Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions

Quinacrine is a potent antiprion compound in cell culture models of prion disease but has failed to show efficacy in animal bioassays and human clinical trials. Previous studies demonstrated that quinacrine inefficiently penetrates the blood-brain barrier (BBB), which could contribute to its lack of efficacy in vivo. As quinacrine is known to be a substrate for P-glycoprotein multi-drug resistance (MDR) transporters, we circumvented its poor BBB permeability by utilizing MDR0/0 mice that are deficient in mdr1a and mdr1b genes. Mice treated with 40 mg/kg/day of quinacrine accumulated up to 100 µM of quinacrine in their brains without acute toxicity. PrPSc levels in the brains of prion-inoculated MDR0/0 mice diminished upon the initiation of quinacrine treatment. However, this reduction was transient and PrPSc levels recovered despite the continuous administration of quinacrine. Treatment with quinacrine did not prolong the survival times of prion-inoculated, wild-type or MDR0/0 mice compared to untreated mice. A similar phenomenon was observed in cultured differentiated prion-infected neuroblastoma cells: PrPSc levels initially decreased after quinacrine treatment then rapidly recovered after 3 d of continuous treatment. Biochemical characterization of PrPSc that persisted in the brains of quinacrine-treated mice had a lower conformational stability and different immunoaffinities compared to that found in the brains of untreated controls. These physical properties were not maintained upon passage in MDR0/0 mice. From these data, we propose that quinacrine eliminates a specific subset of PrPSc conformers, resulting in the survival of drug-resistant prion conformations. Transient accumulation of this drug-resistant prion population provides a possible explanation for the lack of in vivo efficacy of quinacrine and other antiprion drugs

Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth

Oncogenic Function of DACT1 in Colon Cancer through the Regulation of β-catenin

The Wnt/β-catenin signaling pathway plays important roles in the progression of colon cancer. DACT1 has been identified as a modulator of Wnt signaling through its interaction with Dishevelled (Dvl), a central mediator of both the canonical and noncanonical Wnt pathways. However, the functions of DACT1 in the WNT/β-catenin signaling pathway remain unclear. Here, we present evidence that DACT1 is an important positive regulator in colon cancer through regulating the stability and sublocation of β-catenin. We have shown that DACT1 promotes cancer cell proliferation in vitro and tumor growth in vivo and enhances the migratory and invasive potential of colon cancer cells. Furthermore, the higher expression of DACT1 not only increases the nuclear and cytoplasmic fractions of β-catenin, but also increases its membrane-associated fraction. The overexpression of DACT1 leads to the increased accumulation of nonphosphorylated β-catenin in the cytoplasm and particularly in the nuclei. We have demonstrated that DACT1 interacts with GSK-3β and β-catenin. DACT1 stabilizes β-catenin via DACT1-induced effects on GSK-3β and directly interacts with β-catenin proteins. The level of phosphorylated GSK-3β at Ser9 is significantly increased following the elevated expression of DACT1. DACT1 mediates the subcellular localization of β-catenin via increasing the level of phosphorylated GSK-3β at Ser9 to inhibit the activity of GSK-3β. Taken together, our study identifies DACT1 as an important positive regulator in colon cancer and suggests a potential strategy for the therapeutic control of the β-catenin-dependent pathway

Coordination in climbing: effect of skill, practice and constraints manipulation

BACKGROUND: Climbing is a physical activity and sport involving many subdisciplines. Minimization of prolonged pauses, use of a relatively simple path through a route and smooth transitions between movements broadly define skilled coordination in climbing. OBJECTIVES: To provide an overview of the constraints on skilled coordination in climbing and to explore future directions in this emerging field. METHODS: A systematic literature review was conducted in 2014 and retrieved studies reporting perceptual and movement data during climbing tasks. To be eligible for the qualitative synthesis, studies were required to report perceptual or movement data during climbing tasks graded for difficulty. RESULTS: Qualitative synthesis of 42 studies was carried out, showing that skilled coordination in climbing is underpinned by superior perception of climbing opportunities; optimization of spatial-temporal features pertaining to body-to-wall coordination, the climb trajectory and hand-to-hold surface contact; and minimization of exploratory behaviour. Improvements in skilled coordination due to practice are related to task novelty and the difficulty of the climbing route relative to the individual's ability level. CONCLUSION: Perceptual and motor adaptations that improve skilled coordination are highly significant for improving the climbing ability level. Elite climbers exhibit advantages in detection and use of climbing opportunities when visually inspecting a route from the ground and when physically moving though a route. However, the need to provide clear guidelines on how to improve climbing skill arises from uncertainties regarding the impacts of different practice interventions on learning and transfer

The self-organizing fractal theory as a universal discovery method: the phenomenon of life

A universal discovery method potentially applicable to all disciplines studying organizational phenomena has been developed. This method takes advantage of a new form of global symmetry, namely, scale-invariance of self-organizational dynamics of energy/matter at all levels of organizational hierarchy, from elementary particles through cells and organisms to the Universe as a whole. The method is based on an alternative conceptualization of physical reality postulating that the energy/matter comprising the Universe is far from equilibrium, that it exists as a flow, and that it develops via self-organization in accordance with the empirical laws of nonequilibrium thermodynamics. It is postulated that the energy/matter flowing through and comprising the Universe evolves as a multiscale, self-similar structure-process, i.e., as a self-organizing fractal. This means that certain organizational structures and processes are scale-invariant and are reproduced at all levels of the organizational hierarchy. Being a form of symmetry, scale-invariance naturally lends itself to a new discovery method that allows for the deduction of missing information by comparing scale-invariant organizational patterns across different levels of the organizational hierarchy

Key mechanisms governing resolution of lung inflammation

Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the primary responses to injury, infection and irritation, largely mediated by granulocyte effector cells such as neutrophils and eosinophils. Failure to remove an inflammatory stimulus (often resulting in failed resolution of inflammation) can lead to chronic inflammation resulting in tissue injury caused by high numbers of infiltrating activated granulocytes. Successful resolution of inflammation is dependent upon the removal of these cells. Under normal physiological conditions, apoptosis (programmed cell death) precedes phagocytic recognition and clearance of these cells by, for example, macrophages, dendritic and epithelial cells (a process known as efferocytosis). Inflammation contributes to immune defence within the respiratory mucosa (responsible for gas exchange) because lung epithelia are continuously exposed to a multiplicity of airborne pathogens, allergens and foreign particles. Failure to resolve inflammation within the respiratory mucosa is a major contributor of numerous lung diseases. This review will summarise the major mechanisms regulating lung inflammation, including key cellular interplays such as apoptotic cell clearance by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions. The different acute and chronic inflammatory disease states caused by dysregulated/impaired resolution of lung inflammation will be discussed. Furthermore, the resolution of lung inflammation during neutrophil/eosinophil-dominant lung injury or enhanced resolution driven via pharmacological manipulation will also be considered

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.Peer reviewe

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Reprodutibilidade intra e interobservadores da classificação de hipersinal facetário lombar e correlação com a degeneração discal para ressonância magnética Reproducibilidad intra e inter observadores de la clasificación de hiperseñal facetaria lumbar y correlación con la degeneración discal para resonancia magnética Intraobserver and interobserver reproducibility of lumbar facet hypersignal rating and correlation with disc degeneration by magnetic resonance imaging

OBJETIVO: Avaliar a reprodutibilidade intra e interobservadores da "classificação de hipersinal facetário lombar" e avaliar a correlação com a degeneração discal. MÉTODOS: Estudo retrospectivo de imagens de ressonância magnética obtidas de 41 (N=41) pacientes (18 homens e 23 mulheres), com idade variando de 26 a 84 anos, com média de 48 anos e três meses. As imagens foram revisadas por três ortopedistas especialistas em cirurgia de coluna e um radiologista, para avaliar e quantificar a presença do hipersinal facetário lombar. Posteriormente, foi verificada a relação entre a artrose facetária e degeneração discal. RESULTADOS: Foram avaliados e classificados 205 discos lombares e suas facetas articulares pelos quatro examinadores, com os dados analisados pelo Teste de Cronbach e da Análise de Correlação de Spearman com resultados estatisticamente elevados, confirmando boa relação intra e interobservadores para a "classificação de hipersinal facetário". Não foi observada relação estatisticamente significante entre artrose facetária e degeneração discal. CONCLUSÃO: Foram obtidos resultados suficientes para afirmar que existe boa relação intra e interobservadores para a "classificação de hipersinal facetário lombar". Não se verificou relação estatisticamente significante entre artrose facetária e degeneração discal.<br>OBJETIVO: Evaluar la reproducibilidad inter e intra observadores de la "Clasificación de hiperseñal facetaria lumbar" y evaluar la correlación con la degeneración discal. Métodos: Estudio retrospectivo de imágenes de resonancia magnética obtenidas de 41 (N=41) pacientes (18 hombres y 23 mujeres), con la edad de 26 años hasta 84 años y, con promedio de 48 años y 3 meses. Las imágenes fueran revisadas por tres cirujanos ortopedistas especialistas en cirugía de columna vertebral y un radiólogo para evaluar y cuantificar la presencia de hiperseñal facetario lumbar. Después fue verificada la relación entre la artrosis facetaria y la degeneración del disco. RESULTADOS: Fueran evaluados y clasificados 205 discos lumbares y sus facetas articulares por los cuatro examinadores con las informaciones analizadas por la Prueba de Cronbach y el Análisis de Correlación de Spearman, con resultados estadísticamente elevados, confirmando buena relación inter e intra observadores para la "clasificación de hiperseñal facetaria" . No fue observada relación estadísticamente significativa entre artrosis facetaria y degeneración discal. CONCLUSIÓN: Fueran obtenidos resultados suficientes para asegurar que hay buena relación inter y intra observadores para la "Clasificación de hiperseñal facetaria" . No fue verificada relación estadísticamente significativa entre artrosis facetaria y degeneración discal.<br>OBJECTIVE: To assess intraobserver and interobserver reproducibility of lumbar facet hypersignal rating and to assess the correlation with disc degeneration. METHODS: Retrospective study of magnetic resonance imaging of 41 patients (18 male and 23 female), with mean age of 48 years and three months (range 26-84 years). Three independent orthopaedic spine surgeons and one radiologist reviewed the images to assess and quantify the presence of lumbar facet hypersignal. Later, the relation between facet arthrosis and disc degeneration was evaluated. RESULTS: 205 lumbar discs and facets were assessed and rated by four independent observers, the records were analyzed by Cronbach test and Spearman correlation analysis with high statistical outcomes which confirm a good interobserver and intraobserver relation for lumbar facet hypersignal rating. No statistical difference between facet arthrosis and disc degeneration was verified. CONCLUSION: Sufficient outcomes were obtained to confirm the existence of good interobserver and intraobserver relation for lumbar facet hypersignal rating. No statistical difference between facet arthrosis and disc degeneration was verified