Molecular analysis of the site for 2-arachidonylglycerol (2-AG) on the β 2 subunit of GABA A receptors

2-arachidonyl glycerol (2-AG) allosterically potentiates GABAA receptors via a binding site located in transmembrane segment M4 of the β2 subunit. Two amino acid residues have been described that are essential for this effect. With the aim to further describe this potential drug target, we performed a cysteine scanning of the entire M4 and part of M3. All four residues in M4 affecting the potentiation here and the two already identified residues locate to the same side of the α-helix. This side is exposed to M3, where further residues were identified. From the fact that the important residues span > 18 Å, we conclude that the hydrophobic tail of the bound 2-AG molecule must be near linear and that the site mainly locates to the inner leaflet but stretches far into the membrane. The influence of the structure of the head group of the ligand molecule on the activity of the molecule was also investigated. We present a model of 2-AG docked to the GABAA receptor.

Aesthetic outcome of cleft lip and palate treatment. Perceptions of patients, families, and health professionals compared to the general public

The aesthetic outcome of cleft treatment is of great importance due to its complex management and the psychosocial consequences of this defect. The aim of the study was to assess the aesthetic evaluations of patients following cleft surgery by various groups and investigate potential associations of the assessments with life quality parameters. Head photos of 12 adult patients with treated unilateral cleft lip and palate were evaluated by laypeople and professionals. A questionnaire was distributed and answered by the patients and their parents. Intra-panel agreement was high (α > 0.8) for laypeople and professionals. Between-groups agreement was high for both laypeople and professionals, but not when patients and/or parents were tested. Professionals, parents, and patients were more satisfied with patients' appearance than laypeople, although in general all groups were not highly satisfied. Low satisfaction with aesthetics correlated with increased self-reported influence of the cleft in the patients' social activity and professional life (0.56 < rho < 0.74, p < 0.05). These findings highlight the observed negative influence of the cleft on the patient's social activity and professional life and underline the need for the highest quality of surgical outcome for this group of patients.

Molecular Determinants Defining the Triggering Range of Prefusion F Complexes of Canine Distemper Virus

The morbillivirus cell entry machinery consists of a fusion (F) protein trimer that refolds to mediate membrane fusion following receptor-induced conformational changes in its binding partner, the tetrameric attachment (H) protein. To identify molecular determinants that control F refolding, we generated F chimeras between measles virus (MeV) and canine distemper virus (CDV). We located a central pocket in the globular head domain of CDV F that regulates the stability of the metastable, prefusion conformational state of the F trimer. Most mutations introduced into this "pocket'" appeared to mediate a destabilizing effect, a phenotype associated with enhanced membrane fusion activity. Strikingly, under specific triggering conditions (i.e., variation of receptor type and H protein origin), some F mutants also exhibited resistance to a potent morbillivirus entry inhibitor, which is known to block F triggering by enhancing the stability of prefusion F trimers. Our data reveal that the molecular nature of the F stimulus and the intrinsic stability of metastable prefusion F both regulate the efficiency of F refolding and escape from small-molecule refolding blockers. IMPORTANCE: With the aim to better characterize the thermodynamic basis of morbillivirus membrane fusion for cell entry and spread, we report here that the activation energy barrier of prefusion F trimers together with the molecular nature of the triggering "stimulus" (attachment protein and receptor types) define a "triggering range," which governs the initiation of the membrane fusion process. A central "pocket" microdomain in the globular F head contributes substantially to the regulation of the conformational stability of the prefusion complexes. The triggering range also defines the mechanism of viral escape from entry inhibitors and describes how the cellular environment can affect membrane fusion efficiency.

Habitat-dependent geographical variation in ontogenetic allometry of the shiner perch Cymatogaster aggregata Gibbons (Teleostei: Embiotocidae)

Studies of intraspecific morphological variation in fishes have traditionally focused on freshwater rather than marine species. In addition, such studies typically focus on adults, although causes and intensities of selective pressures most likely vary through an individual’s lifetime. In this study, body and head shape of a marine species, shiner perch Cymatogaster aggregata Gibbons were compared among localities along the Pacific Northwest coast of North America. Evidence was found for intraspecific variation in ontogenetic allometry, and for a closer correlation of body shape with environment rather than geographical proximity. This correlation with environment was more evident in younger fish, thereby demonstrating the importance of analysing multiple life stages. A common garden experiment suggests both environmental and genetic bases for the observed differences. Recognizing intraspecific ecomorphological complexity and its specificity to habitat and/or life stage can have important consequences for understanding the role of local adaptation and population dynamics in macroecology.

Persistent Deadlock in Multilateral Trade Negotiations: The Case of Doha

The history of the General Agreement on Tariffs and Trade negotiations is full of anecdotes on missed deadlines, failed ministerial conferences, and brinkmanship situations. Tactics such as walking away from the table or sleep-depriving night sessions are legendary in the context of attempting to overcome impasse in negotiations. This article traces and explains the recurrent deadlock in the Doha Round negotiations. It identifies four structural/contextual factors – ideas, institutions, interests, and information – as necessary for understanding and anticipating potential deadlocks. The article also offers a definition of deadlock, and discusses a set of factors highlighted in the international relations literature that explain the existence and persistence of deadlock. With the help of game theory, it then illustrates the challenges faced by actors during trade negotiations. The article concludes by outlining two general scenarios for the Doha Development Agenda and discusses their implications for the World Trade Organization.

Increment thickness versus dentin bond strength of bulk fill flowables

Objectives: The aim was to investigate the influence of increment thickness on shear bond strength (SBS) to dentin of a conventional and two bulk fill flowable composites. Methods: A total of 135 specimens of ground human dentin were produced (n=15/group; 3 increment thicknesses; 3 flowable composites) and the dentin surfaces were treated with the adhesive system OptiBond FL (Kerr) according to manufacturer’s instructions. Split Teflon molds (inner diameter: 3.6 mm) of 2 mm, 4 mm, or 6 mm height allowing three increment thicknesses were clamped on the dentin surfaces and filled with either the conventional flowable Filtek Supreme XTE ((XTE); 3M ESPE) or the bulk fill flowables Filtek Bulk Fill ((FBF); 3M ESPE) or SDR ((SDR); DENTSPLY Caulk). The flowable composites were light-cured for 20 s (Demi LED; Kerr) and the specimens stored for 24 h (37°C, 100% humidity). Specimens were then subjected to a SBS-test in a universal testing machine at a cross-head speed of 1 mm/min (Zwick Z010; Zwick GmbH & Co.). SBS-values were statistically analysed with a nonparametrical ANOVA followed by exact Wilcoxon rank sum tests (α=0.05). Failure mode of the specimens was determined under a stereomicroscope at 25× magnification. Results: SBS-values (MPa) at 2 mm/4 mm/6 mm increment thicknesses (mean value [standard deviation]) were for XTE: 18.8 [2.6]/17.6 [1.6]/16.7 [3.1], for FBF: 20.6 [2.7]/17.8 [2.7]/18.7 [2.9], and for SDR: 21.7 [2.6]/18.5 [2.6]/20.3 [3.0]. For all three flowable composites, 2 mm increments yielded the highest SBS-values whereas for increments of 4 mm and 6 mm no differences were detected. All specimens presented failure modes involving cohesive failure in dentin. Conclusion: The influence of increment thickness on dentin SBS was less pronounced than expected. However, the high number of cohesive failures in dentin, reflecting the efficiency of the adhesive system, suggests a limited discriminatory power of the SBS-test.

Structure and mechanism of an active lipid-linked oligosaccharide flippase

The flipping of membrane-embedded lipids containing large, polar head groups is slow and energetically unfavourable, and is therefore catalysed by flippases, the mechanisms of which are unknown. A prominent example of a flipping reaction is the translocation of lipid-linked oligosaccharides that serve as donors in N-linked protein glycosylation. In Campylobacter jejuni, this process is catalysed by the ABC transporter PglK. Here we present a mechanism of PglK-catalysed lipid-linked oligosaccharide flipping based on crystal structures in distinct states, a newly devised in vitro flipping assay, and in vivo studies. PglK can adopt inward- and outward-facing conformations in vitro, but only outward-facing states are required for flipping. While the pyrophosphate-oligosaccharide head group of lipid-linked oligosaccharides enters the translocation cavity and interacts with positively charged side chains, the lipidic polyprenyl tail binds and activates the transporter but remains exposed to the lipid bilayer during the reaction. The proposed mechanism is distinct from the classical alternating-access model applied to other transporters.

Family characteristics as risk factors for childhood acute lymphoblastic leukemia: a population-based case-control study

To date, few risk factors for childhood acute lymphoblastic leukemia (ALL) have been confirmed and the scientific literature is full of controversial "evidence." We examined if family characteristics, particularly maternal and paternal age and number of older siblings, were risk factors for childhood acute lymphoblastic leukemia (ALL).

[Orthostatic headache with tachycardia]

We report the case of a 17 year old male patient who presented with a history of orthostatic headache (present in the upright position only) for several months. The diagnostic investigations (MRI of the head and of the spine, lumbar puncture) revealed no signs of an intracranial hypotension or a CSF leak. In standing position, a significant raise of the heart rate (>40 bpm) without fall of the blood pressure occurred together with a bilateral, pressure-like headache. A diagnosis of postural tachycardia syndrome was made. Treatment with increase of fluid and salt intake, elastic compression stockings and regular exercise was successful.

Femoroacetabular impingement

Femoroacetabular impingement (FAI) is a pathomechanical concept describing the early and painful contact of morphological changes of the hip joint, both on the acetabular, and femoral head sides. These can lead clinically to symptoms of hip and groin pain, and a limited range of motion with labral, chondral and bony lesions. Pincer impingement generally involves the acetabular side of the joint where there is excessive coverage of the acetabulum, which may be focal or more diffuse. There is linear contact of the acetabulum with the head/neck junction. Cam impingement involves the femoral head side of the joint where the head is associated with bony excrescences and is aspheric. The aspheric femoral head jams into the acetabulum. Imaging appearances are reviewed below. This type is evident in young males in the second and third decades. The main features of FAI are described.

"Fact versus Fiction – How paratextual information shapes our reading processes"

Our life is full of stories: some of them depict real-life events and were reported, e.g. in the daily news or in autobiographies, whereas other stories, as often presented to us in movies and novels, are fictional. However, we have only little insights in the neurocognitive processes underlying the reading of factual as compared to fictional contents. We investigated the neurocognitive effects of reading short narratives, labeled to be either factual or fictional. Reading in a factual mode engaged an activation pattern suggesting an action-based reconstruction of the events depicted in a story. This process seems to be past-oriented and leads to shorter reaction times at the behavioral level. In contrast, the brain activation patterns corresponding to reading fiction seem to reflect a constructive simulation of what might have happened. This is in line with studies on imagination of possible past or future events.

Rezension zu: Inge Govaere and Hanns Ulrich (eds.): Intellectual Property, Public Policy and International Trade

The contemporary intellectual property rights (IPR) system is not a simple, smoothly working block of rules but is complex and full of ambiguities, and as many argue, imperfections. Some deficits relate on the one hand to the inherent centrality of authorship, originality and mercantilism to the ‘Western’ IP model, which leaves numerous non-Western, collaborative or folkloric modes of production outside the scope of protection. On the other hand, some imperfections stem from the way IPR are granted, whereby creators acquire a temporary monopoly over their works and thus exclude the public from having access to them. In this sense, it is often uncertain whether the existent IPR model appropriately reflects the precarious balance between private and public interests, and whether the best incentives to promote creativity and innovation - the initially stated objectives of intellectual property protection - are offered. The matter becomes still more complicated when one considers that the IPR system is not domestically contained but is globalised and strongly affected by rules at the regional and international levels. The question of whether the balance between private interests and public values is sustained within the international legal framework, epitomised by the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) of the World Trade Organization (WTO), is precisely the topic of the book reviewed here. Review of Intellectual Property, Public Policy, and International Trade, edited by Inge Govaere and Hanns Ullrich, P.I.E. Peter Lang, 2007.