Jobseekers Regime and Flexible New Deal, the Six Month Offer and Support for the Newly Unemployed evaluations: An early process study

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Disease-Associated Mutations Disrupt Functionally Important Regions of Intrinsic Protein Disorder

The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7–2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations

PandA: Unsupervised Learning of Parts and Appearances in the Feature Maps of GANs

Recent advances in the understanding of Generative Adversarial Networks (GANs) have led to remarkable progress in visual editing and synthesis tasks, capitalizing on the rich semantics that are embedded in the latent spaces of pre-trained GANs. However, existing methods are often tailored to specific GAN architectures and are limited to either discovering global semantic directions that do not facilitate localized control, or require some form of supervision through manually provided regions or segmentation masks. In this light, we present an architecture-agnostic approach that jointly discovers factors representing spatial parts and their appearances in an entirely unsupervised fashion. These factors are obtained by applying a semi-nonnegative tensor factorization on the feature maps, which in turn enables context-aware local image editing with pixel-level control. In addition, we show that the discovered appearance factors correspond to saliency maps that localize concepts of interest, without using any labels. Experiments on a wide range of GAN architectures and datasets show that, in comparison to the state of the art, our method is far more efficient in terms of training time and, most importantly, provides much more accurate localized control

Imagery Reduces Feelings of Social Anxiety in a Healthy Population

Abstract Negative mental imagery has been shown to be involved in the onset and maintenance of numerous clinical disorders and as a result there has been growing scientific study of the therapeutic role of positive mental imagery, with studies reporting favourable results. However, with regard to social anxiety (SA) disorder the conventional approach to induce positive mental imagery has been suggested to be too demanding due to impairment in the retrieval of such episodes. Therefore, researchers have called for controlled studies to explore alternative inducement techniques with specific focus upon future orientated methods (a method more suitable for patients with SA). In the current study, we compare the conventional inducement technique (past) to a future orientated inducement technique (future) and a control condition (no imagery) and measure the impact upon selfreported levels of anxiety in a non-clinical population. Seventy-Eight younger students were randomly allocated to one of the two imagery inducement techniques or the control condition (and completed anxiety scales before and after imagery inducement or control task). To capture situational anxiety, phobia and broader short and long term (state versus trait) dysfunction the Liebowitz Social Anxiety Scale and State-Trait Anxiety Inventory were the chosen measures. Results confirmed that positive mental imagery reduces feelings of anxiety and demonstrated, for the first time, the effectiveness of a hypothetical future orientated technique to induce positive mental imagery. These data will provide the groundwork for intervention development in clinical populations with known difficulties capitalising on past based mental imagery

Concurrent adaptation to opposing visual displacements during an alternating movement.

It has been suggested that, during tasks in which subjects are exposed to a visual rotation of cursor feedback, alternating bimanual adaptation to opposing rotations is as rapid as unimanual adaptation to a single rotation (Bock et al. in Exp Brain Res 162:513–519, 2005). However, that experiment did not test strict alternation of the limbs but short alternate blocks of trials. We have therefore tested adaptation under alternate left/right hand movement with opposing rotations. It was clear that the left and right hand, within the alternating conditions, learnt to adapt to the opposing displacements at a similar rate suggesting that two adaptive states were formed concurrently. We suggest that the separate limbs are used as contextual cues to switch between the relevant adaptive states. However, we found that during online correction the alternating conditions had a significantly slower rate of adaptation in comparison to the unimanual conditions. Control conditions indicate that the results are not directly due the alternation between limbs or to the constant switching of vision between the two eyes. The negative interference may originate from the requirement to dissociate the visual information of these two alternating displacements to allow online control of the two arms

Can oral infection be a risk factor for Alzheimer’s disease?

Alzheimer’s disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (Herpes simplex type I) and yeasts (Candida species). A causal relationship between periodontal pathogens/non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteraemias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible aetiology of late onset AD (LOAD)

BRED: A Simple and Powerful Tool for Constructing Mutant and Recombinant Bacteriophage Genomes

Advances in DNA sequencing technology have facilitated the determination of hundreds of complete genome sequences both for bacteria and their bacteriophages. Some of these bacteria have well-developed and facile genetic systems for constructing mutants to determine gene function, and recombineering is a particularly effective tool. However, generally applicable methods for constructing defined mutants of bacteriophages are poorly developed, in part because of the inability to use selectable markers such as drug resistance genes during viral lytic growth. Here we describe a method for simple and effective directed mutagenesis of bacteriophage genomes using Bacteriophage Recombineering of Electroporated DNA (BRED), in which a highly efficient recombineering system is utilized directly on electroporated phage DNA; no selection is required and mutants can be readily detected by PCR. We describe the use of BRED to construct unmarked gene deletions, in-frame internal deletions, base substitutions, precise gene replacements, and the addition of gene tags

A cumulative risk model of child physical maltreatment potential: findings from a community-based study

"Published online before print November 20, 2015"Previous studies have identified the predictive risk factors of child physical maltreatment (CPM). However, a significant number of these studies assessed risk factors in isolation. The cumulative risk hypothesis postulates that health problems are caused by the accumulation of risk factors, independently of the presence or absence of specific risk indicators. Few studies examined the effect of cumulative risk on CPM potential. This study aimed to test two concurrent models of cumulative risk of CPM potential by investigating whether CPM potential was better predicted by a threshold cumulative risk model or a linear cumulative risk model. Data from the National Representative Study of Psychosocial Context of Child Abuse and Neglect in Portugal were used. Parents of school-age children (N = 796) answered to self-report measures regarding sociodemographic variables, history of child maltreatment, psychological distress, and CPM potential. A cumulative risk index was computed, comprising 10 dichotomized risk factors. Evidence for a threshold cumulative effect was found. Additional bivariate logistic regressions revealed that the odds for high-potential CPM were dramatically higher for those parents with six or more risk factors when compared with parents with any one risk factor. By testing and confirming a threshold cumulative effect on CPM potential, it was possible to find a "trigger point" from which a dramatic increase in child physical maltreatment potential occurs.This study was supported by the Portuguese Foundation of Science and Technology through a research grant to the second author (POCTI/PSI/14276/1998