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"Macdonald, T"
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Immunity, Inflammation, and Allergy in the Gut
The gut immune system has the challenge of responding to pathogens while remaining relatively unresponsive to food antigens and the commensal microflora. In the developed world, this ability appears to be breaking down, with chronic inflammatory diseases of the gut commonplace in the apparent absence of overt infections. In both mouse and man, mutations in genes that control innate immune recognition, adaptive immunity, and epithelial permeability are all associated with gut inflammation. This suggests that perturbing homeostasis between gut antigens and host immunity represents a critical determinant in the development of gut inflammation and allergy.
Journal Article
Nitrogen uptake preference of cotton (Gossypium hirsutum L.)
Low molecular weight (LMW) soil organic nitrogen (N) can be a significant source of N in commercial cotton (Gossypium hirsutum L.) systems, potentially comprising a meaningful portion of N uptake in Australian irrigated cotton. Cotton obtains the majority of its N from the soil N pool rather than directly from fertiliser-N. Organic N is the major component of the soil N pool. The purpose of this study was to test the ability of G. hirstutum to take up different organic and inorganic N forms using isotopically labelled compounds. This was done in a sand matrix to reduce potential for microbial competition and enable a clearer view of the physiological capacity of the plant to access different N forms. The experiment showed that cotton took up inorganic N (NO3- and NH4+) and organic N (alanine and urea) concurrently, with a slight preference towards inorganic N overall. The uptake mechanism for organic carbon (C) associated with the organic N was also examined, showing that alanine-C was taken up linearly, with a consistent internal 13C:15N ratio suggesting that some alanine was absorbed intact without extracellular deamination. Overall, the experiment demonstrated that G. hirsutum can rapidly and concurrently access different soil N pools, with a slight preference for inorganic N. The uptake mechanisms for organic N and C are complex, differing between compound types, and warrant further investigation. This study expands the list of plants known to utilise organic N to include commercial cotton, with implications for the management of N fertiliser in cotton growing systems.
Journal Article
Can probiotics modulate human disease by impacting intestinal barrier function?
Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chemical and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is one of the major aetiological factors associated with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotising enterocolitis, irritable bowel syndrome and inflammatory bowel disease. The notion that specific probiotic bacterial strains can affect barrier integrity fuelled research in which in vitro cell lines, animal models and clinical trials are used to assess whether probiotics can revert the diseased state back to homeostasis and health. This review catalogues and categorises the lines of evidence available in literature for the role of probiotics in epithelial integrity and, consequently, their beneficial effect for the reduction of gastrointestinal disease symptoms.
Journal Article
Rapid acquisition and model-based analysis of cell-free transcription–translation reactions from nonmodel bacteria
Native cell-free transcription–translation systems offer a rapid route to characterize the regulatory elements (promoters, transcription factors) for gene expression from nonmodel microbial hosts, which can be difficult to assess through traditional in vivo approaches. One such host, Bacillus megaterium, is a giant Gram-positive bacterium with potential biotechnology applications, although many of its regulatory elements remain uncharacterized. Here, we have developed a rapid automated platform for measuring and modeling in vitro cell-free reactions and have applied this to B. megaterium to quantify a range of ribosome binding site variants and previously uncharacterized endogenous constitutive and inducible promoters. To provide quantitative models for cell-free systems, we have also applied a Bayesian approach to infer ordinary differential equation model parameters by simultaneously using time-course data from multiple experimental conditions. Using this modeling framework, we were able to infer previously unknown transcription factor binding affinities and quantify the sharing of cell-free transcription–translation resources (energy, ribosomes, RNA polymerases, nucleotides, and amino acids) using a promoter competition experiment. This allows insights into resource limiting-factors in batch cell-free synthesis mode. Our combined automated and modeling platform allows for the rapid acquisition and model-based analysis of cell-free transcription–translation data from uncharacterized microbial cell hosts, as well as resource competition within cell-free systems, which potentially can be applied to a range of cell-free synthetic biology and biotechnology applications.
Journal Article
Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth
Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of STAT3/NF-kB-activating cytokines in the neoplastic areas. These data suggest that strategies aimed at the cotargeting of STAT3/NF-kB activation and interaction between them might represent an attractive and novel approach to combat CRC.
Journal Article
Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2
+
neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2
+
neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention.
Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.
Journal Article
Differential regulation of interleukin 17 and interferon γ production in inflammatory bowel disease
Background and Aims:Interleukin 17 (IL17) is now known to be involved in a number of chronic inflammatory disorders. However, the mechanisms regulating its production in inflammatory bowel disease (IBD) are still unclear.Methods:Endoscopic biopsies or surgical specimens were taken from inflamed and uninflamed colonic mucosa of 72 patients with IBD (38 with Crohn’s disease and 34 with ulcerative colitis), and normal colon of 38 control subjects. IL17 and interferon γ (IFNγ) were detected by ELISA in the supernatants of biopsies cultured ex vivo, and anti-CD3/CD28-stimulated lamina propria mononuclear cells (LPMCs) incubated with IL12, IL23, IL1β plus IL6, transforming growth factor β1 (TGFβ1), or anti-IL21 neutralising antibody. Intracellular flow cytometry was performed to analyse mucosal Th17 and Th1/Th17 cells.Results:IL17 production by organ culture biopsies was higher in IBD inflamed mucosa than IBD uninflamed mucosa and controls, and was equivalent in amount to IFNγ. Anti-CD3/CD28-stimulated IBD LPMCs produced higher IL17 amounts compared to controls. The percentages of Th17 and Th1/Th17 cells were increased in patients with IBD. IL23 and IL1β plus IL6 had no effect on IBD LPMC production of IL17; however, IL12 markedly increased IFNγ production and decreased IL17 production. TGFβ1 dose-dependently decreased IFNγ, but had no significant inhibitory effect on IL17 production. Blocking IL21 significantly downregulated IL17 production.Conclusions:Our findings support a role for IL12, TGFβ and IL21 in modulating IL17/IFNγ production in IBD. The abundant IL17 in inflamed IBD mucosa may help explain the relative lack of efficacy of anti-IFNγ antibodies in clinical trials of Crohn’s disease.
Journal Article
Incidence and prevalence of multiple sclerosis in the UK 1990–2010: a descriptive study in the General Practice Research Database
Objectives To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. Design A descriptive study. Setting The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. Main outcome measures Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. Results The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. Conclusions We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.
Journal Article