Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather ...than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with
deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.
MicroRNAs (miRNAs) are involved in posttranscriptional regulation of gene expression. Because several miRNAs are known to affect the stability or translation of developmental regulatory genes, the ...origin of novel miRNAs may have contributed to the evolution of developmental processes and morphology. Lepidoptera (butterflies and moths) is a species-rich clade with a well-established phylogeny and abundant genomic resources, thereby representing an ideal system in which to study miRNA evolution. We sequenced small RNA libraries from developmental stages of two divergent lepidopterans, Cameraria ohridella (Horse chestnut Leafminer) and Pararge aegeria (Speckled Wood butterfly), discovering 90 and 81 conserved miRNAs, respectively, and many species-specific miRNA sequences. Mapping miRNAs onto the lepidopteran phylogeny reveals rapid miRNA turnover and an episode of miRNA fixation early in lepidopteran evolution, implying that miRNA acquisition accompanied the early radiation of the Lepidoptera. One lepidopteran-specific miRNA gene, miR-2768, is located within an intron of the homeobox gene invected, involved in insect segmental and wing patterning. We identified cubitus interruptus (ci) as a likely direct target of miR-2768, and validated this suppression using a luciferase assay system. We propose a model by which miR-2768 modulates expression of ci in the segmentation pathway and in patterning of lepidopteran wing primordia.
Were vertebrates octoploid? Furlong, Rebecca F.; Holland, Peter W. H.
Philosophical transactions - Royal Society. Biological sciences,
04/2002, Letnik:
357, Številka:
1420
Journal Article
Recenzirano
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It has long been suggested that gene and genome duplication play important roles in the evolution of organismal complexity. For example, work by Ohno proposed that two rounds of whole genome doubling ...(tetraploidy) occurred during the evolution of vertebrates: the extra genes permitting an increase in physiological and anatomical complexity. Several modifications of this 'two tetraploidies' hypothesis have been proposed, taking into account accumulating data, and there is wide acceptance of the basic scheme. In the past few years, however, several authors have raised doubts, citing lack of direct support or even evidence to the contrary. Here, we review the evidence for and against the occurrence of tetraploidies in early vertebrate evolution, and present a new compilation of molecular phylogenetic data for amphioxus. We argue that evidence in favour of tetraploidy, based primarily on genome and gene family analyses, is strong. Furthermore, we show that two observations used as evidence against genome duplication are in fact compatible with the hypothesis: but only if the genome doubling occurred by two closely spaced sequential rounds of autotetraploidy. We propose that early vertebrates passed through an autoautooctoploid phase in the evolution of their genomes.
The growing geographic disconnect between consumption of goods, the extraction and processing of resources, and the environmental impacts associated with production activities makes it crucial to ...factor global trade into sustainability assessments. Using an empirically validated environmentally extended global trade model, we examine the relationship between two key resources underpinning economies and human well-being—energy and freshwater. A comparison of three energy sectors (petroleum, gas, and electricity) reveals that freshwater consumption associated with gas and electricity production is largely confined within the territorial boundaries where demand originates. This finding contrasts with petroleum, which exhibits a varying ratio of territorial to international freshwater consumption, depending on the origin of demand. For example, although the United States and China have similar demand associated with the petroleum sector, international freshwater consumption is three times higher for the former than the latter. Based on mapping patterns of freshwater consumption associated with energy sectors at subnational scales, our analysis also reveals concordance between pressure on freshwater resources associated with energy production and freshwater scarcity in a number of river basins globally. These energy-driven pressures on freshwater resources in areas distant from the origin of energy demand complicate the design of policy to ensure security of fresh water and energy supply. Although much of the debate around energy is focused on greenhouse gas emissions, our findings highlight the need to consider the full range of consequences of energy production when designing policy.
Patients who are comatose after cardiac arrest continue to be a challenge, with high mortality. Although there is an American College of Cardiology Foundation/American Heart Association Class I ...recommendation for performing immediate angiography and percutaneous coronary intervention (when indicated) in patients with ST-segment elevation myocardial infarction, no guidelines exist for patients without ST-segment elevation. Early introduction of mild therapeutic hypothermia is an established treatment goal. However, there are no established guidelines for risk stratification of patients for cardiac catheterization and possible percutaneous coronary intervention, particularly in patients who have unfavorable clinical features in whom procedures may be futile and affect public reporting of mortality. An algorithm is presented to improve the risk stratification of these severely ill patients with an emphasis on consultation and evaluation of patients prior to activation of the cardiac catheterization laboratory.
Clinical trial registries can improve the validity of trial results by facilitating comparisons between prospectively planned and reported outcomes. Previous reports on the frequency of planned and ...reported outcome inconsistencies have reported widely discrepant results. It is unknown whether these discrepancies are due to differences between the included trials, or to methodological differences between studies. We aimed to systematically review the prevalence and nature of discrepancies between registered and published outcomes among clinical trials.
We searched MEDLINE via PubMed, EMBASE, and CINAHL, and checked references of included publications to identify studies that compared trial outcomes as documented in a publicly accessible clinical trials registry with published trial outcomes. Two authors independently selected eligible studies and performed data extraction. We present summary data rather than pooled analyses owing to methodological heterogeneity among the included studies.
Twenty-seven studies were eligible for inclusion. The overall risk of bias among included studies was moderate to high. These studies assessed outcome agreement for a median of 65 individual trials (interquartile range IQR 25-110). The median proportion of trials with an identified discrepancy between the registered and published primary outcome was 31%; substantial variability in the prevalence of these primary outcome discrepancies was observed among the included studies (range 0% (0/66) to 100% (1/1), IQR 17-45%). We found less variability within the subset of studies that assessed the agreement between prospectively registered outcomes and published outcomes, among which the median observed discrepancy rate was 41% (range 30% (13/43) to 100% (1/1), IQR 33-48%). The nature of observed primary outcome discrepancies also varied substantially between included studies. Among the studies providing detailed descriptions of these outcome discrepancies, a median of 13 % of trials introduced a new, unregistered outcome in the published manuscript (IQR 5-16%).
Discrepancies between registered and published outcomes of clinical trials are common regardless of funding mechanism or the journals in which they are published. Consistent reporting of prospectively defined outcomes and consistent utilization of registry data during the peer review process may improve the validity of clinical trial publications.
This study aims to investigate the influence of dietary education in patients with gout on a stable dose of urate-lowering therapy (ULT).
Males and females aged >18 years with a history of gout, ...receiving an appropriate and stable dose of ULT, were recruited from two tertiary hospitals and randomised into two groups. The control group received basic advice regarding the importance of compliance with therapy and the benefit of weight loss. The intervention group received comprehensive dietary advice based on the British Society of Rheumatology Guidelines. Both groups received education at baseline and 3 months. Serum urate was measured at baseline, 3 months and 6 months, and a questionnaire was completed at baseline and at 6 months. The primary outcome of the study was to compare the change in serum urate between groups.
Thirty patients were recruited into the study. There was no difference in serum urate between the control and intervention group at 6 months (0.29 mmol/L vs 0.29 mmol/L at baseline and 0.27 mmol/L vs 0.30 mmol/L at 6 months). The intervention group showed a statistically significant improvement in knowledge (8/13 in control group at baseline to 9/13 at 6 months vs 8/13 in intervention group at baseline to 12/13 at 6 months, P < 0.05) and self-reported dietary modification (1 in control vs 7 in intervention P < 0.05) at 6 months.
This randomised controlled trial shows that in patients on ULT, providing education on diet does not lead to any clinically significant difference in serum urate at 6 months.
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