Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

INTER-ACT: prevention of pregnancy complications through an e-health driven interpregnancy lifestyle intervention – study protocol of a multicentre randomised controlled trial

Abstract Background Excessive maternal pre-pregnancy and gestational weight gain are related to pregnancy- and birth outcomes. The interpregnancy time window offers a unique opportunity to intervene in order to acquire a healthy lifestyle before the start of a new pregnancy. Methods INTER-ACT is an e-health driven multicentre randomised controlled intervention trial targeting women at high risk of pregnancy- and birth related complications. Eligible women are recruited for the study at day 2 or 3 postpartum. At week 6 postpartum, participants are randomised into the intervention or control arm of the study. The intervention focuses on weight, diet, physical activity and mental well-being, and comprises face-to-face coaching, in which behavioural change techniques are central, and use of a mobile application, which is Bluetooth-connected to a weighing scale and activity tracker. The intervention is rolled out postpartum (4 coaching sessions between week 6 and month 6) and in a new pregnancy (3 coaching sessions, one in each trimester of pregnancy); the mobile app is used throughout the two intervention phases. Data collection includes data from the medical record of the participants (pregnancy outcomes and medical history), anthropometric data (height, weight, waist- and hip circumferences, skinfold thickness and body composition by bio-electrical impedance analysis), data from the mobile app (physical activity and weight; intervention group only) and questionnaires (socio-demographics, breastfeeding, food intake, physical activity, lifestyle, psychosocial factors and process evaluation). Medical record data are collected at inclusion and at delivery of the subsequent pregnancy. All other data are collected at week 6 and month 6 postpartum and every subsequent 6 months until a new pregnancy, and in every trimester in the new pregnancy. Primary outcome is the composite endpoint score of pregnancy-induced hypertension, gestational diabetes mellitus, caesarean section, and large-for-gestational-age infant in the subsequent pregnancy. Discussion INTER-ACT is a unique randomised controlled lifestyle intervention trial in its implementation between pregnancies and during the subsequent pregnancy, with an e-health driven approach. Trial registration ClinicalTrials.gov Identifier: NCT02989142 . Registered August 2016

Tactical Moments of Creative Destruction for Affordable Housing

The formation of a marketing system often reflects historical legacies that seek to protect and preserve longstanding community interests. These legacies encourage some patterns of adaptive growth, but they may also limit other avenues of productive change. In this essay, we focus on the United States housing system as an illustration of a marketing system with significant legacy structures. Historically, this marketplace system arose to provide safe shelter for citizens and was enacted through building codes. These codes arose for historically important reasons, many of which are still pertinent today. Other legacies, however, inhibit market innovations, such as the significant barriers that exist for developing affordable housing. We argue that change in legacy market systems may require tactical moments of creative destruction. We examine a multi-stakeholder approach across the macro, meso, and micro levels of the marketplace to enable novel solutions for systemic change

Consumer adoption of plant-based meat substitutes: A network of social practices

This research aimed to understand the consumption practices of plant-based meat substitutes (PBMS). Semi-structured in-depth interviews were conducted with consumers and Social Practice Theory (SPT) was adopted as the theoretical framework to explore emerging themes relating to consumer practices. Findings indicate that consumers engage in a number of related practices that include the acquisition, preparation, and consumption of PBMS which were embedded within a larger network of practices that included storage, substitution, and food safety, as well as broader meat-based, meat-free, plant-based, and social and cultural practices. This paper highlights the importance of social and cultural structures in facilitating product awareness, and meaning and skill development in the context of dietary and behavioural change. Implications for research, marketing, and policymaking practices are discussed with regard to the marketing of plant-based meat substitutes as well as shifting consumer behaviour

Sustainable brand image: An examination of ad–brand incongruence

Purpose: The purpose of this paper is to examine how consumer attitudes are affected by corporate brands that have newly adopted a sustainable brand image. Specifically, this paper examines consumer responses to ad–brand incongruity and tests whether two-sided messages yield greater acceptance of incongruence. Design/methodology/approach: In total, 528 responses were collected via an online experiment using a 3×2 between-subjects factorial design which manipulated three levels of perceived ad–brand congruence (congruent, moderately incongruent and extremely incongruent) and two levels of message sidedness (one- and two-sided). Findings: Results indicate that brand managers have to be careful not to create ad–brand incongruence after adopting new brand values and should avoid two-sided messages during this period. Originality/value: This paper tests the use of two-sided messages as resolution hints for ad–brand incongruence and furthers the corporate branding literature incorporating sustainability

Mice chronically fed a westernized experimental diet as a model of obesity, metabolic syndrome and osteoporosis

Background Most studies in animals use diets with several features (for example low-fat, rich in micronutriments), likely to be strongly protective against chronic diseases. Aim of the study The present study, performed in wild type outbred mice, was designed to evaluate the validity of a model of ‘westernized’ (W) diet reproducing, as closely as possible, the overall composition of an average human regime in western countries Results In contrast to the standard (S) diet, the W diet triggered a marked increase in adiposity with some characteristics of metabolic syndrome (hypercholesterolemia, hyperinsulinemia...). There was an heterogeneity in the propensity to become obese upon exposure to the W diet in female mice. Overweight mice also presented some disturbances of renal function, such as hyperalbuminuria and hypocitraturia. Mice adapted to the W diet showed a reduction of bone mineral density, especially the non-obese ones. Conclusion These data suggest that a model of westernized diet could be appropriate for exploring the effects of mutations, drugs, or specific nutritional factors in animals and could be more relevant for human situations

Developmental programming of appetite and growth in male rats increases hypothalamic serotonin (5-HT)5A receptor expression and sensitivity.

BACKGROUND: Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring. METHODS: Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake. RESULTS: Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring. CONCLUSIONS: Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring