•Interleukin-17 is a proinflammatory cytokine involved in chronic inflammation.•Interleukin-17 is involved in the pathogenesis of various immune-mediated diseases.•Several IL-17 and IL-17R inhibitors ...were approved to treat some immune-mediated diseases.•Ixekizumab, Secukinumab, and Brodalumab monoclonal antibodies target IL-17A and IL-17R.•Ixekizumab, Secukinumab, and Brodalumab are extremely effective to treat Psoriasis.
Interleukin-17 (IL-17) is a proinflammatory cytokine involved in chronic inflammation occurring during the pathogenesis of allergy, malignancy, and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis. IL-17 is produced by multiple cell types of adaptive and innate immunity, including T helper 17 cells, CD8 + T cells, γδ T cells, natural killer T cells, and innate lymphoid cells. Monoclonal antibodies (mAbs) targeting IL-17 and/or IL-17R would be a potential approach to study this therapeutic tool for these diseases. In the current review, we aimed to highlight the characteristics of IL-17 and its important role in the pathogenesis of related diseases. Critical evaluation of the mAbs targeting IL-17A and IL-17 receptors (e.g., Ixekizumab, Secukinumab, and Brodalumab) in various immune-mediated diseases will be provided, and finally, their clinical efficacy and safety will be reported.
As the atmosphere warms, precipitation events are becoming less frequent but more intense. A three-year experiment in Kruger National Park, South Africa, found that fewer, more intense precipitation ...events encouraged woody plant encroachment. To test whether or not these treatment responses persisted over time, here, we report results from all five years of that experiment. Grass growth, woody plant growth, total fine root number and area and hydrologic tracer uptake by grasses and woody plants were measured in six treated plots (8 m by 8 m) and six control plots. Treatment effects on soil moisture were measured continuously in one treated and one control plot. During the fourth year, increased precipitation intensity treatments continued to decrease water flux in surface soils (0-10 cm), increase water flux in deeper soils (20+ cm), decrease grass growth and increase woody plant growth. Greater root numbers at 20-40 cm and greater woody plant uptake of a hydrological tracer from 45-60 cm suggested that woody plants increased growth by increasing root number and activity (but not root area) in deeper soils. During the fifth year, natural precipitation events were large and intense so treatments had little effect on precipitation intensity or plant available water. Consistent with this effective treatment removal, there was no difference in grass or woody growth rates between control and treated plots, although woody plant biomass remained higher in treated than control plots due to treatment effects in the previous four years. Across the five years of this experiment, we found that 1) small increases in precipitation intensity can result in large increases in deep (20-130 cm) soil water availability, 2) plant growth responses to precipitation intensity are rapid and disappear quickly, and 3) because woody plants accumulate biomass, occasional increases in precipitation intensity can result in long-term increases in woody plant biomass (i.e., shrub encroachment). While results are likely to be site-specific, they provide experimental evidence of large ecohydrological responses to small changes in precipitation intensity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A genetic analysis of plant characters associated with lodging resistance, yield and other agronomic traits was made on two doubled haploid winter wheat populations grown at two UK locations in the ...2004/2005, 2005/2006 and 2006/2007 seasons. Wide genetic variation was found for traits that affect lodging, including plant height, components of stem strength (stem diameter, wall width and material strength), components of anchorage strength (spread and depth of the root plate), ear area and shoot number per plant. Heritabilities were estimated for each of the key lodging traits, with plant height having the highest heritability and anchorage traits the lowest values. Six quantitative trait loci (QTL) controlling plant height had individual height effects (2 × the additive effect) of 3–9 cm and taken together, could potentially increase plant height by up to 34 cm. Three of the height QTL were also associated with greater yield or greater thousand grain weight, and three were associated with components of stem strength or anchorage strength. QTL were also identified for each of the measured lodging traits, which were unrelated to height. Individual QTL with the largest estimated effects on lodging resistance were for height, stem diameter, stem material strength, stem failure moment, root plate spread and root plate depth. Diagnostic genetic markers for the most important QTL regions are now required to enable breeders to efficiently combine multiple traits together in a single variety that will increase lodging resistance and yield simultaneously.
SCUBA-2 is a 10 000-bolometer submillimetre camera on the James Clerk Maxwell Telescope. The instrument commissioning was completed in 2011 September, and full science operations began in 2011 ...October. To harness the full potential of this powerful new astronomical tool, the instrument calibration must be accurate and well understood. To this end, the algorithms for calculating the line-of-sight opacity have been improved, and the derived atmospheric extinction relationships at both wavebands of the SCUBA-2 instrument are presented. The results from over 500 primary and secondary calibrator observations have allowed accurate determination of the flux conversion factors (FCF) for the 850 and 450 μm arrays. Descriptions of the instrument beam shape and photometry methods are presented. The calibration factors are well determined, with relative calibration accuracy better than 5 per cent at 850 μm and 10 per cent at 450 μm, reflecting the success of the derived opacity relations as well as the stability of the performance of the instrument over several months. The sample size of the calibration observations and accurate FCFs have allowed the determination of the 850 and 450 μm fluxes of several well-known submillimetre sources, and these results are compared with previous measurements from SCUBA.
It is quite an honor to be selected for this John Gaus Award Lecture by a committee of my peers. I want to thank my husband, Bill Berry—my partner for 48 years and sometimes coauthor—and certainly my ...children, Katie Berry and David Berry, who have diverted my attention from policy studies for 35 years now and made life much more enjoyable by their personalities. I especially want to thank my many coauthors who have kept research and writing an engaging endeavor while we have developed friendships that will last a lifetime.
The development of a prognostic mortality risk model for hospitalized COVID-19 patients may facilitate patient treatment planning, comparisons of therapeutic strategies, and public health ...preparations. We retrospectively reviewed the electronic health records of patients hospitalized within a 13-hospital New Jersey USA network between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2, with follow-up through May 29, 2020. With death or hospital discharge by day 40 as the primary endpoint, we used univariate followed by stepwise multivariate proportional hazard models to develop a risk score on one-half the data set, validated on the remainder, and converted the risk score into a patient-level predictive probability of 40-day mortality based on the combined dataset. The study population consisted of 3123 hospitalized COVID-19 patients; median age 63 years; 60% were men; 42% had >3 coexisting conditions. 713 (23%) patients died within 40 days of hospitalization for COVID-19. From 22 potential candidate factors 6 were found to be independent predictors of mortality and were included in the risk score model: age, respiratory rate greater than or equal to25/minute upon hospital presentation, oxygenation <94% on hospital presentation, and pre-hospital comorbidities of hypertension, coronary artery disease, or chronic renal disease. The risk score was highly prognostic of mortality in a training set and confirmatory set yielding in the combined dataset a hazard ratio of 1.80 (95% CI, 1.72, 1.87) for one unit increases. Using observed mortality within 20 equally sized bins of risk scores, a predictive model for an individual's 40-day risk of mortality was generated as -14.258 + 13.460*RS + 1.585*(RS-2.524)^2-0.403*(RS-2.524)^3. An online calculator of this 40-day COVID-19 mortality risk score is available at www.HackensackMeridianHealth.org/CovidRS. A risk score using six variables is able to prognosticate mortality within 40-days of hospitalization for COVID-19.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Normal aging is associated with a degradation of perceptual abilities and a decline in higher-level cognitive functions, notably working memory. To remediate age-related deficits, cognitive training ...programs are increasingly being developed. However, it is not yet definitively established if, and by what mechanisms, training ameliorates effects of cognitive aging. Furthermore, a major factor impeding the success of training programs is a frequent failure of training to transfer benefits to untrained abilities. Here, we offer the first evidence of direct transfer-of-benefits from perceptual discrimination training to working memory performance in older adults. Moreover, using electroencephalography to evaluate participants before and after training, we reveal neural evidence of functional plasticity in older adult brains, such that training-induced modifications in early visual processing during stimulus encoding predict working memory accuracy improvements. These findings demonstrate the strength of the perceptual discrimination training approach by offering clear psychophysical evidence of transfer-of-benefit and a neural mechanism underlying cognitive improvement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The microbiome has been implicated in the initiation and persistence of inflammatory bowel disease. Despite the fact that diet is one of the most potent modulators of microbiome composition and ...function and that dietary intervention is the first-line therapy for treating pediatric Crohn's disease, the relationships between diet-induced remission, enteropathy, and microbiome are poorly understood. Here, we leverage a naturally-occurring canine model of chronic inflammatory enteropathy that exhibits robust remission following nutritional therapy, to perform a longitudinal study that integrates clinical monitoring, 16S rRNA gene amplicon sequencing, metagenomic sequencing, metabolomic profiling, and whole genome sequencing to investigate the relationship between therapeutic diet, microbiome, and disease.
We show that remission induced by a hydrolyzed protein diet is accompanied by alterations in microbial community structure marked by decreased abundance of pathobionts (e.g., Escherichia coli and Clostridium perfringens), reduced severity of dysbiosis, and increased levels of the secondary bile acids, lithocholic and deoxycholic acid. Physiologic levels of these bile acids inhibited the growth of E. coli and C. perfringens isolates, in vitro. Metagenomic analysis and whole genome sequencing identified the bile acid producer Clostridium hiranonis as elevated after dietary therapy and a likely source of secondary bile acids during remission. When C. hiranonis was administered to mice, levels of deoxycholic acid were preserved and pathology associated with DSS colitis was ameliorated. Finally, a closely related bile acid producer, Clostridium scindens, was associated with diet-induced remission in human pediatric Crohn's disease.
These data highlight that remission induced by a hydrolyzed protein diet is associated with improved microbiota structure, an expansion of bile acid-producing clostridia, and increased levels of secondary bile acids. Our observations from clinical studies of exclusive enteral nutrition in human Crohn's disease, along with our in vitro inhibition assays and in vivo studies in mice, suggest that this may be a conserved response to diet therapy with the potential to ameliorate disease. These findings provide insight into diet-induced remission of gastrointestinal disease and could help guide the rational design of more effective therapeutic diets.
Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on ...identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-
Ffluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging.
Few studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age.
Delegations are in the final stages of negotiating the proposed
Agreement under the United Nations Convention on the Law of the Sea on the conservation and sustainable use of marine biological ...diversity of areas beyond national jurisdiction
(BBNJ
Agreement
or
Agreement
). The
Agreement
will have tremendous scope. Geographically it covers all ocean areas beyond national jurisdiction, meaning approximately 60 percent of the earth’s surface. Substantively it deals with a range of complex topics necessary for the conservation and sustainable use of marine biological diversity of areas beyond national jurisdiction, including marine genetic resources, sharing of benefits, measures such as area-based management tools, including marine protected areas, environmental impact assessments and capacity-building and the transfer of marine technology. Existing scholarship primarily explores the substantive choices for the
Agreement
; little examines its proposed institutional structure. This article critically assesses the competing positions advanced during negotiations for the
Agreement’s
institutional structure – the ‘global’ and ‘regional’ positions – and reviews the middle, or ‘compromise’ position adopted by the draft text. It suggests that both global and regional actors will be necessary to conserve and sustainably use marine biological diversity of areas beyond national jurisdiction, and that some form of coordinating mechanism is required to allocate responsibility for particular tasks. Two principles are proposed for use in combination to provide a mechanism to help coordinate
Agreement
organs (global) and regional or sectoral bodies, namely, the principles of subsidiarity and cooperation. These principles are found in existing international and regional structures but are advanced here in dynamic forms, allowing for temporary or quasi-permanent allocation of competences, which can change or evolve over time. This position is also grounded in the international law of treaties and furthers dynamic views of regional and global ocean governance by offering practical coordinating principles that work with the existing
Agreement
text.
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