Dans sa décision de principe sur les droits de chasse des Métis rendue à la suite de l’affaire R. c. Powley, la Cour suprême du Canada recourt au concept de mainmise effective pour marquer les ...limites de la période à considérer afin de déterminer si des pratiques particulières (p. ex., la chasse) font partie intégrante du mode de vie des Métis. Si ces pratiques n’ont pas été explicitement abolies par l’État avant 1982, alors elles font partie aujourd’hui des droits ancestraux des Métis et à ce titre, elles sont protégées par la Constitution. Déterminer la date de la mainmise effective de l’État est un problème empirique qui exige des recherches historiques approfondies. Devant les revendications de la Couronne quant à sa souveraineté et à l’extinction de droits autochtones, diverses activités peuvent servir de critères quant à l’établissement de la mainmise effective sur les régions pionnières (p. ex., les recensements). Des documents historiques montrent que des activités de topométrie et de cartographie ont matérialisé les efforts du gouvernement fédéral pour acquérir des connaissances géographiques. En ce qui concerne la nécessité constante de clarifier les droits ancestraux des Métis, la valeur des sources cartographiques historiques comme moyen de reconstruire la lente évolution des connaissances géographiques de l’État est illustrée par l’exemple de la région d’Ile-à-la-Crosse. La cartographie historique, par conséquent, peut contribuer à clarifier les droits des Métis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this book, the mathematical principles and working methods of single-particle reconstruction are described; a method designed to retrieve three-dimensional structural information from electron ...micrographs showing thousands of “copies” of biological molecules trapped in a thin layer of ice. This technique is uniquely suited to obtain three-dimensional images of molecular machines in different functional states, as it dispenses with the need for crystals. The book starts with an introduction of image formation in the electron microscope, which includes the definition of the contrast transfer function. Next, averaging techniques and tools for image alignment, multivariate data analysis, and classification are described. An introduction into the mathematical principles underlying reconstruction of an object from its projections is followed by detailed accounts on how projection angles are determined, and how reconstruction is done in practice. The book concludes with a chapter on interpretation of density maps reconstructed, including methods for segmentation as well as fitting and docking of atomic coordinates.
In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, ...particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.
Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are heterogeneous intestinal diseases that threaten the health of an increasing number of individuals as their lifestyles become ...westernized. New insights have been discovered with the development of various omics techniques, revealing that gut-microbiota-derived metabolites play important roles in maintaining intestinal homeostasis and modulating the progression of intestinal diseases from both metabolic and immunological perspectives. Clinical metagenomic and metabolomic studies have revealed links between microbial bile acid (BA) metabolism and IBD and CRC progression. Several BA-derived metabolites were recently been demonstrated to play a role in intestinal immunity, providing fresh insights into how BAs affect the course of IBD and CRC. In this review, we discuss recent studies on the involvement of gut microbiota-derived BAs in intestinal immunity, inflammation, and tumorigenesis along with human omics data to provide prospective insights into future prevention and treatment of IBD and CRC.
Background To study the performance of the chimney technique in the treatment of aortic arch pathologic conditions. Methods We retrospectively evaluated the clinical and procedural outcome data of ...patients undergoing endovascular treatment in the aortic arch by use of the chimney technique at four European centers between June 2002 and December 2014. The primary endpoint was technical success. The secondary endpoints were type I endoleak, 30-day mortality, stroke, primary patency of the chimney graft, and freedom from reintervention. Results Ninety-five patients were included in the study. The underlying pathologic conditions were degenerative aneurysm (n = 45, 47.4%), type B aortic dissection (n = 30, 31.6%), dissecting aneurysm (n = 6, 6.5%), penetrating atherosclerotic ulcer (n = 5, 5.3%), type I endoleak after previous thoracic endovascular aortic repair (n = 6, 6.3%), and aortic embolic disease (n = 3, 3.2%). Twenty-one patients (22%) underwent arch-branch debranching before chimney graft implantation. The majority of patients were treated electively (n = 49, 51.6%). Forty-six patients (48.4%) underwent urgent placement of chimney grafts because of their symptoms (n = 25) or rupture (n = 21). Technical success was 89.5%. The 30-day mortality was 9.5% (9 patients). No aorta-related death was observed. A type Ia endoleak occurred in 10 patients (10.5%) intraoperatively, resolving spontaneously within the first 30 days in 50% of these cases. Major stroke was diagnosed in 2 patients (2%). Primary patency of the chimney grafts was 98%, and 5 patients (5.2%) required a reintervention. Conclusions The chimney technique in the aortic arch proved highly and predictably successful, with a low rate of reinterventions.
The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this ...disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.
Plasmonic skyrmions are an optical manifestation of topological defects in a continuous vector field. Identifying them requires characterization of the vector structure of the electromagnetic near ...field on thin metal films. Here we introduce time-resolved vector microscopy that creates movies of the electric field vectors of surface plasmons with subfemtosecond time steps and a 10-nanometer spatial scale. We image complete time sequences of propagating surface plasmons as well as plasmonic skyrmions, resolving all vector components of the electric field and their time dynamics, thus demonstrating dynamic spin-momentum coupling as well as the time-varying skyrmion number. The ability to image linear optical effects in the spin and phase structures of light in the single-nanometer range will allow for entirely novel microscopy and metrology applications.
Human betacoronaviruses OC43 and HKU1 are endemic respiratory pathogens and, while related, originated from independent zoonotic introductions. OC43 is in fact a host-range variant of the species ...Betacoronavirus-1, and more closely related to bovine coronavirus (BCoV)—its presumptive ancestor—and porcine hemagglutinating encephalomyelitis virus (PHEV). The β1-coronaviruses (β1CoVs) and HKU1 employ glycan-based receptors carrying 9-O-acetylated sialic acid (9-O-Ac-Sia). Receptor binding is mediated by spike protein S, the main determinant of coronavirus host specificity. For BCoV, a crystal structure for the receptor-binding domain S1A is available and for HKU1 a cryoelectron microscopy structure of the complete S ectodomain. However, the location of the receptor-binding site (RBS), arguably the single-most important piece of information, is unknown. Here we solved the 3.0-Å crystal structure of PHEV S1A. We then took a comparative structural analysis approach to map the β1CoV S RBS, using the general design of 9-O-Ac-Sia-binding sites as blueprint, backed-up by automated ligand docking, structure-guided mutagenesis of OC43, BCoV, and PHEV S1A, and infectivity assays with BCoV-S–pseudotyped vesicular stomatitis viruses. The RBS is not exclusive to OC43 and related animal viruses, but is apparently conserved and functional also in HKU1 S1A. The binding affinity of the HKU1 S RBS toward short sialoglycans is significantly lower than that of OC43, which we attribute to differences in local architecture and accessibility, and which may be indicative for differences between the two viruses in receptor fine-specificity. Our findings challenge reports that would map the OC43 RBS elsewhere in S1A and that of HKU1 in domain S1B.
I explore the sample size in qualitative research that is required to reach theoretical saturation. I conceptualize a population as consisting of sub-populations that contain different types of ...information sources that hold a number of codes. Theoretical saturation is reached after all the codes in the population have been observed once in the sample. I delineate three different scenarios to sample information sources: "random chance," which is based on probability sampling, "minimal information," which yields at least one new code per sampling step, and "maximum information," which yields the largest number of new codes per sampling step. Next, I use simulations to assess the minimum sample size for each scenario for systematically varying hypothetical populations. I show that theoretical saturation is more dependent on the mean probability of observing codes than on the number of codes in a population. Moreover, the minimal and maximal information scenarios are significantly more efficient than random chance, but yield fewer repetitions per code to validate the findings. I formulate guidelines for purposive sampling and recommend that researchers follow a minimum information scenario.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid ...homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apc
mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.
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