The laulimalide family: total synthesis and biological evaluation of neolaulimalide, isolaulimalide, laulimalide and a nonnatural analogue

We herein describe in full detail the first total synthesis of the antitumor agents neolaulimalide and isolaulimalide as well as a highly efficient route to laulimalide. A Kulinkovich reaction followed by a cyclopropyl-allyl rearrangement is used to install the exo-methylene group. The C(2)-C(16) aldehyde fragment is coupled with the C(17)-C(28) sulfone fragments by a highly (E)-selective Julia-Lythgoe-Kocienski olefination to deliver the key intermediates of all three syntheses. Various conditions for the Yamaguchi macrolactonization are applied to close the individual macrocycles. Finally a carefully elaborated endgame was developed to solve the problem of acyl migration in the case of neolaulimalide. All compounds were tested against several cell lines. The cytotoxicity of neolaulimalide could be confirmed for the first time since its original isolation and it could be shown that it induces tubulin polymerization as efficiently as laulimalide.

Intracellular localization of the BCL-2 family member BOK and functional implications

The pro-apoptotic BCL-2 family member BOK is widely expressed and resembles the multi-BH domain proteins BAX and BAK based on its amino acid sequence. The genomic region encoding BOK was reported to be frequently deleted in human cancer and it has therefore been hypothesized that BOK functions as a tumor suppressor. However, little is known about the molecular functions of BOK. We show that enforced expression of BOK activates the intrinsic (mitochondrial) apoptotic pathway in BAX/BAK-proficient cells but fails to kill cells lacking both BAX and BAK or sensitize them to cytotoxic insults. Interestingly, major portions of endogenous BOK are localized to and partially inserted into the membranes of the Golgi apparatus as well as the endoplasmic reticulum (ER) and associated membranes. The C-terminal transmembrane domain of BOK thereby constitutes a 'tail-anchor' specific for targeting to the Golgi and ER. Overexpression of full-length BOK causes early fragmentation of ER and Golgi compartments. A role for BOK on the Golgi apparatus and the ER is supported by an abnormal response of Bok-deficient cells to the Golgi/ER stressor brefeldin A. Based on these results, we propose that major functions of BOK are exerted at the Golgi and ER membranes and that BOK induces apoptosis in a manner dependent on BAX and BAK.

Skin and mucosa care in systemic sclerosis - patients' and family caregivers' experiences and expectations of a specific education programme: a qualitative study

BACKGROUND Skin and mucosal manifestations such as skin thickening, pruritus, reduced microvascular circulation, digital lesions, appearance-related changes, and dryness of the eyes and mucosa are common in systemic sclerosis (SSc). A specific skin and mucosa care education programme for patients and their family caregivers should increase their self-efficacy and improve coping strategies. AIMS The aims of this qualitative study were to explore the participants' experiences of both everyday life with skin and mucosal manifestations and the programme itself, while identifying unmet needs for programme development. METHODS Narrative interviews were conducted with eight SSc patients and two family caregivers of individuals with SSc. Using qualitative content analysis techniques, the transcribed interviews were systematically summarized and categories inductively developed. RESULTS The findings illustrated participants' experiences of skin and mucosal symptoms and revealed them to be experts in finding the right therapy mix alone (before diagnosis) and also in collaboration with health professionals (after diagnosis). Participants emphasized that the programme gave them useful education on skin and mucosa care. They described how they had to cope alone with the lack of information on pathophysiology, people's reactions, and the impact on their family and working lives. Nevertheless, participants said that they maintained a positive attitude by not dwelling on future disabilities. CONCLUSIONS Patients and family caregivers benefited from the individualized and SSc-specific education on skin and mucosa care. Future improvements to the programme should focus on imparting understandable information on SSc pathophysiology, dealing with disfigurement and seeking reliable disease information, as well as facilitating peer support.

Family-related values and future orientation in adolescence: A German-Russian comparison

This article compares family values and family future orientation between German and Russian adolescents. Based on different cultural values in Germany and Russia a higher family orientation of Russian as compared to German adolescents was assumed. Adolescents from both countries responded to a questionnaire of general and family-related values and family-related future orientation in the framework of the VOC-study. Results showed that for both German and Russian adolescents a future family of one's own is of high importance. The majority of adolescents from both countries (and both genders) reported wanting to get married in the future and to have (preferably two) children. Russian as compared to German adolescents reported a higher importance of traditional family values and child-related values (value of children), as well as a stronger desire to have children. Russian girls were most likely to abandon own career plans for the benefit of a future family. The results are discussed with regard to psychological models of cultural values' and the notion of a regaining strength of traditional family values in the course of social change in Germany and Russia.

Sustainable development in international law making and trade: International food governance and trade in agriculture

This timely book provides an accessible insight into how the concept of sustainable development can be made operational through its translation into legal terms. Understood as a multidimensional legal principle, sustainable development facilitates coherent international law making. Using this notion as an analytical lens on the WTO Agreement on Agriculture, the book considers the unresolved question of what a sustainable and coherent agricultural trade agreement could look like.

The World Trade Organization - Law, Practice and Policy, 3rd edition

The WTO is one of the most important intergovernmental organizations in the world, yet the way in which it functions as an organization and the scope of its authority and power are still poorly understood. This comprehensively revised new edition of the acclaimed work by an outstanding team of WTO law specialists provides a complete overview of the law and practice of the WTO.

Family Firm Incumbent’s Attitude toward Intra-family Succession: Antecedents and Effects on Intentions

Research shows that intention for intra-family succession is an important determinant of family firm behavior. To provide a systematic analysis of the antecedents of such intention, we use the theory of planned behavior to model the incumbent leader’s attitude toward intra-family succession because that particular attitude is idiosyncratic to family firms. Empirical tests using a sample of 271 Italian incumbent leaders of family firms show that, as predicted by planned behavior theory, attitude and self-efficacy are significant predictors of intention. They show further that attitude is affected by the number of children, emotional attachment, and need for control.