Abstract
Background
MicroRNAs miRNAs are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease IBD pathogenesis. Here we define ...the cell-specific miRNA profiles and investigate its biomarker potential in IBD.
Methods
In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn’s disease CD, 14 ulcerative colitis UC, eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients 97 UC, 98 CD, 98 non-IBD, 1 IBDU using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards.
Results
In stage 1, each leukocyte subset CD4+ and CD8+ T-cells and CD14+ monocytes was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p p = 0.01, miR-3615 p = 0.02 and miR-4792 p = 0.01. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio HR 1.98, interquartile range IQR: 1.20–3.27; logrank p = 1.80 × 10–3), in particular CD HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met.
Interpretation
We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.
Mating system and effective pollen dispersal were studied in a natural stand of knobcone pine (Pinus attenuata Lemmon.) using 11 isozyme loci. Analyses were performed by fitting neighbourhood and ...mixed-mating models to multilocus genotypic arrays of offspring from four mother trees. Neighbourhoods consisted of all potential outcross males within 11 m of each mother tree (44, on average). Average outcrossing rates of the mother trees were estimated to be 0.97 and 0.96 for the respective models, whereas the population-wide outcrossing rate based on the mixed-mating model and a broader sample of mother trees was 0.92. The estimated proportion of offspring sired by males outside the neighbourhood of each mother tree was 0.56. Thus about 41 per cent of matings resulted from outcrossing with nearby males (within neighbourhoods). Distance and direction of individual males from mother trees and the size (tree height) of males played significant roles in determining outcross mating patterns within neighbourhoods. Male mating success increased with both proximity and tree size, although males east of mother trees accounted for more offspring than males in other directions. Despite the role of proximity, directionality and tree size in determining mating success within neighbourhoods, the effective number of males mating with each female seems to be large.
Plasmacytoid dendritic cells (pDCs) are potent producers of type I IFN (IFN-I) during viral infection and respond to IFN-I in a positive feedback loop that promotes their function. IFN-I shapes ...dendritic cell responses during helminth infection, impacting their ability to support Th2 responses. However, the role of pDCs in type 2 inflammation is unclear. Previous studies have shown that pDCs are dispensable for hepatic or splenic Th2 responses during the early stages of murine infection with the trematode
at the onset of parasite egg laying. However, during
infection, an ongoing Th2 response against mature parasite eggs is required to protect the liver and intestine from acute damage and how pDCs participate in immune responses to eggs and adult worms in various tissues beyond acute infection remains unclear. We now show that pDCs are required for optimal Th2 cytokine production in response to
eggs in the intestinal-draining mesenteric lymph nodes throughout infection and for egg-specific IFN-γ at later time points of infection. Further, pDC depletion at chronic stages of infection led to increased hepatic and splenic pathology as well as abrogated Th2 cell cytokine production and activation in the liver. In vitro, mesenteric lymph node pDCs supported Th2 cell responses from infection-experienced CD4
T cells, a process dependent on pDC IFN-I responsiveness, yet independent of Ag. Together, these data highlight a previously unappreciated role for pDCs and IFN-I in maintaining and reinforcing type 2 immunity in the lymph nodes and inflamed tissue during helminth infection.
Fuck: The Police Adams, Ian T.
Police quarterly,
04/2024
Journal Article
Recenzirano
Odprti dostop
This study focuses on police profanity, with a particular interest developing reasonable policy to regulate the use of the word “fuck.” Officers employ “fuck” as a linguistic tool to accomplish a ...range of goals, such as establishing authority, fostering solidarity, and diffusing tension. However, “fuck” can also be used derogatorily, and negatively impact public assessments of police actions. Policy in this area is either absent, overly broad, or inappropriate to its intended use. Following brief, unstructured interviews with line and executive officers, I propose a novel policy theory of profanity, deriving target and intent. I test the theory with a pre-registered experiment administered to a national sample of police and human resources executives ( n = 1492), with each respondent evaluating multiple vignettes ( n = 5280 observations). Results support the proposed theory and generate useful recommendations for practitioners interested in strengthening the ability of agencies to constrain professionally inappropriate use of profanity in the police workplace.
Objective
To assess long term survival and patient characteristics associated with survival following acute myocardial infarction (AMI) in Australia and New Zealand.
Design
Cohort study.
Setting, ...participants
All patients admitted with AMI (ICD‐10‐AM codes I21.0‒I21.4) to all public and most private hospitals in Australia and New Zealand during 2009‒2015.
Main outcome measure
All‐cause mortality up to seven years after an AMI.
Results
239 402 initial admissions with AMI were identified; the mean age of the patients was 69.3 years (SD, 14.3 years), 154 287 were men (64.5%), and 64 335 had ST‐elevation myocardial infarction (STEMI; 26.9%). 7‐year survival after AMI was 62.3% (STEMI, 70.8%; non‐ST‐elevation myocardial infarction NSTEMI, 59.2%); survival exceeded 85% for people under 65 years of age, but was 17.4% for those aged 85 years or more. 120 155 patients (50.2%) underwent revascularisation (STEMI, 72.2%; NSTEMI, 42.1%); 7‐year survival exceeded 80% for patients in each group who underwent revascularisation, and was lower than 45% for those who did not. Being older (85 years or older v 18–54 years: adjusted hazard ratio aHR, 10.6; 95% CI, 10.1–11.1) or a woman (aHR, 1.15; 95% CI, 1.13–1.17) were each associated with greater long term mortality during the study period, as was prior heart failure (aHR, 1.79; 95% CI, 1.76‒1.83). Several non‐cardiac conditions and geriatric syndromes common in these patients were independently associated with lower long term survival, including major and metastatic cancer, cirrhosis and end‐stage liver disease, and dementia.
Conclusion
AMI care in Australia and New Zealand is associated with high rates of long term survival; 7‐year rates exceed 80% for patients under 65 years of age and for those who undergo revascularisation. Efforts to further improve survival should target patients with NSTEMI, who are often older and have several comorbid conditions, for whom revascularisation rates are low and survival after AMI poor.
Aspergillus nidulans reproduces asexually by forming thousands of mitotically derived spores atop highly specialized multicellular organs termed conidiophores. We have identified a gene called flbA ...(for fluffy low brlA expression) that is required for initiation of A. nidulans conidiophore development. flbA mutants form abnormal colonies that have a distinct fluffy phenotype characterized by tightly interwoven aerial hyphae that autolyse as the colony matures. The requirement for flbA in conidiophore development precedes activation of brlA, a primary regulator of conidiophore development. The wild-type flbA gene was isolated and found to encode a 3.0 kb mRNA that is expressed throughout the A. nidulans asexual life cycle. Overexpression ot flbA using an inducible promoter resulted in misscheduled expression of brlA in vegetative cells and caused hyphal tips to differentiate into spore-producing structures. Sequence analysis of a nearly full-length flbA cDNA clone showed that flbA is predicted to encode a 717-amino-acid polypeptide with 30% identity to the Saccharomyces cerevisiae SST2 proteln. SST2 is required by yeast cells for resuming growth following prolonged exposure to yeast mating pheromone and for mating partner discrimination. We propose that flbA plays a related role in a signalling pathway for Aspergillus conidiophore development.
Transgenic mice expressing simian virus 40 T antigen under control of the insulin gene regulatory region vary in their response to this protein. Each lineage is characteristically either tolerant to ...T antigen, or not, in which case autoantibodies arise with high frequency, and lymphocytes infiltrate and disrupt the pancreatic islets. Both non-tolerance and the autoimmune response appear to result from delayed onset of T antigen expression during beta cell development.
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