Protease inhibitors prevent plasminogen-mediated, but not pemphigus vulgaris-induced, acantholysis in human epidermis

Pemphigus is an autoimmune blistering disease of the skin and mucous membranes. It is caused by autoantibodies directed against desmosomes, which are the principal adhesion structures between epidermal keratinocytes. Binding of autoantibodies leads to the destruction of desmosomes resulting in the loss of cell-cell adhesion (acantholysis) and epidermal blisters. The plasminogen activator system has been implicated as a proteolytic effector in pemphigus. We have tested inhibitors of the plasminogen activator system with regard to their potential to prevent pemphigus-induced cutaneous pathology. In a human split skin culture system, IgG preparations of sera from pemphigus vulgaris patients caused histopathologic changes (acantholysis) similar to those observed in the original pemphigus disease. All inhibitors that were tested (active site inhibitors directed against uPA, tPA, and/or plasmin; antibodies neutralizing the enzymatic activity of uPA or tPA; substances interfering with the binding of uPA to its specific cell surface receptor uPAR) failed to prevent pemphigus vulgaris IgG-mediated acantholysis. Plasminogen-mediated acantholysis, however, was effectively antagonized by the synthetic active site serine protease inhibitor WX-UK1 or by p-aminomethylbenzoic acid. Our data argue against applying anti-plasminogen activator/anti-plasmin strategies in the management of pemphigus

Moduli Webs and Superpotentials for Five-Branes

We investigate the one-parameter Calabi-Yau models and identify families of D5-branes which are associated to lines embedded in these manifolds. The moduli spaces are given by sets of Riemann curves, which form a web whose intersection points are described by permutation branes. We arrive at a geometric interpretation for bulk-boundary correlators as holomorphic differentials on the moduli space and use this to compute effective open-closed superpotentials to all orders in the open string couplings. The fixed points of D5-brane moduli under bulk deformations are determined.Comment: 41 pages, 1 figur

Behavioral and psychological symptoms of dementia: The effects of physical activity at adult day service centers

Adult day services (ADS) are an increasingly popular option for caregivers of people with dementia, but there is little research on the effects of activities on the behavior and mood of the client. This study examines participation by 94 individuals in different types of adult day-care activities and their association with changes in behavior and psychological symptoms of dementia (BPSD) for the client during a three-month span. Three domains of BPSD were examined: restless behaviors, mood behaviors, and positive behaviors. Using growth curve modeling, results show that the restless and mood behavior domains, on average, were stable over three months, whereas positive behaviors increased. For all three behavior domains there were individual differences in average level of BPSD. Average rate of change for individuals also varied from the mean for restless and mood behaviors. Physical activities, social activities, engaging activities, and watching and listening activities, along with a day-care dosage variable, were used as covariates to explain these individual differences in change. Engaging activities explained some of the individual variance for restless behaviors; as individuals increased one increment in engaging activities, they had fewer restless behavior problems over time. These results suggest that some features of programming may be related to improvements in restless behavior

Dilemmas of Development and The Reconstruction of Fashion

Sustainable development by its nature appears elusive. It seems the more we try to capture and pin it down the more it moves away from us leading us into murkier waters and all manner of contradictions. No more is this felt than in the fashion industry where we are presented with a number of oppositions. The fashion cycle renders styles obsolete before they have worn out generating waste and over-consumptive practices. But it can also bring into the fore practices that have resonance to sustainable development in terms of their location, orientation and consideration for the environment. As studies emerge considering the detrimental environmental impacts of the manufacture and consumption of new clothes, second-hand clothes have become a focus for research endeavours considering how they can be reincorporated into the fashion system and have resonance to an ever ‘fashion’ hungry consumer. This chapter discusses methods for the processing of second-hand clothes into fashionable items and, by drawing on the wealth of ‘waste’ materials through reselling, restyling and remanufacturing, argues that ways of re-appropriating them into a more environmentally focused fashion industry is possible and necessary. It sets out as it hypothesis that the global fashion system has value in its transformative powers but that damaging and exploitative forces are still preventing it from being a force for good. This is due to the nature of the items being produced, the way they are manufactured and how they are ultimately consumed and disposed of

Genetic and environmental mechanisms underlying stability and change in problem behaviors at ages 3, 7, 10, and 12.

Maternal ratings on internalizing (INT) and externalizing (EXT) behaviors were collected in a large, population-based longitudinal sample. The numbers of participating twin pairs at ages 3, 7, 10, and 12 were 5,602, 5,115, 2,956, and 1,481, respectively. Stability in both behaviors was accounted for by genetic and shared environmental influences. The genetic contribution to stability (INT: 43%; EXT: 60%) resulted from the fact that a subset of genes expressed at an earlier age was still active at the next time point. A common set of shared environmental factors operated at all ages (INT: 47%; EXT: 34%). The modest contribution of nonshared environmental factors (INT: 10%; EXT: 6%) could not be captured by a simple model. Significant age-specific influences were found for all components, indicating that genetic and environmental factors also contributed to changes in problem behavior. Understanding the origins, nature, and course of psychopathology across childhood is important for clinical purposes as well as for scientific purposes. Of particular clinical importance are the mechanisms underlying continuity. The longer an individual continues along a maladaptive pathway, the more difficult it is to reclaim a normal developmental trajectory (Sroufe, 1990). Further

Does it look safe? An eye tracking study into the visual aspects of fear of crime

Studies of fear of crime often focus on demographic and social factors, but these can be difficult to change. Studies of visual aspects have suggested that features reflecting incivilities, such as litter, graffiti, and vandalism increase fear of crime, but methods often rely on participants actively mentioning such aspects, and more subtle, less conscious aspects may be overlooked. To address these concerns, the present study examined people’s eye movements while they judged scenes for safety. Forty current and former university students were asked to rate images of day-time and night-time scenes of Lincoln, UK (where they studied) and Egham, UK (unfamiliar location) for safety, maintenance and familiarity, while their eye movements were recorded. Another twenty-five observers not from Lincoln or Egham rated the same images in an internet survey. Ratings showed a strong association between safety and maintenance and lower safety ratings for night-time scenes for both groups, in agreement with earlier findings. Eye movements of the Lincoln participants showed increased dwell times on buildings, houses, and vehicles during safety judgments, and increased dwell times on streets, pavements, and markers of incivilities for maintenance. Results confirm that maintenance plays an important role in perceptions of safety, but eye movements suggest that observers also look for indicators of current or recent presence of people

Techno-Ecological Synergy: A Framework for Sustainable Engineering

Even though the importance of ecosystems in sustaining all human activities is well-known, methods for sustainable engineering fail to fully account for this role of nature. Most methods account for the demand for ecosystem services, but almost none account for the supply. Incomplete accounting of the very foundation of human well-being can result in perverse outcomes from decisions meant to enhance sustainability and lost opportunities for benefiting from the ability of nature to satisfy human needs in an economically and environmentally superior manner. This paper develops a framework for understanding and designing synergies between technological and ecological systems to encourage greater harmony between human activities and nature. This framework considers technological systems ranging from individual processes to supply chains and life cycles, along with corresponding ecological systems at multiple spatial scales ranging from local to global. The demand for specific ecosystem services is determined from information about emissions and resource use, while the supply is obtained from information about the capacity of relevant ecosystems. Metrics calculate the sustainability of individual ecosystem services at multiple spatial scales and help define necessary but not sufficient conditions for local and global sustainability. Efforts to reduce ecological overshoot encourage enhancement of life cycle efficiency, development of industrial symbiosis, innovative designs and policies, and ecological restoration, thus combining the best features of many existing methods. Opportunities for theoretical and applied research to make this framework practical are also discussed

FADS2 Genetic Variance in Combination with Fatty Acid Intake Might Alter Composition of the Fatty Acids in Brain

Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition

Going underground: Resort to terrorism in mass mobilization dissident campaigns

© The Author(s) 2018. When and why do groups participating in mass dissent choose to initiate terrorist campaigns? I argue that groups involved in civil wars and mass civil resistance might face similar organizational pressures, which encourage the initiation of terrorism due to higher tactical effectiveness. Internal organizational pressure might depend on leaders’ expectations of a decline in followers’ commitment with protracted use of mass tactics. This is likely to motivate leaders to initiate terrorist campaigns to secure organizational survival. External organizational pressures might depend on increasing dissident campaigns’ fragmentation. This intensifies competition making leaders more likely to initiate terrorism so as to establish themselves at the forefront of their movements. The findings provide empirical support consistent with my claims and indicate no significant difference between civil wars and mass civil resistance movements with regards to these effects. Contrary to the common idea that the use of conventional violence should entail a higher willingness to engage in illegal violence against non-combatants, this finding suggests that conflict dynamics affect the decision to initiate terrorism and that terrorist campaigns have a coherent strategic logic across different types of mass dissent.Economic and Social Research Council (1511095

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112