Foreword

The postsynaptic density protein-95/disks large/zonula occludens-1 (PDZ) protein domain family is one of the most common proteinprotein interaction modules in mammalian cells, with paralogs present in several hundred human proteins. PDZ domains are found in most cell types, but neuronal proteins, for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context

Corporate Social Responsibility and Islamic Financial Institutions (IFIs): Management Perceptions from IFIs in Bahrain

Islamic finance is gaining greater attention in the finance industry, and this paper analyses how Islamic financial institutions (IFIs) are responding to the welfare needs of society. Using interview data with managers and content analysis of the disclosures, this study attempts to understand management perceptions of corporate social responsibility (CSR) in IFIs. A thorough understanding of CSR by managers, as evident in the interviews, has not been translated fully into practice. The partial use of IFIs’ potential role in social welfare would add further challenges in the era of financialisation

Druggable proteins influencing cardiac structure and function: Implications for heart failure therapies and cancer cardiotoxicity

Dysfunction of either the right or left ventricle can lead to heart failure (HF) and subsequent morbidity and mortality. We performed a genome-wide association study (GWAS) of 16 cardiac magnetic resonance (CMR) imaging measurements of biventricular function and structure. Cis-Mendelian randomization (MR) was used to identify plasma proteins associating with CMR traits as well as with any of the following cardiac outcomes: HF, non-ischemic cardiomyopathy, dilated cardiomyopathy (DCM), atrial fibrillation, or coronary heart disease. In total, 33 plasma proteins were prioritized, including repurposing candidates for DCM and/or HF: IL18R (providing indirect evidence for IL18), I17RA, GPC5, LAMC2, PA2GA, CD33, and SLAF7. In addition, 13 of the 25 druggable proteins (52%; 95% confidence interval, 0.31 to 0.72) could be mapped to compounds with known oncological indications or side effects. These findings provide leads to facilitate drug development for cardiac disease and suggest that cardiotoxicities of several cancer treatments might represent mechanism-based adverse effects

The only African wild tobacco, Nicotiana africana: Alkaloid content and the effect of herbivory

Herbivory in some Nicotiana species is known to induce alkaloid production. This study examined herbivore-induced defenses in the nornicotine-rich African tobacco N. africana, the only Nicotiana species indigenous to Africa. We tested the predictions that: 1) N. africana will have high constitutive levels of leaf, flower and nectar alkaloids; 2) leaf herbivory by the African bollworm Helicoverpa armigera will induce increased alkaloid levels in leaves, flowers and nectar; and 3) increased alkaloid concentrations in herbivore-damaged plants will negatively affect larval growth. We grew N. africana in large pots in a greenhouse and exposed flowering plants to densities of one, three and six fourth-instar larvae of H. armigera, for four days. Leaves, flowers and nectar were analyzed for nicotine, nornicotine and anabasine. The principal leaf alkaloid was nornicotine (mean: 28 µg/g dry mass) followed by anabasine (4.9 µg/g) and nicotine (0.6 µg/g). Nornicotine was found in low quantities in the flowers, but no nicotine or anabasine were recorded. The nectar contained none of the alkaloids measured. Larval growth was reduced when leaves of flowering plants were exposed to six larvae. As predicted by the optimal defense theory, herbivory had a localized effect and caused an increase in nornicotine concentrations in both undamaged top leaves of herbivore damaged plants and herbivore damaged leaves exposed to one and three larvae. The nicotine concentration increased in damaged compared to undamaged middle leaves. The nornicotine concentration was lower in damaged leaves of plants exposed to six compared to three larvae, suggesting that N. africana rather invests in new growth as opposed to protecting older leaves under severe attack. The results indicate that the nornicotine-rich N. africana will be unattractive to herbivores and more so when damaged, but that potential pollinators will be unaffected because the nectar remains alkaloid-free even after herbivory

Natural course of behavioral addictions: A 5-year longitudinal study

BACKGROUND: Resolving the theoretical controversy on the labeling of an increasing number of excessive behaviors as behavioral addictions may also be facilitated by more empirical data on these behavioral problems. For instance, an essential issue to the classification of psychiatric disorders is information on their natural course. However, longitudinal research on the chronic vs. episodic nature of behavioral addictions is scarce. The aim of the present study, therefore, was to provide data on prevalence, substance use comorbidity, and five-year trajectories of six excessive behaviors—namely exercising, sexual behavior, shopping, online chatting, video gaming, and eating. METHODS: Analyses were based on the data of the Quinte Longitudinal Study, where a cohort of 4,121 adults from Ontario, Canada was followed for 5 years (2006 to 2011). The response rate was 21.3%, while retention rate was 93.9%. To assess the occurrence of each problem behavior, a single self-diagnostic question asked people whether their over-involvement in the behavior had caused significant problems for them in the past 12 months. To assess the severity of each problem behavior reported, the Behavioral Addiction Measure was administered. A mixed design ANOVA was used to investigate symptom trajectories over time for each problem behavior and whether these symptom trajectories varied as a function of sex. RESULTS: The large majority of people reported having problematic over-involvement for just one of these behaviors and just in a single time period. A main effect of time was found for each problem behavior, indicating a moderately strong decrease in symptom severity across time. The time x sex interaction was insignificant in each model indicating that the decreasing trend is similar for males and females. The data also showed that help seeking was very low in the case of excessive sexual behavior, shopping, online chatting, and video gaming but substantially more prevalent in the case of excessive eating and exercising. CONCLUSIONS: The present results indicate that self-identified excessive exercising, sexual behavior, shopping, online chatting, video gaming, and/or eating tend to be fairly transient for most people. This aspect of the results is inconsistent with conceptualizations of addictions as progressive in nature, unless treated. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12888-015-0383-3) contains supplementary material, which is available to authorized users

Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses

BACKGROUND: Translation factors eIF4E and eIF4G form eIF4F, which interacts with the messenger RNA (mRNA) 5' cap to promote ribosome recruitment and translation initiation. Variations in the association of eIF4F with individual mRNAs likely contribute to differences in translation initiation frequencies between mRNAs. As translation initiation is globally reprogrammed by environmental stresses, we were interested in determining whether eIF4F interactions with individual mRNAs are reprogrammed and how this may contribute to global environmental stress responses. RESULTS: Using a tagged-factor protein capture and RNA-sequencing (RNA-seq) approach, we have assessed how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change globally in response to three defined stresses that each cause a rapid attenuation of protein synthesis: oxidative stress induced by hydrogen peroxide and nutrient stresses caused by amino acid or glucose withdrawal. We find that acute stress leads to dynamic and unexpected changes in eIF4F-mRNA interactions that are shared among each factor and across the stresses imposed. eIF4F-mRNA interactions stabilised by stress are predominantly associated with translational repression, while more actively initiating mRNAs become relatively depleted for eIF4F. Simultaneously, other mRNAs are insulated from these stress-induced changes in eIF4F association. CONCLUSION: Dynamic eIF4F-mRNA interaction changes are part of a coordinated early translational control response shared across environmental stresses. Our data are compatible with a model where multiple mRNA closed-loop complexes form with differing stability. Hence, unexpectedly, in the absence of other stabilising factors, rapid translation initiation on mRNAs correlates with less stable eIF4F interactions

Phylogenetic Constraints Do Not Explain the Rarity of Nitrogen-Fixing Trees in Late-Successional Temperate Forests

Symbiotic nitrogen (N)-fixing trees are rare in late-successional temperate forests, even though these forests are often N limited. Two hypotheses could explain this paradox. The 'phylogenetic constraints hypothesis' states that no late-successional tree taxa in temperate forests belong to clades that are predisposed to N fixation. Conversely, the 'selective constraints hypothesis' states that such taxa are present, but N-fixing symbioses would lower their fitness. Here we test the phylogenetic constraints hypothesis.Using U.S. forest inventory data, we derived successional indices related to shade tolerance and stand age for N-fixing trees, non-fixing trees in the 'potentially N-fixing clade' (smallest angiosperm clade that includes all N fixers), and non-fixing trees outside this clade. We then used phylogenetically independent contrasts (PICs) to test for associations between these successional indices and N fixation. Four results stand out from our analysis of U.S. trees. First, N fixers are less shade-tolerant than non-fixers both inside and outside of the potentially N-fixing clade. Second, N fixers tend to occur in younger stands in a given geographical region than non-fixers both inside and outside of the potentially N-fixing clade. Third, the potentially N-fixing clade contains numerous late-successional non-fixers. Fourth, although the N fixation trait is evolutionarily conserved, the successional traits are relatively labile.These results suggest that selective constraints, not phylogenetic constraints, explain the rarity of late-successional N-fixing trees in temperate forests. Because N-fixing trees could overcome N limitation to net primary production if they were abundant, this study helps to understand the maintenance of N limitation in temperate forests, and therefore the capacity of this biome to sequester carbon

Shape Variation in Aterian Tanged Tools and the Origins of Projectile Technology: A Morphometric Perspective on Stone Tool Function

BACKGROUND: Recent findings suggest that the North African Middle Stone Age technocomplex known as the Aterian is both much older than previously assumed, and certainly associated with fossils exhibiting anatomically modern human morphology and behavior. The Aterian is defined by the presence of 'tanged' or 'stemmed' tools, which have been widely assumed to be among the earliest projectile weapon tips. The present study systematically investigates morphological variation in a large sample of Aterian tools to test the hypothesis that these tools were hafted and/or used as projectile weapons. METHODOLOGY/PRINCIPAL FINDINGS: Both classical morphometrics and Elliptical Fourier Analysis of tool outlines are used to show that the shape variation in the sample exhibits size-dependent patterns consistent with a reduction of the tools from the tip down, with the tang remaining intact. Additionally, the process of reduction led to increasing side-to-side asymmetries as the tools got smaller. Finally, a comparison of shape-change trajectories between Aterian tools and Late Paleolithic arrowheads from the North German site of Stellmoor reveal significant differences in terms of the amount and location of the variation. CONCLUSIONS/SIGNIFICANCE: The patterns of size-dependent shape variation strongly support the functional hypothesis of Aterian tools as hafted knives or scrapers with alternating active edges, rather than as weapon tips. Nevertheless, the same morphological patterns are interpreted as one of the earliest evidences for a hafting modification, and for the successful combination of different raw materials (haft and stone tip) into one implement, in itself an important achievement in the evolution of hominin technologies

Linking Employee Stakeholders to Environmental Performance: The Role of Proactive Environmental Strategies and Shared Vision

Drawing on the natural-resource-based view (NRBV), we propose that employee stakeholder integration is linked to environmental performance through firms’ proactive environmental strategies, and that this link is contingent on shared vision. We tested our model with a cross-country and multi-industry sample. In support of our theory, results revealed that firms’ proactive environmental strategies translated employee stakeholder integration into environmental performance. This relationship was pronounced for high levels of shared vision. Our findings demonstrate that shared vision represents a key condition for advancing the corporate greening agenda through proactive environmental strategies. We discuss implications for the CSR and the environmental management literatures, with a particular focus on the NRBV and stakeholder integration debates

Macrophages in Breast Cancer: Do Involution Macrophages Account for the Poor Prognosis of Pregnancy-Associated Breast Cancer?

Macrophage influx is associated with negative outcomes for women with breast cancer and has been demonstrated to be required for metastasis of mammary tumors in mouse models. Pregnancy-associated breast cancer is characterized by particularly poor outcomes, however the reasons remain obscure. Recently, post-pregnancy mammary involution has been characterized as having a wound healing signature. We have proposed the involution-hypothesis, which states that the wound healing microenvironment of the involuting gland is tumor promotional. Macrophage influx is one of the prominent features of the involuting gland, identifying the macrophage a potential instigator of tumor progression and a novel target for breast cancer treatment and prevention