Laser-induced Gratings in Eu3+- Glasses

Physic

Properties and Applications of Laser Induced Gratings in Rare Earth Doped Glasses

Physic

A micro-volume adaptation of a stopped-flow system; use with μg quantities of muscle proteins

Stopped-flow spectroscopy is a powerful method for measuring very fast biological and chemical reactions. The technique however is often limited by the volumes of reactants needed to load the system. Here we present a simple adaptation of commercial stopped-flow system that reduces the volume needed by a factor of 4 to ≈120 μl. After evaluation the volume requirements of the system we show that many standard myosin based assays can be performed using <100 μg of myosin. This adaptation both reduces the volume and therefore mass of protein required and also produces data of similar quality to that produced using the standard set up. The 100 μg of myosin required for these assays is less than that which can be isolated from 100 mg of muscle tissue. With this reduced quantity of myosin, assays using biopsy samples become possible. This will allow assays to be used to assist diagnoses, to examine the effects of post translational modifications on muscle proteins and to test potential therapeutic drugs using patient derived samples

Disruption of IL-33 Signaling Limits Early CD8+ T Cell Effector Function Leading to Exhaustion in Murine Hemophagocytic Lymphohistiocytosis

Danger signals mediated through ST2, the interleukin-33 (IL-33) receptor, amplify CD8+ T cell-mediated inflammation in the murine model of familial hemophagocytic lymphohistiocytosis type 2 (FHL2), and blockade of ST2 provides a potential therapeutic strategy in this disease. However, the long-term effects of disrupting IL-33/ST2 signaling on the CD8+ T cell compartment are unknown. Here, we examined the evolution of the T cell response in murine FHL type 2 in the absence of ST2 signaling and found that CD8+ T cells gradually undergo exhaustion, similar to a related nonfatal FHL model. ST2 inhibition indirectly promotes CD8+ T cell exhaustion, and in contrast to other forms of FHL, reversal of exhaustion does not affect mortality. Disruption of IL-33 signaling exerts a more significant impact on the CD8+ T cell compartment early in the course of disease by intrinsically limiting CD8+ T cell proliferative and cytokine production capacity. Our data thus suggest that while ST2 blockade ultimately enables the development of CD8+ T cell exhaustion in late-stage murine FHL2, exhaustion is merely an effect, rather than the cause, of extended survival in these mice. The acute impact of ST2 inhibition on both the quantity and quality of the effector CD8+ T cell response more likely underlies the protective benefits of this treatment. This study provides evidence that redefines the relationship between CD8+ T cell exhaustion and mortality in murine FHL and supports the therapeutic use of ST2 blockade during the acute stage of disease

Personal non-commercial use only

ABSTRACT. Objective. Macrophage activation syndrome (MAS) is a well described, but purportedly uncommon manifestation of systemic juvenile idiopathic arthritis (SJIA). There is evidence to suggest that macrophage activation is integral to the pathogenesis of SJIA. Accordingly, many patients with SJIA may have evidence of mild MAS that is not appreciated clinically. We investigated the prevalence of occult MAS in children with SJIA by reviewing bone marrow aspirates (BMA). Methods. Patients diagnosed with SJIA who underwent bone marrow aspiration were identified retrospectively. Patients admitted with a diagnosis of fever of unknown origin and discharged with a diagnosis other than SJIA or malignancy, and who had a BMA, were identified as controls. The BMA were reviewed by a single hematopathologist for evidence of MAS, ranging from activated macrophages to frank hemophagocytic cells. Results. Eight of 15 (53%) patients with SJIA had BMA suggestive of MAS. Two of 15 patients (13%) were diagnosed clinically with MAS. Three patients (20%) were noted to have frank hemophagocytosis, only one of whom was diagnosed with MAS clinically. There were no statistically significant differences in the laboratory values for the patients with and without evidence of MAS on BMA. There was no evidence of increased macrophage activity or hemophagocytosis in any of the control BMA. Conclusion. Occult MAS appears to be common in patients with SJIA who undergo BMA. This suggests that macrophage activation may be integral to the pathogenesis of SJIA, with implications for treatment. (First Releas

Hexacoordinate Ru-based olefin metathesis catalysts with pH-responsive N-heterocyclic carbene (NHC) and N-donor ligands for ROMP reactions in non-aqueous, aqueous and emulsion conditions

Three new ruthenium alkylidene complexes (PCy3)Cl2(H2ITap)Ru=CHSPh (9), (DMAP)2Cl2(H2ITap)Ru=CHPh (11) and (DMAP)2Cl2(H2ITap)Ru=CHSPh (12) have been synthesized bearing the pH-responsive H2ITap ligand (H2ITap = 1,3-bis(2’,6’- dimethyl-4’-dimethylaminophenyl)-4,5-dihydroimidazol-2-ylidene). Catalysts 11 and 12 are additionally ligated by two pH-responsive DMAP ligands. The crystal structure was solved for complex 12 by X-ray diffraction. In organic, neutral solution, the catalysts are capable of performing standard ring-opening metathesis polymerization (ROMP) and ring closing metathesis (RCM) reactions with standard substrates. The ROMP with complex 11 is accelerated in the presence of two equiv of H3PO4, but is reduced as soon as the acid amount increased. The metathesis of phenylthiomethylidene catalysts 9 and 12 is sluggish at room temperature, but their ROMP can be dramatically accelerated at 60 °C. Complexes 11 and 12 are soluble in aqueous acid. They display the ability to perform RCM of diallylmalonic acid (DAMA), however, their conversions are very low amounting only to few turnovers before decomposition. However, both catalysts exhibit outstanding performance in the ROMP of dicyclopentadiene (DCPD) and mixtures of DCPD with cyclooctene (COE) in acidic aqueous microemulsion. With loadings as low as 180 ppm, the catalysts afforded mostly quantitative conversions of these monomers while maintaining the size and shape of the droplets throughout the polymerization process. Furthermore, the coagulate content for all experiments staye

Histopathologic Response Criteria Predict Survival of Patients with Resected Lung Cancer After Neoadjuvant Chemotherapy

Introduction:We evaluated the ability of histopathologic response criteria to predict overall survival (OS) and disease-free survival (DFS) in patients with surgically resected non-small cell lung cancer (NSCLC) treated with or without neoadjuvant chemotherapy.Methods:Tissue specimens from 358 patients with NSCLC were evaluated by pathologists blinded to the patient treatment and outcome. The surgical specimens were reviewed for various histopathologic features in the tumor including percentage of residual viable tumor cells, necrosis, and fibrosis. The relationship between the histopathologic findings and OS was assessed.Results:The percentage of residual viable tumor cells and surgical pathologic stage were associated with OS and DFS in 192 patients with NSCLC receiving neoadjuvant chemotherapy in multivariate analysis (p = 0.005 and p = 0.01, respectively). There was no association of OS or DFS with percentage of viable tumor cells in 166 patients with NSCLC who did not receive neoadjuvant chemotherapy (p = 0.31 and p = 0.45, respectively). Long-term OS and DFS were significantly prolonged in patients who had ⩽10% viable tumor compared with patients with >10% viable tumor cells (5 years OS, 85% versus 40%, p < 0.0001 and 5 years DFS, 78% versus 35%, p < 0.001).Conclusion:The percentages of residual viable tumor cells predict OS and DFS in patients with resected NSCLC after neoadjuvant chemotherapy even when controlled for pathologic stage. Histopathologic assessment of resected specimens after neoadjuvant chemotherapy could potentially have a role in addition to pathologic stage in assessing prognosis, chemotherapy response, and the need for additional adjuvant therapies