Abstract
Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA. Tofacitinib is a selective JAK1, 3 ...inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3. Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patient-reported outcomes as well as disease modification. Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX. An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016. In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs.
Under conditions of hypoxia, most eukaryotic cells can shift their primary metabolic strategy from predominantly mitochondrial respiration towards increased glycolysis to maintain ATP levels. This ...hypoxia‐induced reprogramming of metabolism is key to satisfying cellular energetic requirements during acute hypoxic stress. At a transcriptional level, this metabolic switch can be regulated by several pathways including the hypoxia inducible factor‐1α (HIF‐1α) which induces an increased expression of glycolytic enzymes. While this increase in glycolytic flux is beneficial for maintaining bioenergetic homeostasis during hypoxia, the pathways mediating this increase can also be exploited by cancer cells to promote tumour survival and growth, an area which has been extensively studied. It has recently become appreciated that increased glycolytic metabolism in hypoxia may also have profound effects on cellular physiology in hypoxic immune and endothelial cells. Therefore, understanding the mechanisms central to mediating this reprogramming are of importance from both physiological and pathophysiological standpoints. In this review, we highlight the role of HIF‐1α in the regulation of hypoxic glycolysis and its implications for physiological processes such as angiogenesis and immune cell effector function.
figure legend Schematic outlining the functional physiological consequences of enhanced glycolytic metabolism in endothelial cells and immune cells.
The ability to ensure proteostasis is critical for maintaining proper cell function and organismal viability but is mitigated by aging. We analyzed the role of the endoplasmic reticulum unfolded ...protein response (UPRER) in aging of C. elegans and found that age-onset loss of ER proteostasis could be reversed by expression of a constitutively active form of XBP-1, XBP-1s. Neuronally derived XBP-1s was sufficient to rescue stress resistance, increase longevity, and activate the UPRER in distal, non-neuronal cell types through a cell-nonautonomous mechanism. Loss of UPRER signaling components in distal cells blocked cell-nonautonomous signaling from the nervous system, thereby blocking increased longevity of the entire animal. Reduction of small clear vesicle (SCV) release blocked nonautonomous signaling downstream of xbp-1s, suggesting that the release of neurotransmitters is required for this intertissue signaling event. Our findings point toward a secreted ER stress signal (SERSS) that promotes ER stress resistance and longevity.
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•In nematodes, the ability to respond to ER stress is lost with age•Constitutively active xbp-1s rescues ER stress resistance in older animals•Neuronal xbp-1s protects against ER stress and extends lifespan•Neuronal xbp-1s leads to the distal activation of the UPRER via neurosecretion
In C. elegans, activation of the unfolded protein response (UPR) regulator XBP-1 in neurons produces a signal that stimulates UPR in intestinal cells, improving stress resistance and extending lifespan.
Quantitative PCR (qPCR) has become the gold standard technique to measure cDNA and gDNA levels but the resulting data can be highly variable, artifactual and non-reproducible without appropriate ...verification and validation of both samples and primers. The root cause of poor quality data is typically associated with inadequate dilution of residual protein and chemical contaminants that variably inhibit Taq polymerase and primer annealing. The most susceptible, frustrating and often most interesting samples are those containing low abundant targets with small expression differences of 2-fold or lower. Here, Droplet Digital PCR (ddPCR) and qPCR platforms were directly compared for gene expression analysis using low amounts of purified, synthetic DNA in well characterized samples under identical reaction conditions. We conclude that for sample/target combinations with low levels of nucleic acids (Cq ≥ 29) and/or variable amounts of chemical and protein contaminants, ddPCR technology will produce more precise, reproducible and statistically significant results required for publication quality data. A stepwise methodology is also described to choose between these complimentary technologies to obtain the best results for any experiment.
The unprecedented COVID‐19 crisis presents an imperative for mental health care systems to make digital mental health interventions a routine part of care. Already because of COVID‐19, many ...therapists have rapidly moved to using telehealth in place of in‐person contact. In response to this shift, Waller and colleagues compiled a series of expert recommendations to help clinicians pivot to delivering teletherapy to address eating disorders during COVID‐19. However, numerous barriers still impede widespread adoption and implementation of digital interventions. In this commentary, we aim to extend the recommendations for clinicians offered by Waller and colleagues by presenting a roadmap of the systems‐ and policy‐level requirements that are needed. We advocate for addressing barriers associated with training, licensing, safety, privacy, payment, and evaluation, as these factors have greatly limited use of these promising interventions. We also indicate that longer‐term goals should include introducing truly innovative digital mental health practices, such as stepped‐care models and simultaneously providing preventive and self‐management services in addition to clinical services, into the health care system. Now is the time to catalyze change and comprehensively address the barriers that have prevented widespread delivery of these efficacious digital services to the millions of people who would benefit.
Bioinformatics researchers are now confronted with analysis of ultra large-scale data sets, a problem that will only increase at an alarming rate in coming years. Recent developments in open source ...software, that is, the Hadoop project and associated software, provide a foundation for scaling to petabyte scale data warehouses on Linux clusters, providing fault-tolerant parallelized analysis on such data using a programming style named MapReduce.
An overview is given of the current usage within the bioinformatics community of Hadoop, a top-level Apache Software Foundation project, and of associated open source software projects. The concepts behind Hadoop and the associated HBase project are defined, and current bioinformatics software that employ Hadoop is described. The focus is on next-generation sequencing, as the leading application area to date.
Hadoop and the MapReduce programming paradigm already have a substantial base in the bioinformatics community, especially in the field of next-generation sequencing analysis, and such use is increasing. This is due to the cost-effectiveness of Hadoop-based analysis on commodity Linux clusters, and in the cloud via data upload to cloud vendors who have implemented Hadoop/HBase; and due to the effectiveness and ease-of-use of the MapReduce method in parallelization of many data analysis algorithms.
Anthocyanins in Cardiovascular Disease Wallace, Taylor C.
Advances in nutrition (Bethesda, Md.),
January 2011, 2011-Jan, 2011-01-00, Letnik:
2, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Anthocyanins are a group of abundant and widely consumed flavonoid constituents that occur ubiquitously in the plant kingdom, providing the bright red-orange to blue-violet colors present in many ...fruit- and vegetable-based food products. Their intake has been estimated to be up to 9-fold higher than that of other dietary flavonoids. Anthocyanins have become increasingly important to the food industry as their use as natural alternatives to artificial colors has become widespread and knowledge of their health-promoting properties has become more evident. Epidemiological studies suggest that increased consumption of anthocyanins lowers the risk of cardiovascular disease (CVD), the most common cause of mortality among men and women. Anthocyanins frequently interact with other phytochemicals, exhibiting synergistic biological effects but making contributions from individual components difficult to decipher. Over the past 2 decades, many peer-reviewed publications have demonstrated that in addition to their noted in vitro antioxidant activity, anthocyanins may regulate different signaling pathways involved in the development of CVD. This review summarizes the latest developments on the bioavailability/bioactivity and CVD preventative activities of anthocyanins, including results from in vitro cell culture and in vivo animal model systems as related to their multiple proposed mechanisms of action. Limited yet promising data from epidemiological studies and human clinical trials are also presented. Future studies aimed at enhancing the absorption of anthocyanins and characterizing their metabolic and/or breakdown products are necessary to ultimately evaluate their use for protection/prevention against the development of CVD.
Vegetation affects precipitation patterns by mediating moisture, energy and trace-gas fluxes between the surface and atmosphere. When forests are replaced by pasture or crops, evapotranspiration of ...moisture from soil and vegetation is often diminished, leading to reduced atmospheric humidity and potentially suppressing precipitation. Climate models predict that large-scale tropical deforestation causes reduced regional precipitation, although the magnitude of the effect is model and resolution dependent. In contrast, observational studies have linked deforestation to increased precipitation locally but have been unable to explore the impact of large-scale deforestation. Here we use satellite remote-sensing data of tropical precipitation and vegetation, combined with simulated atmospheric transport patterns, to assess the pan-tropical effect of forests on tropical rainfall. We find that for more than 60 per cent of the tropical land surface (latitudes 30 degrees south to 30 degrees north), air that has passed over extensive vegetation in the preceding few days produces at least twice as much rain as air that has passed over little vegetation. We demonstrate that this empirical correlation is consistent with evapotranspiration maintaining atmospheric moisture in air that passes over extensive vegetation. We combine these empirical relationships with current trends of Amazonian deforestation to estimate reductions of 12 and 21 per cent in wet-season and dry-season precipitation respectively across the Amazon basin by 2050, due to less-efficient moisture recycling. Our observation-based results complement similar estimates from climate models, in which the physical mechanisms and feedbacks at work could be explored in more detail.
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