Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction ...has been implicated but the mechanism not established.
We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis.
MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished.
This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease.
C-type lectin receptor (CLR) agonists emerged as superior inducers of primary B cell responses in early life compared with Toll-like receptor (TLR) agonists, while both types of adjuvants are potent ...in adults.
Here, we explored the mechanisms accounting for the differences in neonatal adjuvanticity between a CLR-based (CAF
01) and a TLR4-based (GLA-SE) adjuvant administered with influenza hemagglutinin (HA) in neonatal mice, by using transcriptomics and systems biology analyses.
On day 7 after immunization, HA/CAF01 increased IL6 and IL21 levels in the draining lymph nodes, while HA/GLA-SE increased IL10. CAF01 induced mixed Th1/Th17 neonatal responses while T cell responses induced by GLA-SE had a more pronounced Th2-profile. Only CAF01 induced T follicular helper (Tfh) cells expressing high levels of IL21 similar to levels induced in adult mice, which is essential for germinal center (GC) formation. Accordingly, only CAF01- induced neonatal Tfh cells activated adoptively transferred hen egg lysozyme (HEL)-specific B cells to form HEL
GC B cells in neonatal mice upon vaccination with HEL-OVA.
Collectively, the data show that CLR-based adjuvants are promising neonatal and infant adjuvants due to their ability to harness Tfh responses in early life.
The authors describe in detail the basic concepts of the design, the composition of the data flow, and the tools developed to monitor the trigger in real time. The results of the trigger performance ...in terms of efficiencies achieved during the first two and a half years of operation in the LEP (Large Electron Positron Collider) machine are also shown. So far, a total of approximately 10/sup 6/ hadronic Z/sup 0/s have been collected from 21 million recorded events. The DELPHI trigger system provides an efficiency nearly 100% over the covered solid angle for all particles and physical channels. The system has also proved to be stable despite very different beam conditions. This is a consequence of the high redundancy provided by the different detectors for all e/sup +/e/sup -/ final state processes, which also ensures a method for calculating the absolute trigger efficiencies using data only.< >
Delphi (DEtector with Lepton, Photon and Hadron Identification) is one of the four experiment of the LEP (Large Electron Positron) collider at CERN. The detector is laid out to provide a nearly 4/spl ...pi/ coverage for charged particle tracking, electromagnetic, hadronic calorimetry and extended particle identification. The trigger system consists of four levels. The first two are synchronous with the BCO (Beam Cross Over) and rely on hard-wired control units, while the last two are performed asynchronously with respect to the BCO and are driven by the Delphi host computers. The aim of this paper is to give a comprehensive global view of the trigger system architecture presenting, in detail the first two levels, their various hardware components and the latest modifications introduced in order to improve their performance and make more user friendly the whole software user interface.< >
Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic ...penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A.
Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS< or = 18 ms; QRS in wild-type littermates: 10-18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a(+/-) mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones.
Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present a review of experimental and theoretical results on the nucleation and growth of single-walled nanotubes, with particular emphasis on the growth of nanotube bundles emerging from catalyst ...particles obtained from evaporation-based elaboration techniques. General results are first discussed. Experiments strongly suggest a root-growth process in which carbon, dissolved at high temperatures in catalytic particles, segregates at the surface at lower temperatures to form tube embryos and finally nanotubes through a nucleation and growth process. A theoretical analysis of the reasons carbon does not always form graphene sheets to wrap the particles suggests analogies with other surface or interface instabilities, in particular, with those found in epitaxial growth. In the second part, detailed experimental results for nickel-rare earth metal catalysts are presented. By using various electron microscopy techniques, it is shown that carbon and the rare earth metal co-segregate at the surface of the particle and form carbide platelets, providing nucleation sites for nanotubes growing in directions perpendicular to the surface. A simple theoretical model is then presented in which the role of the rare earth metal is just to transfer electrons from metal to carbon. The graphene sheet is shown to become unstable; pentagons and heptagons are favored, which can explain the occurrence of local curvatures and of tube embryos. Finally, a brief discussion of some recent atomistic models is given.
In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best-characterized target PPARγ have been proposed ...as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated nonmalignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. Although studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious.
These findings uncover a novel mechanism by which the thiazolidinedione compound rosiglitazone contributes to tumorigenesis, thus highlighting a potential risk associated with its use in patients with established tumors.
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