It has become apparent that the intestinal microbiota orchestrates important aspects of our metabolism, immunity, and development. Recent work has demonstrated that the microbiota also influences ...brain function in healthy and diseased individuals. Of great interest are reports that intestinal bacteria play a role in the pathogenic cascade of both Parkinson and Alzheimer diseases. These neurodegenerative disorders both involve misfolding of endogenous proteins that spreads from one region of the body to another in a manner analogous to prions. The mechanisms of how the microbiota influences or is correlated with disease require elaboration. Microbial proteins or metabolites may influence neurodegeneration through the promotion of amyloid formation by human proteins or by enhancing inflammatory responses to endogenous neuronal amyloids. We review the current knowledge concerning bacterial amyloids and their potential to influence cerebral amyloid aggregation and neuroinflammation. We propose the term "mapranosis" to describe the process of microbiota-associated proteopathy and neuroinflammation. The study of amyloid proteins made by the microbiota and their influence on health and disease is in its infancy. This is a promising area for therapeutic intervention because there are many ways to alter our microbial partners and their products, including amyloid proteins.
The choice of reference genes that are stably expressed amongst treatment groups is a crucial step in real-time quantitative PCR gene expression studies. Recent guidelines have specified that a ...minimum of two validated reference genes should be used for normalisation. However, a quantitative review of the literature showed that the average number of reference genes used across all studies was 1.2. Thus, the vast majority of studies continue to use a single gene, with β-actin (ACTB) and/or glyceraldehyde 3-phosphate dehydrogenase (GAPDH) being commonly selected in studies of vertebrate gene expression. Few studies (15%) tested a panel of potential reference genes for stability of expression before using them to normalise data. Amongst studies specifically testing reference gene stability, few found ACTB or GAPDH to be optimal, whereby these genes were significantly less likely to be chosen when larger panels of potential reference genes were screened. Fewer reference genes were tested for stability in non-model organisms, presumably owing to a dearth of available primers in less well characterised species. Furthermore, the experimental conditions under which real-time quantitative PCR analyses were conducted had a large influence on the choice of reference genes, whereby different studies of rat brain tissue showed different reference genes to be the most stable. These results highlight the importance of validating the choice of normalising reference genes before conducting gene expression studies.
Despite being the most abundant synaptic vesicle membrane protein, the function of synaptophysin remains enigmatic. For example, synaptic transmission was reported to be completely normal in ...synaptophysin knockout mice; however, direct experiments to monitor the synaptic vesicle cycle have not been carried out. Here, using optical imaging and electrophysiological experiments, we demonstrate that synaptophysin is required for kinetically efficient endocytosis of synaptic vesicles in cultured hippocampal neurons. Truncation analysis revealed that distinct structural elements of synaptophysin differentially regulate vesicle retrieval during and after stimulation. Thus, synaptophysin regulates at least two phases of endocytosis to ensure vesicle availability during and after sustained neuronal activity.
Neurotransmitter release at synapses involves a highly specialized form of membrane fusion that is triggered by Ca(2+) ions and is optimized for speed. These observations were established decades ...ago, but only recently have the molecular mechanisms that underlie this process begun to come into view. Here, we summarize findings obtained from genetically modified neurons and neuroendocrine cells, as well as from reconstituted systems, which are beginning to reveal the molecular mechanism by which Ca(2+)-acting on the synaptic vesicle (SV) protein synaptotagmin I (syt)-triggers rapid exocytosis. This work sheds light not only on presynaptic aspects of synaptic transmission, but also on the fundamental problem of membrane fusion, which has remained a puzzle that has yet to be solved in any biological system.
This randomized trial compared a long-acting beta-agonist (LABA) plus a glucocorticoid with a LABA plus a long-acting muscarinic antagonist for preventing exacerbations of chronic obstructive ...pulmonary disease. The exacerbation rate was lower with the latter treatment.
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with an accelerated decline in lung function,
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impaired quality of life,
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hospitalization,
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and increased mortality.
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COPD exacerbations are costly to health care systems.
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Thus, prevention of exacerbations is a key goal in the management of COPD.
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Inhaled long-acting bronchodilators not only control symptoms but also prevent COPD exacerbations.
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Inhaled glucocorticoids are also known to reduce the frequency of exacerbations and have been studied in combination with inhaled long-acting beta-agonists (LABAs).
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In one trial, the combination of a LABA plus an inhaled glucocorticoid (salmeterol–fluticasone) in fixed doses and . . .
The Process of Empowerment Cattaneo, Lauren Bennett; Chapman, Aliya R
The American psychologist,
10/2010, Letnik:
65, Številka:
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Journal Article
Recenzirano
In this article, we propose a model of the process of empowerment. The notion of empowerment is compelling and much employed across many subfields inside and outside of psychology, but the lack of ...consistency in the ways prior literature has defined it is an obstacle to meaningful synthesis of findings and consistent application in practice. Our empowerment process model builds on prior work in taking the following steps: articulating empowerment as an iterative process, identifying core elements of that process, and defining the process in a way that is practically useful to both researchers and practitioners with terms that are easily communicated and applied. The components of the model are personally meaningful and power-oriented goals, self-efficacy, knowledge, competence, action, and impact. Individuals move through the process with respect to particular goals, doubling back repeatedly as experience promotes reflection. We make specific recommendations for research and practice and discuss applications to social justice.
Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-related SC) are now recognized as components of a multisystem IgG4-related disease (IgG4-RD). We aimed to define the ...clinical course and long-term outcomes in patients with AIP/IgG4-SC recruited from two large UK tertiary referral centers.
Data were collected from 115 patients identified between 2004 and 2013, and all were followed up prospectively from diagnosis for a median of 33 months (range 1-107), and evaluated for response to therapy, the development of multiorgan involvement, and malignancy. Comparisons were made with national UK statistics.
Although there was an initial response to steroids in 97%, relapse occurred in 50% of patients. IgG4-SC was an important predictor of relapse (P<0.01). Malignancy occurred in 11% shortly before or after the diagnosis of IgG4-RD, including three hepatopancreaticobiliary cancers. The risk of any cancer at diagnosis or during follow-up when compared with matched national statistics was increased (odds ratio=2.25, CI=1.12-3.94, P=0.02). Organ dysfunction occurred within the pancreas, liver, kidney, lung, and brain. Mortality occurred in 10% of patients during follow-up. The risk of death was increased compared with matched national statistics (odds ratio=2.07, CI=1.07-3.55, P=0.02).
Our findings suggest that AIP and IgG4-SC are associated with significant morbidity and mortality owing to extrapancreatic organ failure and malignancy. Detailed clinical evaluation for evidence of organ dysfunction and associated malignancy is required both at first presentation and during long-term follow-up.
Kindred cells can have different genomes because of dynamic changes in DNA. Single-cell sequencing is needed to characterize these genomic differences but has been hindered by whole-genome ...amplification bias, resulting in low genome coverage. Here, we report on a new amplification method—multiple annealing and looping-based amplification cycles (MALBAC)—that offers high uniformity across the genome. Sequencing MALBAC-amplified DNA achieves 93% genome coverage ≥1x for a single human cell at 25x mean sequencing depth. We detected digitized copy-number variations (CNVs) of a single cancer cell. By sequencing three kindred cells, we were able to identify individual single-nucleotide variations (SNVs), with no false positives detected. We directly measured the genome-wide mutation rate of a cancer cell line and found that purine-pyrimidine exchanges occurred unusually frequently among the newly acquired SNVs.
Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological ...manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward.
Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure.
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