreement. Couples with greater health protective communication and commitment were more likely to have a monogamy agreement. Couples of Latino and Hispanic ethnicity and those with children were less likely to have a monogamy agreement. Only commitment was related to sustained monogamy. Having children, greater health protective communication, and perceived vulnerability to HIV and STIs were associated with HIV testing within the couple

Stimulus Complexity and Chunk Tightness Interact to Impede Perceptual Restructuring During Problem Solving

The mutual influence of stimulus complexity and chunk tightness on perceptual restructuring was examined using a chunk decomposition task (CDT). Participants attempted to remove components of Chinese characters in order to produce new, valid characters. Participants had their electroencephalogram recorded while completing a CDT in conditions of low or high stimulus complexity, crossed with two levels of chunk tightness. Tight chunks overlapped spatially whereas loose chunks did not. Both increasing chunk tightness and increasing stimulus complexity impaired performance (lower accuracy, longer reaction times), and these factors interacted such that highly complex, tight chunks produced the worst performance. These factors also had interacting effects on the late positive complex (LPC). The LPC amplitude was reduced by increasing chunk tightness, but this effect was attenuated for highly complex stimuli. These results suggest that though chunk tightness and stimulus complexity impair performance in the CDT, they have dissociable neural underpinnings

Environmental attributes influencing the distribution of Burkholderia pseudomallei in Northern Australia

Factors responsible for the spatial and temporal clustering of Burkholderia pseudomallei in the environment remain to be elucidated. Whilst laboratory based experiments have been performed to analyse survival of the organism in various soil types, such approaches are strongly influenced by alterations to the soil micro ecology during soil sanitisation and translocation. During the monsoonal season in Townsville, Australia, B. pseudomallei is discharged from Castle Hill (an area with a very high soil prevalence of the organism) by groundwater seeps and is washed through a nearby area where intensive sampling in the dry season has been unable to detect the organism. We undertook environmental sampling and soil and plant characterisation in both areas to ascertain physiochemical and macro-floral differences between the two sites that may affect the prevalence of B. pseudomallei. In contrast to previous studies, the presence of B. pseudomallei was correlated with a low gravimetric water content and low nutrient availability (nitrogen and sulphur) and higher exchangeable potassium in soils favouring recovery. Relatively low levels of copper, iron and zinc favoured survival. The prevalence of the organism was found to be highest under the grasses Aristida sp. and Heteropogon contortus and to a lesser extent under Melinis repens. The findings of this study indicate that a greater variety of factors influence the endemicity of melioidosis than has previously been reported, and suggest that biogeographical boundaries to the organisms' distribution involve complex interactions

Structural consequences of nucleophosmin mutations in acute myeloid leukemia.

Mutations affecting NPM1 (nucleophosmin) are the most common genetic lesions found in acute myeloid leukemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumor suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukemic cells. This mutant phenotype is the result of the substitution of several C-terminal residues, including one or two conserved tryptophan residues, with a leucine-rich nuclear export signal. The exact molecular mechanism underlying the loss of nucleolar retention, and the role of the tryptophans, remains unknown. In this study we have determined the structure of an independently folded globular domain in the C terminus of NPM1 using NMR spectroscopy, and we report that the conserved tryptophans are critical for structure. This domain is necessary for the nucleolar targeting of NPM1 and is disrupted by mutations in AML with cytoplasmic NPM1. Furthermore, we identify conserved surface-exposed lysine residues that are functionally rather than structurally important for nucleolar localization. This study provides new focus for efforts to understand the pathogenesis of AML with cytoplasmic NPM1 and may be used to aid the design of small molecules that target the C-terminal domain of NPM1 to act as novel anti-proliferative and anti-leukemia therapeutics

Multivariate pattern analysis of electroencephalography data reveals information predictive of charitable giving

Charitable donations are an altruistic behavior whereby individuals donate money or other resources to benefit others while the recipient is normally absent from the context. Several psychological factors have been shown to influence charitable donations, including a cost-benefit analysis, the motivation to engage in altruistic behavior, and the perceived psychological benefits of donation. Recent work has identified the ventral medial prefrontal cortex (MPFC) for assigning value to options in social decision making tasks, with other regions involved in empathy and emotion contributing input to the value computation (e.g. Hare et al., 2010; Hutcherson et al., 2015; Tusche et al., 2016). Most impressively, multivariate pattern analysis (MVPA) has been applied to fMRI data to predict donation behavior on a trial-by-trial basis from ventral MPFC activity (Hare et al., 2010) while identifying the contribution of emotional processing in other regions to the value computation (e.g. Tusche et al., 2016). MVPA of EEG data may be able to provide further insight into the timing and scalp topography of neural activity related to both value computation and emotional effects on donation behavior. We examined the effect of incidental emotional states and the perceived urgency of the charitable cause on donation behavior using support vector regression on EEG data to predict donation amount on a trial by trial basis. We used positive, negative, and neutral pictures to induce incidental emotional states in participants before they made donation decisions concerning two types of charities. One category of charity was oriented toward saving people from current suffering, and the other was to prevent future suffering. Behaviorally, subjects donated more money in a negative emotional state relative to other emotional states, and more money to alleviate current over future suffering. The data-driven multivariate pattern analysis revealed that the electrophysiological activity elicited by both emotion-priming pictures and charity cues could predict the variation in donation magnitude on a trial-by-trial basis

The Impact of Deliberative Strategy Dissociates ERP Components Related to Conflict Processing vs. Reinforcement Learning

We applied the event-related brain potential (ERP) technique to investigate the involvement of two neuromodulatory systems in learning and decision making: The locus coeruleus–norepinephrine system (NE system) and the mesencephalic dopamine system (DA system). We have previously presented evidence that the N2, a negative deflection in the ERP elicited by task-relevant events that begins approximately 200 ms after onset of the eliciting stimulus and that is sensitive to low-probability events, is a manifestation of cortex-wide noradrenergic modulation recruited to facilitate the processing of unexpected stimuli. Further, we hold that the impact of DA reinforcement learning signals on the anterior cingulate cortex (ACC) produces a component of the ERP called the feedback-related negativity (FRN). The N2 and the FRN share a similar time range, a similar topography, and similar antecedent conditions. We varied factors related to the degree of cognitive deliberation across a series of experiments to dissociate these two ERP components. Across four experiments we varied the demand for a deliberative strategy, from passively watching feedback, to more complex/challenging decision tasks. Consistent with our predictions, the FRN was largest in the experiment involving active learning and smallest in the experiment involving passive learning whereas the N2 exhibited the opposite effect. Within each experiment, when subjects attended to color, the N2 was maximal at frontal–central sites, and when they attended to gender it was maximal over lateral-occipital areas, whereas the topology of the FRN was frontal–central in both task conditions. We conclude that both the DA system and the NE system act in concert when learning from rewards that vary in expectedness, but that the DA system is relatively more exercised when subjects are relatively more engaged by the learning task