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The crystal structure of the full-length glucagon receptor in complex with a glucagon analogue NNC1702 reveals how the peptide ligand interacts with its target and shows the conformational changes required for receptor activation. The glucagon receptor is a class B G-protein-coupled receptor with an important role in glucose homeostasis. Activation of this receptor triggers the release of glucose, making it an important target for the treatment of type 2 diabetes. Beili Wu and colleagues now report the crystal structure of the full-length glucagon receptor bound to a glucagon analogue and a partial agonist, NNC1702. The 3.0 A resolution of the structure provides key insights into how the peptide ligand interacts with its target and the conformational changes involved in the initial stages of activation. The structural data is reinforced by using double electron–electron resonance (DEER) spectroscopy, which demonstrates the extent of rearrangement that is involved in accommodating the glucagon analogue. Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases1,2,3,4,5,6,7,8. Previous work9,10,11 has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved12,13,14. These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 A-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR–NNC0640–mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation—which requires conformational changes of the stalk, first extracellular loop and TMD—that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.

It follows explicitly from the EC VAT Directive that the deduction of input VAT depends on a positive link between on the one hand the incurred expenses and on the other hand the planned or actually completed taxed output transactions. In theory and in practice, however, the deeper nature of this link constantly gives rise to uncertainty, and thus also uncertainty in relation to the necessary distinction between direct costs and overhead costs. The purpose of this article is to analyse the recent case law of the Court of Justice of the European Union (ECJ) with a view to assessing the status of the relevant test used when establishing the link between a taxable person's different input and output transactions.

Gold exploration in the Bjornesund region has been carried out since the early 1990s, and gold was found in the central part of the Bjornesund East area by NunaOil and the Geological Survey of Denmark and Greenland (GEUS). Records of stream sediment samples with elevated gold concentrations up to several hundred parts per billion led to the recognition that amphibolites in the central part of the Bjornesund East could be a promising target and work in 1996 led to the discovery of hydrothermally altered amphibolites with up to several hundred ppb gold. However, exploration work was limited to grassroots prospecting and none of the targets were drilled. The aim of new field work was to target areas in the Bjornesund supracrustal belt which mainly consists of amphibolites but also comprises significant proportions of diorite, anorthosite, leucogabbro, granitoid rocks and ultramafic to mafic rocks that occur as relatively thin slivers in the amphibolite. We tested if the targeted areas were favourable for gold mineralisation and investigated the relationship between the mineral potential mapping and the actual geology. Here we demonstrate that based on older data we located new gold mineralising systems in the western part of the Bjornesund supracrustal belt, identified platinum-enriched mafic to ultramafic rocks and located new occurrences of corundum at amphibolite-anorthosite contacts (Schlatter

Objective: To evaluate the use of palpation of the coccyx (the coccygeal movement test, CMT) as a possible objective screening tool for the assessment of adequate localization of the pelvic floor muscles (PFMs). Subjects and Methods: Twenty-four healthy female volunteers, known to be able to locate their PFMs, were given instructions (allocated at random) to perform a ‘correct contraction', ‘straining' or ‘nothing' when examined by six independent assessors using the CMT. The assessors were blinded to the instructions and to the test results recorded by other assessors. Data were available for 137 observations, and these were dichotomized into either ‘able to contract' (‘correct contraction') or ‘not able to contract' (‘straining' or ‘nothing'). This information was used to calculate the sensitivity, specificity and positive and negative predictive values for the CMT. Results: The CMT correctly identified 56/58 observations when women did not perform the contraction of the PFMs compared to 61/79 observations when they did. Hence, the sensitivity and specificity were 97 and 77%, respectively. Conclusion: This study showed that the CMT was a useful test to identify women who were able to localize their PFMs compared to those who were not, making it a potentially useful initial screening test in structured training programmes for the PFMs.

Hay-making structures are part of the agricultural landscape of meadows and pastures. Hay meadows are still used and found all over Europe, but their distribution patterns as well as their characteristics and regional features depend on geographical area, climate, culture, and intensity of agriculture. Intensively used hay meadows are the most dominant, using heavy machinery to store hay mostly as rounded or square bales. Traditional hay-making structures represent structures or constructions, used to quickly dry freshly cut fodder and to protect it from humidity. The &lsquo, ancient&rsquo, forms of traditional hay-making structures are becoming a relic, due to mechanisation and the use of new technologies. Both the need for drying hay and the traditional methods for doing so were similar across Europe. Our study of hay-making structures focuses on their current state, their development and history, current use and cultural values in various European countries. Regarding the construction and use of hay-making structures, we have distinguished three different types, which correlate to natural and regional conditions: (1) temporary hay racks of various shapes, (2) hay barracks, a special type of shelters for storing hay and (3) different types of permanent construction and buildings for drying and storing hay. Hay-making structures have been mostly preserved in connection with traditional agricultural landscapes, and particularly in the more remote regions or where associated with strong cultural identity.

Schistosomiasis remains one of the most prevalent parasitic diseases in the tropics and subtropics, but current statistics are outdated due to demographic and ecological transformations and ongoing control efforts. Reliable risk estimates are important to plan and evaluate interventions in a spatially explicit and cost-effective manner. We analysed a large ensemble of georeferenced survey data derived from an open-access neglected tropical diseases database to create smooth empirical prevalence maps for Schistosoma mansoni and Schistosoma haematobium for a total of 13 countries of eastern Africa. Bayesian geostatistical models based on climatic and other environmental data were used to account for potential spatial clustering in spatially structured exposures. Geostatistical variable selection was employed to reduce the set of covariates. Alignment factors were implemented to combine surveys on different age-groups and to acquire separate estimates for individuals aged ≤20 years and entire communities. Prevalence estimates were combined with population statistics to obtain country-specific numbers of Schistosoma infections. We estimate that 122 million individuals in eastern Africa are currently infected with either S. mansoni, or S. haematobium, or both species concurrently. Country-specific population-adjusted prevalence estimates range between 12.9% (Uganda) and 34.5% (Mozambique) for S. mansoni and between 11.9% (Djibouti) and 40.9% (Mozambique) for S. haematobium. Our models revealed that infection risk in Burundi, Eritrea, Ethiopia, Kenya, Rwanda, Somalia and Sudan might be considerably higher than previously reported, while in Mozambique and Tanzania, the risk might be lower than current estimates suggest. Our empirical, large-scale, high-resolution infection risk estimates for S. mansoni and S. haematobium in eastern Africa can guide future control interventions and provide a benchmark for subsequent monitoring and evaluation activities.

Denne rapport indeholder en kvalitativt baseret undersøgelse af, hvorvidt bygningsreglements energibestemmelser bliver overholdt ved renovering af større bygninger, dvs. etageboliger, institutioner og erhvervsejendomme. Bygningsreglementets bestemmelser omfatter dels faste krav om energieffektivisering ved udskiftning af komponenter, fx vinduer og kedler, og dels krav om rentable energieffektiviseringer ved renovering af bygningsdele, fx tag, ydervægge og gulv. Undersøgelsen er baseret på anonyme interview med en række af byggeriets organisationer samt rådgivere og udførende. På baggrund af de gennemførte interview må det konkluderes, at der kan være problemer med manglende overholdelse af bygningsreglementets bestemmelser. Problemet gælder primært den del, der omhandler renovering af bygningsdele. Her vil det ofte være muligt at argumentere for, at det ikke er rentabelt at renovere op til dagens standard, men det er langt fra altid, at beregningerne faktisk gennemføres, og i andre tilfælde gennemføres de på en måde, som der kan sættes spørgsmålstegn ved rigtigheden af.

Background Adolescents have the highest risk for food allergy-related fatalities. Our main aim was to investigate the level of risk in everyday social situations as perceived by adolescents/young adults with peanut allergy, their families, and their friends. Methods The web-based ‘Colours Of Risks’ (COR) questionnaire was completed by 70 patients (aged 12–23 years), 103 mothers and fathers, 31 siblings (aged 12–26 years), and 42 friends (aged 12–24 years). COR deals with six main contexts (home, school/university, work, visiting/social activities, special occasions/parties, and vacations), each with 1-12 items. Response categories are green (I feel safe), yellow (I feel uncertain), or red (I feel everything is risky). Results There was a high level of agreement between participants in defining situations as safe, uncertain, or risky, but female patients and mothers rated fewer situations as safe compared to male patients and fathers. Being with close friends and family, and attending planned parties without alcohol were perceived as situations of low risk. While 94% of patients took an epinephrine auto-injector (EAI) into risky situations, only 65% took it into safe situations. In contrast to the close family, 31% of the friends did not know the patient had an EAI, and fewer knew how to administer the EAI. Conclusion Young adults with peanut allergy face challenges when moving from the safe home with ready assistance if needed, to independence with unpredictable surroundings and less certain help. Perceived ‘safe’ situations may in fact be the riskiest, as patients often do not take the EAI with them.

Bruken av setrene har endret seg og seterlandskapet har vært i endring over lang tid. NIBIO har i løpet av sju somre gjennomført en undersøkelse av setermiljøer spredt rundt i landet. Rapporten viser, gjennom bilder og statistikk, dagens situasjon med hensyn til setrenes bruk og tilgjengelighet, innhold og tilstand i bygningsmiljøer, og gjengroing av setervoller. 300 områder á 5 km x 5 km i 17 fylker er befart i felt og nær 1700 seteranlegg er registrert.

Tryptophan hydroxylase (TPH) catalyzes the initial and rate-limiting step in the biosynthesis of serotonin, which is associated with a variety of disorders such as depression and irritable bowel syndrome. TPH exists in two isoforms: TPH1 and TPH2. TPH1 catalyzes the initial step in the synthesis of serotonin in the peripheral tissues, while TPH2 catalyzes this step in the brain. In this study, the steady-state kinetic mechanism for the catalytic domain of human TPH1 has been determined. Varying substrate tryptophan (Trp) and tetrahydrobiopterin (BH4) results in a hybrid Ping Pong-ordered mechanism in which the reaction can either occur through a Ping Pong or a sequential mechanism depending on the concentration of tryptophan. The catalytic domain of TPH1 shares a sequence identity of 81% with TPH2. Despite the high sequence identity, differences in the kinetic parameters of the isoforms have been identified; i.e., only TPH1 displays substrate tryptophan inhibition. This study demonstrates that the difference can be traced to an active site loop which displays different properties in the TPH isoforms. Steady-state kinetic results of the isoforms, and variants with point mutations in a loop lining the active site, show that the kinetic parameters of only TPH1 are significantly changed upon mutations. Mutations in the active site loop of TPH1 result in an increase in the substrate inhibition constant, Ki, and therefore turnover rate. Molecular dynamics simulations reveal that this substrate inhibition mechanism occurs through a closure of the cosubstrate, BH4, binding pocket, which is induced by Trp binding.

The paper presents a case on self-management in the Danish social housing sector as a way of providing affordable housing. It is based on an evaluation of a Danish concept for affordable housing, Social Housing Plus (“AlmenBolig+”). The concept was introduced in 2007, and so far app 1.400 housing units have been established. The concept includes a number of approaches to reduce the rent, some are “traditional” physical-technical approaches for affordable housing, e.g. reducing production costs and limiting standards. However, a central element in the concept has been the introduction of “self-management” amongst the residents, which is a new and controversial approach in the Danish social housing sector, where the traditional approach is a high service level regarding maintenance, operation and administration, but these services also have a high impact on the rent. This paper will outline the ideas behind the Social Housing Plus-concept, the preconditions for the self-management approach, and the experiences so far from the various housing estates built on the concept. This will include a discussion of the social impacts of the self-management among the residents, e.g. in relation to a participation and sense of ownership, but also various challenges in the concept. Broadly speaking, the paper aim to examine and assess the potential for self-management as a way to establish affordable housing, as well as the limits of the concept. Methodologically, the evaluation is based on qualitative interviews and surveys amongst residents and housing associations, as well as quantitative assessments of the outcome regarding rent level and household composition in the housing estates. The paper presents a case on self-management in the Danish social housingsector as a way of providing affordable housing. It is based on an evaluation ofa Danish concept for affordable housing, Social Housing Plus (“AlmenBolig+”).The concept was introduced in 2007, and so far app 1.400 housing units havebeen established. The concept includes a number of approaches to reduce therent, some are “traditional” physical-technical approaches for affordablehousing, e.g. reducing production costs and limiting standards. However, acentral element in the concept has been the introduction of “self-management”amongst the residents, which is a new and controversial approach in the Danishsocial housing sector, where the traditional approach is a high service levelregarding maintenance, operation and administration, but these services alsohave a high impact on the rent. This paper will outline the ideas behind theSocial Housing Plus-concept, the preconditions for the self-managementapproach, and the experiences so far from the various housing estates built onthe concept. This will include a discussion of the social impacts of the selfmanagement among the residents, e.g. in relation to a participation and sense of ownership, but also various challenges in the concept. Broadly speaking, the paper aim to examine and assess the potential for self-management as a way to establish affordable housing, as well as the limits of the concept.Methodologically, the evaluation is based on qualitative interviews and surveysamongst residents and housing associations, as well as quantitativeassessments of the outcome regarding rent level and household composition inthe housing estates.