Direct evidence of soft mode behavior near the Burns' temperature in PbMg1/3_{1 / 3}Nb2/3_{2 / 3}O3_{3} (PMN) relaxor ferroectric

Inelastic neutron scattering measurements of the relaxor ferroelectric PbMg$_{1 / 3}$Nb$_{2 / 3}$O$_{3}$ (PMN) in the temperature range 490~K$<$T$<$880~K directly observe the soft mode (SM) associated with the Curie-Weiss behavior of the dielectric constant $\varepsilon$(T). The results are treated within the framework of the coupled SM and transverse optic (TO1) mode and the temperature dependence of the SM frequency at q=0.075 a* is determined. The parameters of the SM are consistent with the earlier estimates and the frequency exhibits a minimum near the Burns temperature ($\approx$ 650K)Comment: 6 figure

Organizational and Leadership Implications for Transformational Development

Transformational development is a concept of change that originated in the Christian context but has now become generally used in the work of both secular and faith-based organizations. The growing use of the concept by organizations that are fundamentally different has naturally led to some confusion about what the concept means and what it takes to effectively implement it. In this article, we describe the key features of the concept and how they are important in determining the organizational requirements for its effective implementation. Drawing on a few cases, the paper highlights the centrality of faith in transformational development work

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)

Practical implementation of adaptive optics in multiphoton microscopy

A dedicated two-photon microscope incorporating adaptive-optic correction of specimen-induced aberrations is presented. Wavefront alteration of the scanning laser beam was achieved by use of a micromachined deformable mirror. Post scan head implementation produces a compact module compatible with the Bio-Rad MRC-600 scan head. Automatic aberration correction using feedback from the multiphoton fluorescence intensity allowed the adaptive optic to extend the imaging depth attainable in both artificial and biological refractive-index mismatched samples. With a 1.3-NA, x40, Nikon oil immersion objective, the imaging depth in water was extended from approximately 3.4 to 46.2 µm with a resolution defined by a FWHM axial point-spread function of 1.25 µm

Generalized heteroclinic cycles in spherically invariant systems and their perturbations

In this paper we want to investigate the effects of forced symmetry breaking perturbations, see Lauterbach and Roberts [29], as well as [28, 31], on the heteroclinic cycle which was found in the l=1, l=2 mode interaction by Armbruster and Chossat [1, 12] and generalized by Chossat and Guyard [25, 14]. We show that this cycle is embedded in a larger class of cycles, which we call a generalized heteroclinic cycle (GHC). After describing the structure of this set we discuss its stability. The main problem is to find a selection principle, that is to give a mechanism which enables the physical system to select one particular heteroclinic cycle on this generalized heteroclinic cycle. After that the persistence under symmetry breaking perturbations is investigated. We will discuss also the application to the spherical Benard problem, which was the initial motivation for this work. (orig.)Available from TIB Hannover: RR 5549(303)+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.

Mutations within the NALP3/cryopyrin/CIAS1 gene are responsible for three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. The NALP3 protein is homologous to NALP1, which is a component of the inflammasome, a molecular platform that activates the proinflammatory caspases-1 and -5. NALP3 (and other members of the NALP family) lacks the C-terminal, CARD-containing sequence of NALP1, and its role in caspase activation is unclear. Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. Increased inflammasome activity is therefore likely to be the molecular basis of the symptoms associated with NALP3-dependent autoinflammatory disorders