Frizzled as a G protein-coupled receptor : the role of disheveled and G proteins for signal specification

Cell communication governed and coordinated by the WNT family of lipoglycoproteins comprises essential physiological processes active throughout the life-span of metazoan organisms. In humans, severe diseases and congenital birth defects have been directly linked to disturbances in WNT signaling. In line with the general scheme of cell signaling transduction, WNT proteins bind and activate cell surface receptors in order to relay signaling to intracellular effector molecules which subsequently acts to execute changes in cell fates; such as proliferation, differentiation, migration and polarization. Thus far, a variety of structurally and functionally different proteins are identified as WNT receptors and/or co-receptors. The ten members of the Frizzled (FZD) family of seven transmembrane-spanning proteins are the preponderant receptors of WNTs and are shown to interact with heterotrimeric G proteins and the scaffold phosphoprotein Dishevelled (DVL) to activate downstream signaling events. Due to homology in secondary structure, FZDs are classified as G protein coupled receptors (GPCRs), but display unconventional constitution and signaling properties in respect to e.g. the well-studied Class A 7TMRs. This fact generated the generally accepted notion that FZDs in fact are not GPCRs. The work presented in this thesis investigates the functional and molecular relationship between WNTs, FZDs, G proteins and DVL from a pharmacological point of view. The link between WNTs and G proteins has been established mainly through epigenetic studies and in genetically manipulated systems. Using the [-35S]GTP method to assay G protein activity we demonstrated that WNTs are able to activate G proteins of the PTX-sensitive Gi/o family even at endogenous protein levels, thus providing evidence that the WNT-G protein connection indeed is not an artifact imposed by alterations in protein stochiometry. Functional selectivity or biased agonism is a recently established feature of ligand activity at GPCRs and have provided important insights into the pharmacological aspects of 7TMR signaling. By assessment of downstream WNT signaling events and FRAP analysis of FZD6 lateral diffusion we find that WNT isoforms are not homologous in signaling pathway activation at a specific receptor or in a defined cellular milieu. Thus, our conclusion suggests that WNTs might be able to act as endogenous biased agonists at FZDs. Even though recent biochemical and bioinformatics data provides the definite evidence of FZDs as true GPCRs, signal transduction mechanisms and selectivity in the interactions of FZDs, G proteins and DVL are largely unknown. Here we report, using a double fluorophores FRAP and cell surface cross-linking approach, that FZD6 protein precouples to Gi1 and Gq and that the interaction is sensitive and dynamic to WNT stimulation. We also demonstrate that DVL is an essential component in the FZD6-G protein precoupled complex. Interestingly, we find that the effect of DVL is concentration-dependent: a low as well as a high concentration of DVL destabilizes the receptor-G protein complex. Additionally, we establish that a point mutation, R511C, in the FZD6 C-terminal region gives rise to autosomal recessive nail dysplasia and renders the receptor dysfunctional in G protein precoupling

Aspects of biliary tract cancer : incidence and reproductive risk factors

Biliary tract cancer, including cancer of the extra-hepatic bile ducts, cancer of the Ampulla of Vater and gallbladder cancer, is a devastating disease with poor prognosis. The incidence of biliary tract cancer is decreasing worldwide, for unknown reasons. One of two aims of this thesis was to evaluate the Swedish Cancer Register regarding biliary tract cancer and to assess the incidence of biliary tract cancer in Sweden. Secondly, an association between sex hormone exposure, particularly estrogen, and biliary tract cancer has been suggested. Thus, the second aim of this thesis was to evaluate the effect of sex hormone exposure on biliary tract cancer risk. Study I and II were based on data from the Swedish Cancer Register, the Swedish Patient Register and the Swedish Causes of Death Register. Study I was a validation study of biliary tract cancer diagnoses in the Cancer Register, using data from the Patient Register and the Cause of Death Register as comparison. Overall, 44% of patients diagnosed with biliary tract cancer between 1990 and 2009 were not found in the Cancer Register. The underreporting increased with increasing patient age and later time period. Study II indicated a decreasing incidence trend of biliary tract cancer. However, the mortality rates were higher than the incidence rates after the mid 1980’s and onwards. Moreover, the incidence trends based on data from the Patient Register suggested a more stable or only slightly decreasing trend. Thus, even though the incidence of biliary tract cancer may be decreasing, the extent of the decline is likely over-estimated. Study III investigated the association between reproductive factors and biliary tract cancer. Women and men were included in the study, but analyzed separately, to enable differentiation between hormone exposure and other factors. The risk of cancers of the extrahepatic bile ducts (including the Ampulla of Vater) is likely not influenced by reproductive factors because similar associations were seen in women and men. However, an association between reproductive factors and gallbladder cancer was observed in women, but not as clearly in men. Study IV investigated the risk of biliary tract cancer in a cohort of men with prostate cancer, a proxy for estrogen exposure (prostate cancer treatment). There was no clear association, although a slightly decreased risk was indicated. However, men with the highest presumed estrogen exposure had an increased risk of biliary tract cancer, though the association was not statistically significant. Study V investigated the association between menopausal hormone therapy and biliary tract cancer. A slightly reduced risk of gallbladder cancer was suggested for users of menopausal hormone therapy compared to non-users, but the association was not statistically significant. However, an increased risk of gallstone disease was noted however. In conclusion, there is substantial under-reporting of biliary tract cancer to the Swedish Cancer Register, especially in the elderly and in the later time period. The decreasing incidence trends of biliary tract cancer in Sweden are likely over-estimated, as a consequence of under-reporting. Furthermore, the role of sex hormones in the etiology of biliary tract cancer is uncertain. Sex hormone exposure may influence the risk of gallbladder cancer specifically but not biliary tract cancer as a whole. Future etiological research should separate gallbladder cancer from other extra-hepatic cancer

Granskning av en ridskolas hästkunskapsmaterial

Equestrianism is a big sport in Sweden with many practitioners. It is a dangerous sport and it is important for the rider to be aware of the risks, to study equine ethology and know how to handle the horse, to avoid accidents. Today most people have their first contact with a horse through a horseback riding school. Ölmstad rid- och körsällskap is a riding school that provides their pupils with a different kind of lessons. The lessons are 90 minutes long and contain both riding and horse-knowledge education. These lessons are designed to raise awareness among the pupils. At Ölmstad rid- och körsällskap the staff had for a long time noticed a lack of horse knowledge and therefore started this concept. This kind of lessons have been operating for seven years. During this time, the riding school has created a large theoretical teaching material. This paper examines some of the teaching material and compare it to scientific facts to consider whether it is scientifically true. Further on, the need of change and clarification of the material was also considered. It seems important to have knowledge of equine ethology to be a good horse trainer and rider. Moreover, it also seems important that equine knowledge increases among horse enthusiasts for improving horse welfare. The examined material seems overall consistent with science but some changes and clarifications are proposed in this work. Finally, this kind of lessons, with horse-knowledge education, may be a future concept for Swedish riding schools. It can be a contribution to raise awareness and of important grant to horse welfare

Liste des coléoptères du Sinai

Bakgrund: Närstående är genom mänsklig närhet och trygghet mycket värdefulla för patienter i palliativ vård. Idag sker en allt större del av den palliativa vården i hemmet vilket innebär att närstående ges en mer central roll i vårdandet. Forskning visar att närstående kan uppleva både emotionella, fysiska, sociala och psykologiska utmaningar vilket ökar risken för ohälsa. Det är av stor vikt att närstående blir sedda, erkända och inte känner sig ensamma i vårdandet. En intervention syftar till att avsiktligt bli involverad i en svår situation, antingen för att förbättra den eller för att förhindra att situationen försämras. Syfte: Syftet med litteraturöversikten var att belysa interventioner som uppmärksammar närstående inom palliativ hemsjukvård. Metod: En litteraturöversikt genomfördes utifrån syftet med studien. Både studier med kvalitativ- och kvantitativ design inkluderades. Artikelsökningar gjordes i databaserna CINAHL och PubMed. Resultatet baseras på tio vetenskapliga artiklar publicerade mellan år 2015-2020. Resultat: Resultatet beskrivs i tre kategorier utifrån likheter och tyngdpunkter i hur interventionerna utförs; interventioner som synliggör närstående, kunskapsbyggande interventioner och terapeutiska interventioner. Resultatet visar att det finns interventioner som uppmärksammar närstående till patienter i palliativ hemsjukvård och att dessa har effekt i form av minskad ångest, mindre vårdbörda och ökad livskvalitet hos närstående. Slutsats: Specialistsjuksköterskor i palliativ vård ska erbjuda stöd till patienter och närstående. Interventioner som uppmärksammar närstående i palliativ hemsjukvård finns och bör på ett strukturerat sätt erbjudas i klinisk verksamhet.Background: The family members are important for the patient in palliative care. They provide security and are valuable. Today an increasing part of palliative care takes place in the home, which means that the family members are given a more central role in the care. Research shows that family members can experience both emotional, physical, social, and psychological challenges which increases the risk of illness. It is of great importance that the family members get the attention, are validated, and not feel alone in the care of the patient. Interventions aims to help family members to improve their situation or prevent the situation from getting worse. Aim: The aim with the literature review was to describe interventions that pay attention to family members in palliative home care. Method: The study design was a literature review. Both qualitative and quantitative publications were included. The databases PubMed and CINAHL were used to search the articles. A total of 10 articles, published between the years 2015–2020, were selected and analysed in the results of the literature review.   Results: The results are described in three categories based on similarities in how the intervention is made. The categories are interventions for the family members to make them visible and confirmed, knowledge-building interventions and therapeutic interventions. The results show that there are interventions that pay attention to family members in palliative home care and that these interventions have an effect that shows a reduction of anxiety, caregiver burden and more quality of life. Conclusion: Specialist nurses in palliative care should offer support to patients and their family members.  Interventions that make  the family members visible in palliative homecare exist and should be offered in a structured way

"Hej, hej, följer du med mig hem?" - En studie kring personalens attityder kring genus, sexualitet och självbestämmande på LSS-boenden för människor med intellektuell funktionsnedsättning

This paper investigates the possibilities and hindrances for expressing identity and sexuality for people with intellectual disability. People with intellectual disabilities in Sweden are faced with care in special needs homes, provided by the public sector as well as private service providers and foundations. Legal support for the organized care is Lag om stöd och service till vissa funktionshindrade (1993). This law emphasizes the rights of autonomy, integrity and supportive work from healthcare providers. However, ambiguities may arise regarding the interpretation of the law in terms of self-determination in situations like self-harm or non-normative actions. Using vignette as a method we managed to derive material for analyzing attitudes and norms among the staff working in organizations with people of intellectual disabilities. Theories used are mainly based upon a constructivist perspective but also including theories of norms, power and feminism. We found that in relation to staff working in special needs homes, clients have wide opportunities of expressing and investigate their sexuality. Furthermore in their work as special need employees, communication using different kinds of illustrative examples is essential as a method for assisting the clients. Though there are findings saying that attitudes among the staff are less permissive towards some norm-breaking behaviour. Nevertheless, pursuing a somewhat emancipatory agenda for people with intellectual disability, our results have shown a positive side in the work with people with intellectual disabilities and how questions about sexuality and identity can be raised and possibilities enhanced

Neurosci Lett

Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers

Киберпространство и виртуальная реальность: попытка историко-философского анализа

Материалы IV Республик. науч. конф. студентов, магистрантов и аспирантов, Гомель, 12 мая 2011 г

Характер регенерации костной ткани альвеолярного отростка нижней челюсти после удаления ретинированного зуба мудрости

ЗУБ МУДРОСТИ /ХИРАЛЬВЕОЛЯРНЫЙ ОТРОСТОКРЕГЕНЕРАЦИЯ ПЕРИОДОНТАЛЬНОЙ ТКАНИ НАПРАВЛЕННАЯЗУБ РЕТИНИРОВАННЫЙ /ХИРКОСТЬ И КОСТНЫЕ ТКАН

White matter hyperintensities and working memory: an explorative study

Contains fulltext : 73317.pdf (publisher's version ) (Closed access)White matter hyperintensities (WMH) are commonly observed in elderly people and may have the most profound effect on executive functions, including working memory. Surprisingly, the Digit Span backward, a frequently employed working memory task, reveals no association with WMH. In the present study, it was investigated whether more detailed analyses of WMH variables and study sample selection are important when establishing a possible relationship between the Digit Span backward and WMH. To accomplish this, the Digit Span backward and additional working memory tests, WMH subscores, and cardiovascular risk factors were examined. The results revealed that performance on the Digit Span backward test is unrelated to WMH, whereas a relationship between other working memory tests and WMH was confirmed. Furthermore, a division between several white matter regions seems important; hyperintensities in the frontal deep white matter regions were the strongest predictor of working memory performance.16 p