37 research outputs found
Gut mucosal DAMPs in IBD: From mechanisms to therapeutic implications
Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation. </p
Lawson criterion for ignition exceeded in an inertial fusion experiment
For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37Â MJ of fusion for 1.92Â MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion
Mitochondrial damage-associated molecular patterns (DAMPs) in inflammatory bowel disease
Background
The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s
disease (CD) are chronic relapsing inflammatory disorders which have a rising
incidence and cause significant morbidity. There are currently several
treatment options with many more in the drug pipeline, but there are a lack of
accurate biomarkers for decisions on treatment choice, assessment of disease
activity and prognostication. There is a growing interest and desire for
personalised or ‘precision’ medicine in IBD where novel biomarkers may help
individualise IBD care in terms of diagnosis, choice of therapy, monitoring of
response and detection of relapse. One class of functionally active biomarkers
which have yet to be thoroughly investigated in IBD is damage-associated
molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). It has
been recently shown that gut mitochondrial dysfunction can result in loss of
epithelial barrier function and the development of colitis. Mitochondrial DAMPs
have recently been described as elevated in several inflammatory diseases.
Hypothesis
The primary hypothesis of this thesis is that circulating levels of mtDNA is
elevated in IBD. Secondary hypotheses are: (a) levels of other mitochondrial
DAMPs are elevated in IBD, (b) circulating mtDNA can be used as a novel
biomarker in IBD and (c) mtDNA is released locally at sites of inflammation in
IBD.
Methods
Plasma and serum were collected prospectively from recruited IBD patients
and non-IBD controls. Faeces and colonic tissue were collected from a subset
of these patients. mtDNA in serum, plasma and faeces was measured using
qPCR (amplifying COXIII/ND2 genes). Mass spectrometry was used to detect
mitochondrial formylated peptides in the plasma of a subset of patients. IBD
tissue was assessed for (a) mitochondrial damage using transmission electron
microscopy (TEM) and (b) TLR9 expression, the target for mtDNA.
Results
97 patients with IBD (67 UC and 30 CD), and 40 non-IBD controls were
recruited. Plasma mtDNA levels were increased in UC and CD (both p<0.0001)
compared to non-IBD controls; with significant correlations with blood (CRP,
albumin, white cell count), clinical and endoscopic markers of severity; and
disease activity. In active UC, we detected significantly higher circulating
mitochondrial formylated peptides and faecal mtDNA levels (vs. non-IBD
controls [p<0.01 and <0.0001 respectively]) with demonstrable TEM evidence
of intestinal mucosal mitochondrial damage. In active IBD, TLR9+ lamina
propria inflammatory cells were significantly higher in UC/CD compared to
controls (both p<0.05).
Conclusions
Taken together, the findings suggest mtDNA is released during active
inflammation in inflammatory bowel disease and is a potential novel
mechanistic biomarker
Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases
Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases