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Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma.We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish).Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAFWe unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.

Genetic sequencing is identifying an expanding number of variants of GABAsubA/subreceptors associated with human epilepsies. We identified a new de novo variant of the β2 subunit (β2L51M) of the inhibitory GABAsubA/subreceptor associated with seizures. Our analysis determined the pathogenicity of the variant and the effects of anti-seizure medications. Our data demonstrates that the variant reduced cell surface trafficking and peak GABA-gated currents. Synaptic currents mediated by variant-containing receptors decayed faster than wild-type and single receptor currents showed that the variant shortened the duration of receptor activity by decreasing receptor open times. We tested the effects of the anti-seizure medications, midazolam, carbamazepine and valproate and found that all three enhance variant receptor surface expression. Additionally, midazolam restored receptor function by increasing single receptor active periods and synaptic current decay times towards wild-type levels. By contrast, valproate increased synaptic peak currents, event frequency and promoted synaptic bursting. Our study identifies a new disease-causing variant to the GABAsubA/subreceptor, profiles its pathogenic effects and demonstrates how anti-seizure drugs correct its functional deficits.

In this article, I re-think official educational organization toward friction-zones. Thinking with a swimming event in physical education, and Deleuze’s notion of pure difference and its accompanying characteristics, non-linearity, decentralization, pluralistic knowledge, virtual and actual multiplicities, nomadic waiting, and open ends, I outline conditions for official educational organization in the encounter between divergent knowledges. The aim is to bring teachers and students closer to each other and paradoxically let up-coming concepts, meanings, and ideas act instead of silence everything that is not in line with predefined educational goals. It is to create common histories of learning and knowledge productions, and hence to produce common grounds in/by motion. Ultimately, it is about inclusive processes in/by motion. And, it is also a call for us all to pay attention and resist unintentional productions of exclusion, and thus all colonizing processes that includes superior knowledge.

Cone snails use separately evolved venoms for prey capture and defence. While most use a harpoon for prey capture, the Gastridium clade that includes the well-studied Conus geographus and Conus tulipa, have developed a net hunting strategy to catch fish. This unique feeding behaviour requires secretion of “nirvana cabal” peptides to dampen the escape response of targeted fish allowing for their capture directly by mouth. However, the active components of the nirvana cabal remain poorly defined. In this study, we evaluated the behavioural effects of likely nirvana cabal peptides on the teleost model, Danio rerio (zebrafish). Surprisingly, the conantokins (NMDA receptor antagonists) and/or conopressins (vasopressin receptor agonists and antagonists) found in C. geographus and C. tulipa venom failed to produce a nirvana cabal-like effect in zebrafish. In contrast, low concentrations of the non-competitive adrenoceptor antagonist ρ-TIA found in C. tulipa venom (EC50 = 190 nM) dramatically reduced the escape response of zebrafish larvae when added directly to aquarium water. ρ-TIA inhibited the zebrafish α1-adrenoceptor, confirming ρ-TIA has the potential to reverse the known stimulating effects of norepinephrine on fish behaviour. ρ-TIA may act alone and not as part of a cabal, since it did not synergise with conopressins and/or conantokins. This study highlights the importance of using ecologically relevant animal behaviour models to decipher the complex neurobiology underlying the prey capture and defensive strategies of cone snails.

To investigate the acute exercise effects of dynamic standing exercise on blood glucose and blood lactate among children and adolescents with cerebral palsy who are nonambulant.Twenty-four participants with cerebral palsy who are nonambulant performed 30 minutes of dynamic standing exercise using a motorized device enabling assisted passive movements in an upright weight-bearing position. Capillary blood samples were taken from the fingertip for measurement of blood glucose and blood lactate at rest and at the end of exercise.At rest, the participants had hyperlactatemia that was unaffected after exercise, presented as median and interquartile range at rest 1.8 (1.3:2.7) mmol/L, and after exercise 2.0 (1.1:2.5) mmol/L. Children and adolescents with Gross Motor Function Classification System, level V, had higher lactate levels at rest (2.5 [1.8:2.9] vs 1.4 [1.0:2.0]; P = .030) and after exercise (2.3 [2.0:2.6] vs 1.2 [0.9:2.2]; P = .032) compared with children and adolescents with Gross Motor Function Classification System, level IV, respectively. A statistically significant larger decrease in blood lactate levels after exercise was observed in children and adolescents with higher resting blood lactate levels (ρ = .56; P = .004). There were no statistically significant changes in blood glucose.Forty percentage of the participants had mild hyperlactatemia at rest and participants with the highest blood lactate levels at rest had the greatest decrease in blood lactate levels after one bout of exercise. Children and adolescents who were classified with the highest level of the Gross Motor Function Classification Scale had higher blood lactate levels. More studies are needed on how to prevent chronically high resting levels of lactate with exercise in children with cerebral palsy who are nonambulant.

This paper invites readers to an encounter of novel learning in the school subject physical education, and specifically swimming training. In collaboration with Deleuze’s immanent philosophy and creative observations in a case-assemblage, I speculate about productive experiences and educational events as movements toward physical activation, higher education, and the dissolution of health inequalities. Troubling situations of a standardized model of swimming training is combined with a quantum space where multiple divergent ideas, forces, and feelings interact and produce unforeseen learnings, values, and qualities. Frictions between segmented spaces and quantum spaces orient/reorient the student’s/swimming instructor’s/my/your? learning, values, and qualities. Finally, I emphasize quantum spaces as the heart of educational movement and the importance of creating open educational systems to perhaps think physical education forward.

The Mediator complex subunit 13-like (MED13L) protein is part of the multi-protein mediator complex and plays an important role in gene transcription. Polymorphisms in the MED13L gene have been linked to congenital heart anomalies and intellectual disabilities. Despite recent evidence of indirect links of MED13L to cytokine release and inflammation, impact of genetic variations in MED13L on immune cells remains unexplored. The B10.RIII and RIIIS/J mouse strains vary in susceptibility to induced experimental autoimmune disease models. From sequencing data of the two mouse strains, we identified six polymorphisms in the coding regions of Med13l. By using congenic mice, we studied the effect of these polymorphisms on immune cell development and function along with susceptibility to collagen-induced arthritis, an animal model for Rheumatoid Arthritis (RA). Combining in vivo disease data, in vitro functional data, and computational analysis of the reported non-synonymous polymorphisms, we report that genetic polymorphisms in Med13l do not affect the immune phenotype in these mice and are predicted to be non-disease associated. © The Author(s) 2018 This work was supported by The Danish Rheumatism Association, The AP Møller Research grant for Medical Science, and The Oticon foundation.

This article challenge research political assumptions of research interests as context specific phenomena predefined by researchers and others in case study research on sports. By adopting a Deleuzian perspective of materiality, the aim is to overturn academic power dimensions as well as anthropocentric focuses and instead explore how research interests emerge in case-assemblages. This is a radical shift that re-theorizes the production of research interests as co-produced capacities in researching bodies. The analysis is done by mapping territorializing, deterritorializing, and reterritorializing affects as well as molar and molecular affects. We use these affects to explore how our research interest evolved in a case study on a swimming event. We conclude by extending this critical exploration to the production of research interests in general and the exaggerated belief that research interests are attributes of specific human bodies (researchers) that precede studies.

Background: Susceptibility to Rheumatoid Arthritis (RA) is dependent on complex interactions among genetic and environmental factors. Protein candidates and their role in pathways leading to chroni ...

G protein-coupled receptors (GPCRs) convert extracellular stimuli to intracellular responses that regulate numerous physiological processes. Crystallographic and biophysical advances in GPCR structural analysis have aided investigations of structure-function relationships that clarify our understanding of these dynamic receptors, but the molecular mechanisms associated with activation and signaling for individual GPCRs may be more complex than was previously appreciated. Here, we investigated the proposed water-mediated, hydrogen-bonded activation switch between the conserved NPxxY motif on transmembrane helix 7 (TMH7) and a conserved tyrosine in TMH5, which contributes to α

G protein-coupled receptors (GPCRs) convert extracellular stimuli to intracellular responses that regulate numerous physiological processes. Crystallographic and biophysical advances in GPCR structural analysis have aided investigations of structure-function relationships that clarify our understanding of these dynamic receptors, but the molecular mechanisms associated with activation and signaling for individual GPCRs may be more complex than was previously appreciated. Here, we investigated the proposed water-mediated, hydrogen-bonded activation switch between the conserved NPxxY motif on transmembrane helix 7 (TMH7) and a conserved tyrosine in TMH5, which contributes to α1B-adrenoceptor (α1B-AR) and β2-AR activation. Disrupting this bond by mutagenesis stabilized the α1B-AR and the β2-AR in inactive-state conformations, which displayed decreased agonist potency for stimulating downstream IP1 and cAMP signaling, respectively. Compared to that for wild-type receptors, agonist-mediated β-arrestin recruitment was substantially reduced or abolished for all α1B-AR and β2-AR inactive-state mutants. However, the inactive-state β2-ARs exhibited decreased agonist affinity, whereas the inactive-state α1B-ARs had enhanced agonist affinity. Conversely, antagonist affinity was unchanged for inactive-state conformations of both α1B-AR and β2-AR. Removing the influence of agonist affinity on agonist potency gave a measure of signaling efficacy, which was markedly decreased for the α1B-AR mutants but little altered for the β2-AR mutants. These findings highlight the pharmacological heterogeneity of inactive-state GPCR conformations, which may facilitate the rational design of drugs that target distinct conformational states of GPCRs.

Mo-clay was used by German doctors to treat injured soldiers' wounds during the First World War. Today, there are anecdotal cases of mo-clay being beneficial for patients suffering from psoriasis, ...

Changes in the labor marked globally and in the Nordic countries involve new forms of work and atypical employment among young workers. A significant proportion of young workers are in temporary po ...

AimTo investigate what registered nurses (RNs) with a PhD working in clinical practice experience in terms of their role, function and work context. BackgroundPrevious studies have shown that RNs with a graduate degree contribute to better and safer care for patients. However, little is known about what further academic schooling of RNs, at PhD level, means for clinical practice. MethodQualitative design, with semi-structured interviews and inductive content analysis. ResultsThe main areas of responsibilities for RNs with a PhD working in clinical practice were related to practice development and implementation of research results. In their work, they experienced barriers to the full use of their competence; the expectations and prerequisites of the organisation were not clearly defined, and they often lacked a mandate to create conditions for quality improvement of nursing care. ConclusionsRNs with a PhD can contribute to evidence-based practice (EBP), clinical training, as well as the development of clinical research. Their roles and responsibilities need to be clarified, and for this, they need support from managers. Implications for Nursing ManagementNurse managers have the opportunity to partner with RNs with a PhD to support the EBP process and help structure nursing practice in more efficient ways. Funding Agencies|Karolinska University Hospital

Previously, we showed that no two of seven opioids administered by the intracerebroventricular route had the same potency rank order for evoking antinociception, constipation and respiratory depression in rats. To gain insight at the cellular level, this study was designed to systematically investigate the activity profiles of six commonly used opioid ligands using the forskolin-stimulated cAMP assay and a β-arrestin2 recruitment assay in cultured HEK-293 cells transfected with MOP(μ), DOP(δ) or KOP(κ) receptors(-r). Morphine was a potent agonist at the MOP-r in the cAMP assay whereas it was a weak agonist at the KOP-r and DOP-r. Oxycodone had moderate efficacy and low potency at the MOP-r. Buprenorphine was a potent MOP-r and DOP-r agonist; its efficacy rank order was DOP > MOP > KOP. Fentanyl was a potent agonist at the MOP-r; its efficacy rank order was MOP > DOP > KOP. For DPDPE, its agonist efficacy was confined to the DOP-r, whereas for U69593, its efficacy rank order was KOP>> MOP. For the β-arrestin2 assay, fentanyl had full efficacy at the MOP-r whereas morphine and oxycodone were weak with insignificant efficacy at DOP and KOP receptors. Buprenorphine did not recruit β-arrestin2 at all three opioid-receptors. DPDPE and U69593 had full efficacy for β-arrestin2 recruitment to the DOP-r and KOP-r respectively. Despite the low efficacy and potency of morphine, oxycodone and buprenorphine in recruiting β-arrestin2 to the MOP-r herein, these opioids all evoked respiratory depression and constipation in rats. Together, our findings discount a key role for β-arrestin2 recruitment at the MOP-r in evoking opioid-related side-effects.

Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg's binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis.

Patient safety is an important global issue. While it is well known that patients can suffer from adverse events in nursing care, there is a lack of knowledge as to how they experience them.

Since working-class masculinity has traditionally been closely connected to wage labor and the ability to provide for oneself, the lack of resources associated with unemployment among working-class men implies a need to redefine one’s own self-understanding. This chapter discusses the narratives of 12 young unemployed working-class men living in a small, deindustrialized town on the east coast of Sweden. From a situation much characterized by deficiency and marginalization, an alternative understanding of the meaning of work is developing, intertwined with alternative conceptions of masculinity. These tendencies are partly related to the state of unemployment and the marginalized position stemming from it, indicating that important and critical changes to masculinity are taking place also there, far from the more privileged locations.

Aims and objectives The aim of this study was to identify the most common serious adverse events that occurred in nursing homes and their most frequent contributing factors to contribute to improvement of safe nursing care. Background There is a need to improve safe nursing care in nursing homes. Residents are often frail and vulnerable with extensive needs for nursing care. A relatively minor adverse event in nursing care can cause serious injury that could have been preventable. Design This was a retrospective study, with a total sample of data regarding adverse events (n=173) in nursing homes, concerning nursing care reported by health care providers in Sweden to the Health and Social Care Inspectorate. The reports were analysed with content analysis and the frequencies of the adverse events, and their contributing factors, were described with descriptive statistics. Results Medication errors, falls, delayed or inappropriate intervention and missed nursing care caused the vast majority (89%) of the serious adverse events. A total of 693 possible contributing factors were identified. The most common contributing factors were 1) lack of competence 2) incomplete, or lack of documentation 3) teamwork failure 4) and inadequate communication. Conclusions The contributing factors frequently interacted yet they varied between different groups of serious adverse events. The resident's safety depends on the availability of staff's competence as well as adequate documentation about the resident's condition. Lack of competence was underestimated by health care providers. Relevance to clinical practice Registered Nurses and assistant nurses need to have awareness of contributing factors to adverse events in nursing care. A holistic approach to improve patient safety in nursing homes requires competence of the staff, safe environments as well as resident's and relative's participation. This article is protected by copyright. All rights reserved.

In this article, we discuss challenges and implications of thinking with new materialisms and the Deleuzian philosophy of immanence in qualitative case studies. The aim is to establish a terrain and language of “minor case studies.” Deleuze denies two-world ontologies and the ontologically status of single bodies, emphasizing instead how assemblages of human and non-human bodies together produce the world. In this terrain, cases are not objects of inquiry, but life-giving forces that create movement. This in turn changes the premises for how we can approach and explore cases. Rather than represent, comment and explain what cases are, we illustrate how a case-assemblage creates possibilities for event-based thinking regarding interesting phenomena (cases), and how these cases are twisted, stretched and pulled out of a conventional case study design. We conclude by discussing epistemological consequences of new materialist ontology.

Ligand binding and conformational changes that accompany signaling from G protein-coupled receptors (GPCRs) have mostly focused on the role of transmembrane helices and intracellular loop regions. However, recent studies, including several GPCRs cocrystallized with bound ligands, suggest that the extracellular surface (ECS) of GPCRs plays an important role in ligand recognition, selectivity, and binding, as well as potentially contributing to receptor activation and signaling. This study applied alanine-scanning mutagenesis to investigate the role of the complete ECS of the α1B-adrenoreceptor on norepinephrine (NE) potency, affinity, and efficacy. Half (24 of 48) of the ECS mutations significantly decreased NE potency in an inositol 1-phosphate assay. Most mutations reduced NE affinity (17) determined from [(3)H]prazosin displacement studies, whereas four mutations at the entrance to the NE binding pocket enhanced NE affinity. Removing the influence of NE affinity and receptor expression levels on NE potency gave a measure of NE efficacy, which was significantly decreased for 11 of 48 ECS mutants. These different effects tended to cluster to different regions of the ECS, which is consistent with different regions of the ECS playing discrete functional roles. Exposed ECS residues at the entrance to the NE binding pocket mostly affected NE affinity, whereas buried or structurally significant residues mostly affected NE efficacy. The broad potential for ECS mutations to affect GPCR function has relevance for the increasing number of nonsynonymous single nucleotide polymorphisms now being identified in GPCRs.

Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior, memory, and learning through four G protein-coupled receptors that are also implicated in high-profile disorders. Targeting these receptors is challenging because of the difficulty in obtaining ligands that retain selectivity across rodents and humans for translational studies. We identified a selective and more stable oxytocin receptor (OTR) agonist by subtly modifying the pharmacophore framework of human oxytocin and vasopressin. [Se-Se]-oxytocin-OH displayed similar potency to oxytocin but improved selectivity for OTR, an effect that was retained in mice. Centrally infused [Se-Se]-oxytocin-OH potently reversed social fear in mice, confirming that this action was mediated by OTR and not by V1a or V1b vasopressin receptors. In addition, [Se-Se]-oxytocin-OH produced a more regular contraction pattern than did oxytocin in a preclinical labor induction and augmentation model using myometrial strips from cesarean sections. [Se-Se]-oxytocin-OH had no activity in human cardiomyocytes, indicating a potentially improved safety profile and therapeutic window compared to those of clinically used oxytocin. In conclusion, [Se-Se]-oxytocin-OH is a novel probe for validating OTR as a therapeutic target in various biological systems and is a promising new lead for therapeutic development. Our medicinal chemistry approach may also be applicable to other peptidergic signaling systems with similar selectivity issues.

The G protein-coupled receptor (GPCR) superfamily is an important drug target that includes over 1000 membrane receptors that functionally couple extracellular stimuli to intracellular effectors. Despite the potential of extracellular surface (ECS) residues in GPCRs to interact with subtype-specific allosteric modulators, few ECS pharmacophores for class A receptors have been identified. Using the turkey β1-adrenergic receptor crystal structure, we modeled the α1B-adrenoceptor (α1B-AR) to help identify the allosteric site for ρ-conopeptide TIA, an inverse agonist at this receptor. Combining mutational radioligand binding and inositol 1-phosphate signaling studies, together with molecular docking simulations using a refined NMR structure of ρ-TIA, we identified 14 residues on the ECS of the α1B-AR that influenced ρ-TIA binding. Double mutant cycle analysis and docking confirmed that ρ-TIA binding was dominated by a salt bridge and cation-π between Arg-4-ρ-TIA and Asp-327 and Phe-330, respectively, and a T-stacking-π interaction between Trp-3-ρ-TIA and Phe-330. Water-bridging hydrogen bonds between Asn-2-ρ-TIA and Val-197, Trp-3-ρ-TIA and Ser-318, and the positively charged N terminus and Glu-186, were also identified. These interactions reveal that peptide binding to the ECS on transmembrane helix 6 (TMH6) and TMH7 at the base of extracellular loop 3 (ECL3) is sufficient to allosterically inhibit agonist signaling at a GPCR. The ligand-accessible ECS residues identified provide the first view of an allosteric inhibitor pharmacophore for α1-adrenoceptors and mechanistic insight and a new set of structural constraints for the design of allosteric antagonists at related GPCRs. Background: Mechanistic insight into allosteric modulation of GPCRs can facilitate antagonist design. Results: Extracellular surface residues (ECS) of the α1B-adrenoceptor at the base of extracellular loop 3 interact with the allosteric antagonist TIA. Conclusion: The identified ECS pharmacophore provides the first structural constraints for allosteric antagonist design at α1-adrenoceptors. Significance: Binding to the ECS of a GPCR can allosterically inhibit agonist signaling.

Many Roma people in Sweden are on the margins of society and face problems of social exclusion, institutional discrimination, low education, unemployment, and poor health. The aim is to describe how a group of Roma people, in West Sweden, understand health, well-being, and quality of life within the Roma context, and how they cope with their life-situation. Data consisted of qualitative interviews. The data were analyzed qualitatively using a phenomenological hermeneutic approach. The respondents mainly understood the concept of Health as “being healthy” and “feeling good”. Elements that were crucial part of the respondents’ health perception were being employed, having an education, social support from family and friends, freedom and security, and the extent of involvement in society. The results indicate that the respondents perceive their health and life situation as good, despite of their marginalized situation and discrimination.

Background: Inhibition of Abl kinases has an ameliorating effect on the rodent model for multiple sclerosis, experimental autoimmune encephalomyelitis, and arrests lymphocyte activation. The family of Abl kinases consists of the Abl1/Abl and Abl2/Arg tyrosine kinases. While the Abl kinase has been extensively studied in immune activation, roles for Arg are incompletely characterized. To investigate the role for Arg in experimental autoimmune encephalomyelitis, we studied disease development in Arg-/- mice. Methods: Arg-/- and Arg+/+ mice were generated from breeding of Arg+/- mice on the C57BL/6 background. Mice were immunized with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide and disease development recorded. Lymphocyte phenotypes of wild type Arg+/+ and Arg-/- mice were studied by in vitro stimulation assays and flow cytometry. Results: The breeding of Arg+/+ and Arg-/- mice showed skewing in the frequency of born Arg-/- mice. Loss of Arg function did not affect development of experimental autoimmune encephalomyelitis, but reduced the number of splenic B-cells in Arg-/- mice following immunization with MOG peptide. Conclusions: Development of MOG-induced experimental autoimmune encephalomyelitis is not dependent on Arg, but Arg plays a role for the number of B cells in immunized mice. This might suggest a novel role for the Arg kinase in B-cell trafficking or regulation. Furthermore, the results suggest that Arg is important for normal embryonic development.

Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor-ligand interactions similar to KOR agonist dynorphin A (1-8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor.

Disulfide bond engineering is an important approach to improve the metabolic half-life of cysteine-containing peptides. Eleven analogues of oxytocin were synthesized including disulfide bond replacements by thioether, selenylsulfide, diselenide, and ditelluride bridges, and their stabilities in human plasma and activity at the human oxytocin receptor were assessed. The cystathionine (K(i) = 1.5 nM, and EC₅₀ = 32 nM), selenylsulfide (K(i) = 0.29/0.72 nM, and EC₅₀ = 2.6/154 nM), diselenide (K(i) = 11.8 nM, and EC₅₀ = 18 nM), and ditelluride analogues (K(i) = 7.6 nM, and EC₅₀ = 27.3 nM) retained considerable affinity and functional potency as compared to oxytocin (K(i) = 0.79 nM, and EC₅₀ = 15 nM), while shortening the disulfide bridge abolished binding and functional activity. The mimetics showed a 1.5-3-fold enhancement of plasma stability as compared to oxytocin (t(½) = 12 h). By contrast, the all-D-oxytocin and head to tail cyclic oxytocin analogues, while significantly more stable with half-lives greater than 48 h, had little or no detectable binding or functional activity.

Two lines of thoughts have historically characterised the understanding of sexuality in old age in Western society. On the one hand elderly persons sexuality have been portrayed in literature and dramas since the antiquity and onwards. However these images have often been negative, ridiculing sexuality in late life. On the other hand old age has been associated with asexuality – philosophers, and other intellectuals as well as religious authorities have often articulated this position. In addition you may say that the asexual standpoint generally has been positively charged. Nevertheless attitudes towards sexuality in old age began to change in the midst of the 20th century. This is for instance apparent in works from sexology, not the least the Kinsey reports (1948, 1953), but also Masters’ and Johnson’s publications from the 1960s. During the 1960s a book that specifically dealt with old age and sexuality was published, namely Sexuality After Sixty (1965), by the American sexologist Isadore Rubin. In this publication the view on sexuality is particularly positive. Rubin for instance claims that it is vital and good for the health to keep sexually active as long as possible. This statement is supported by Masters and Johnson. Rubin’s and Masters’ and Johnson’s writings are illustrative for their time and may be related to the current social and cultural context of sexual debate, youth culture and young people revolting against authorities and old-fashioned thinking. Youth becomes a norm at this point in history. My interpretations mainly deal with how youth culture, sexuality and gender identity interrelates. Masculinity seems to be strongly associated with heterosexual intercourse, and aging appears to be antithetic to masculinity – the status of the man diminishes as the aging process proceeds. The connotations to femininity also alter, but not in the same sense as with masculinity.

This paper is a report of a study conducted to explore, from a gender perspective, older people's experiences of nursing care after a stroke.Little attention has been given to gender differences in nursing care. The majority of people who have a stroke are older. Improving knowledge of the gender perspectives of older men and women regarding nursing care after stroke is crucial.This was a qualitative study based on interviews with five women and five men between 66 and 75 years of age, who had received nursing care at a ward for stroke rehabilitation. The data were collected in 2006. Qualitative content analysis of the interviews was carried out.A main theme and five categories, all common to both men and women, were identified. The main theme, to promote recovery of the body, encompassed the categories. There were, however, gender differences in how the nursing care received was experienced. The ways patients experienced nursing care seemed to be linked with their lives as women and men before they had the stroke. Their perceptions are linked with their lives as women and men before they had their stroke. Both men and women will reclaim former abilities but what they perceive to be the goals of nursing care and rehabilitation may differ.Nurses need to increase their awareness and knowledge concerning the similarities and gender differences in the experiences and needs of older people, both men and women.

We are evaluating the immune enhancing activities of cytokines for their optimum utility in augmenting cellular immune responses against lung cancer. In this study, we evaluated the mechanism of antitumor responses following IL-7 administration to mice bearing established Lewis lung cancer. IL-7 decreased tumor burden with concomitant increases in the frequency of CD4 and CD8 T lymphocyte subsets, T cell activation markers CXCR3, CD69, and CD127low, effector memory T cells, and T cell cytolytic activity against parental tumor cells. Accompanying the antitumor responses were increases in IFN-γ, CXCL9, CXCL10, and IL-12. Individual neutralization of CD4, CD8 T lymphocytes, or the CXCR3 ligands CXCL9 and CXCL10 reversed the antitumor benefit of IL-7, indicating their importance for optimal responses in vivo. Furthermore, IL-7 decreased the tumor-induced apoptosis of T cells with subsequent decrease of the proapoptotic marker Bim. We assessed the impact of IL-7 treatment on regulatory T cells that negatively impact antitumor immune responses. IL-7 decreased regulatory T Foxp3 as well as cell suppressive activity with a reciprocal increase in SMAD7. These results indicate that IL-7 induces CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer.

International audience; We report the discovery of conopressin-T, a novel bioactive peptide isolated from Conus tulipa venom. Conopressin-T belongs to the vasopressin-like peptide family and displays high sequence homology to the mammalian hormone oxytocin (OT) and to vasotocin, the endogenous vasopressin analogue found in teleost fish, the cone snail's prey. Conopressin-T was found to act as a selective antagonist at the human V1a receptor. All peptides in this family contain two conserved amino acids within the exocyclic tripeptide (Pro7 and Gly9), which are replaced with Leu7 and Val9 in conopressin-T. Whereas conopressin-T binds only to OT and V1a receptors, an L7P analogue had increased affinity for the V1a receptor and weak V2 receptor binding. Surprisingly, replacing Gly9 with Val9 in OT and vasopressin revealed that this position can function as an agonist/antagonist switch at the V1a receptor. NMR structures of both conopressin-T and L7P analogue revealed a marked difference in the orientation of the exocyclic tripeptide that may serve as templates for the design of novel ligands with enhanced affinity for the V1a receptor.

Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing rodent models for Rheumatoid Arthritis in the context of how these models have been utilized for developing established therapy in Rheumatoid Arthritis and, furthermore, the present use of animal models for studies of novel drug candidates. We have studied the literature in the field for the use of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although a single Rheumatoid Arthritis in vivo model cannot mirror the complexity of disease development, there exist a number of good animal models for Rheumatoid Arthritis, each defining some parts in disease development, which are useful for studies of drug response. We find that many of the established drugs were not tested in in vivo models before being used in the clinic, but rather animal models have been subsequently used to find mechanisms for efficacy. Finally, we report a number of novel drugs, tested in preclinical in vivo models, presently in clinical trials.

The need for brushing before the first thinning has increased during the last few years. This brushing involves taking away small trees and bushes making it able for the harvester operator to see better and choose the correct trees to be harvested. In today’s silviculture the brushing is often neglected which means that the undergrowth becomes dense and leads to less efficiency for harvesters and a rise in costs. A well brushed first thinning will make the harvesting costs low and time efficient. In brushing before the 1st thinning all stems below 9 cm d bh are traditionally taken down. This has a tendency to become stereotyped; i.e. brushes are also taken away in areas where stronger nature conservation should be applied, as in wetlands, edge zones, etc. The harvester operator then gets stuck in these zones which threaten the biodiversity. This study aims at examining two different types of brushing methods before the thinning, the traditional one and another (new) method where environmental and nature protection aspects were taken into account to a greater degree; i.e. where more stems and undergrowth have been left over and edge zones were not brushed. The study results show that the latter one is to prefer as the more cost efficient one. It also protects the harvester to drive out into the edge zones. This method is also beneficial for the wildlife. Most harvester operators were positive to a new brushing manual.

The Abelson non-receptor tyrosine kinases, c-Abl and Arg, are important regulators of cellular processes in cancer, inflammation, infection, and neuronal dynamics. Recent research on the role for these kinases in processes involving interactions with the cytoskeleton or signaling molecules, may lead to further insight into the pathogenesis of a variety of disorders, including chronic inflammatory diseases. In a mouse model for multiple sclerosis, we recently reported that Arg deficient mice develop T-cell mediated autoimmune neuro-inflammation with the same severity as littermate controls, but display a different B-cell phenotype upon immunization. Here we comment on these results and discuss the role for Arg in B-cell activation and homeostasis.

Purpose The purpose of this study was to investigate how young women and men perceive the Internet as a phenomenon and what role and meaning they ascribe to the Internet as an arena for defining themselves and for shaping their identity. Methodology/approach The empirical data consist of narratives written by Swedish adolescents. Using content analysis the analysis was carried out in three steps: (1) finding categories and themes, (2) calculation of statistical differences in category frequencies, (3) a theoretically informed interpretation of central themes, using Bourdieu’s concept of different forms of capital, and Giddens’ concept of “pure relations.” Findings The narratives exemplify how computer literacy and technological competence can be converted into social, cultural, and symbolic capital. Gender differences occur both in statistical differences between category frequencies in girls’ and boys’ narratives and in the interpretation of central themes. But there are also several examples that show more complex and contradictory tendencies, exceeding or transformative of gender differences and hierarchy. Originality/value This study considers adolescents’ own perspectives on an arena of great importance. The analyses have been performed both qualitatively and quantitatively, which gives a nuanced picture of young people’s self-defining experiences on the Internet.

Background: Immigrants in general seem to be more vulnerable than the host populations to developing nutrition-related chronic conditions. This may be in part related to diverging dietary habits. Objective: The aim of the study was to examine the nutrient intake and its relationship to metabolic variables among immigrant versus native Swedish women. Design: A cross-sectional health survey of 157 randomly selected foreign-born and native Swedish women. This included 24 h dietary recall repeated four times and administered in the native language. Results: Underreporting was significant, especially among immigrant women. There were no major differences in terms of energy distribution of the macronutrients between very low energy reporters and acceptable energy reporters, indicating that the dietary data reflected the qualitative composition in spite of the underreporting of energy intake. Immigrant women consumed less alcohol and obtained a lower proportion of their energy from saturated fatty acids, but a higher proportion from polyunsaturated fatty acids, sucrose and total carbohydrates. Associations between dietary variables and metabolic risk factors were relatively weak. Conclusions: Underreporting might have attenuated possible associations between diet and risk factors. The study illustrates specific problems in the dietary assessment and the need to develop valid techniques when studying groups of people of diverging ethnic backgrounds. Keywords: dietary intake; immigrants; Iran; metabolic risk factors; Sweden; Turkey; underreporting

Both environmental and genetic factors can dramatically affect reproductive performance in mice. In this study we have focused on the identification of genetic regions, quantitative trait loci (QTL), which affect the breeding capacity of female mice. We have identified polymorphic microsatellite markers for the mouse strains used and performed a genomewide scan on 237 females from a gene-segregating backcross between a high breeder and a relatively poor breeder. The high-breeder mouse strain we used is the inbred NFR/N mouse (MHC haplotype H-2q), which has extraordinary good breeding properties. The moderate breeder chosen for F1 and N2 progeny was B10.Q, which is a genetically well-characterized MHC-congenic mouse of the H-2q haplotype. Each of the 237 females of the N2 generation was allowed to mate twice with MHC-congenic B10.RIII (H-2r) males and twice with B10.Q males. A predetermined number of phenotypes related to reproductive performance were recorded, and these included litter size, neonatal growth, and pregnancy rate. Loci controlling litter size were detected on chromosomes 1 (Fecq3) and 9 (Fecq4). The neonatal growth phenotype was affected by Fecq3 and a locus on chromosome 9 (Neogq1). On chromosome 11 two loci affecting the pregnancy rate (Pregq1 and Pregq2) were identified. Furthermore, on chromosomes 13 and 17 we found loci (Pregq3 and Pregq4) influencing the outcome of allogeneic pregnancy (allogeneic by means of MHC disparity between mother and fetuses). A locus on chromosome 1 affecting maternal body weight was also identified and has been denoted Bwq7. It is well known that reproductive performance is polygenically controlled, and the identification of the major loci in this complex process opens the possibility of investigating the natural genetic control of reproduction.