Active Crack Obstruction Mechanisms in Crofer® 22H at 650 °C.

Increased cyclic loading of components and materials in future thermal energy conversion systems necessitates novel materials of increased fatigue resistance. The widely used 9-12% Cr steels were developed for high creep strength and thus base load application at temperatures below 620 °C. At higher temperature, these materials present unstable grain structure, prone to polygonization under thermomechanical fatigue loading and limited resistance to steam oxidation. This seminal study compares thermomechanical fatigue resistance and long crack propagation of the advanced ferritic-martensitic steel grade 92 and Crofer® 22H, a fully ferritic, high chromium (22 wt. %) stainless steel, strengthened by Laves phase precipitation. Crofer® 22H features increased resistance to fatigue and steam oxidation resistance up to 650 °C. Both thermomechanical fatigue (crack initiation) and residual (crack propagation) lifetime of Crofer® 22H exceeded that of grade 92. The main mechanisms for improved performance of Crofer® 22H were increased stability of grain structure and "dynamic precipitation strengthening" (DPS). DPS, i.e., thermomechanically triggered precipitation of Laves phase particles and crack deflection at Laves phase-covered sub-grain boundaries, formed in front of crack tips, actively obstructed crack propagation in Crofer® 22H. In addition, it is hypothesized that local strengthening may occur near the crack tip because of grain refinement, which in turn may be impacted by testing frequency.

Relationship between transitional objects and personality disorders in female psychiatric inpatients: a prospective study.

Patients often bring transitional objects (TO) to inpatient units. The authors quantified the frequency of TO possession in an inpatient psychiatric setting and assessed whether TO use is specific to a personality disorder (PD) diagnosis, focusing on borderline PD (BPD). TO possession was assessed using the Transitional Objects Questionnaire, and PD diagnosis was established using standard DSM-IV clinical interviews. Of the 104 female patients assessed, 57.7% showed TO use; 84% of BPD patients, 71% of BPD-trait patients, 65% of patients with PD traits (other than BPD), and 56% of PD patients (other than BPD) displayed TO use, whereas 30.6% of patients without PD showed TO use. Patients with TOs were significantly younger and had significantly longer hospital stays. The specificity and sensitivity for TO use in the BPD group were 0.506 and 0.84, respectively. The authors conclude that TO use is closely related to PD diagnosis, but is not specific to BPD.

IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: long term results of an ISIORT pooled analysis.

PURPOSE: Linac-based intraoperative radiotherapy with electrons (IOERT) was implemented to prevent local recurrences after breast conserving therapy (BCT) and was delivered as an intraoperative boost to the tumor bed prior to whole breast radiotherapy (WBI). A collaborative analysis has been performed by European ISIORT member institutions for long term evaluation of this strategy. MATERIAL AND METHODS: Until 10/2005, 1109 unselected patients of any risk group have been identified among seven centers using identical methods, sequencing and dosage for intra- and postoperative radiotherapy. A median IOERT dose of 10 Gy was applied (90% reference isodose), preceding WBI with 50-54 Gy (single doses 1.7-2 Gy). RESULTS: At a median follow up of 72.4 months (0.8-239), only 16 in-breast recurrences were observed, yielding a local tumor control rate of 99.2%. Relapses occurred 12.5-151 months after primary treatment. In multivariate analysis only grade 3 reached significance (p=0.031) to be predictive for local recurrence development. Taking into account patient age, annual in-breast recurrence rates amounted 0.64%, 0.34%, 0.21% and 0.16% in patients <40 years; 40-49 years; 50-59 years and ≥ 60 years, respectively. CONCLUSION: In all risk subgroups, a 10 Gy IOERT boost prior to WBI provided outstanding local control rates, comparing favourably to all trials with similar length of follow up.

Structural features and domain organization of huntingtin fibrils.

Misfolding and aggregation of huntingtin is one of the hallmarks of Huntington disease, but the overall structure of these aggregates and the mechanisms by which huntingtin misfolds remain poorly understood. Here we used site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy to study the structural features of huntingtin exon 1 (HDx1) containing 46 glutamine residues in its polyglutamine (polyQ) region. Despite some residual structuring in the N terminus, we find that soluble HDx1 is highly dynamic. Upon aggregation, the polyQ domain becomes strongly immobilized indicating significant tertiary or quaternary packing interactions. Analysis of spin-spin interactions does not show the close contact between same residues that is characteristic of the parallel, in-register structure commonly found in amyloids. Nevertheless, the same residues are still within 20 Å of each other, suggesting that polyQ domains from different molecules come into proximity in the fibrils. The N terminus has previously been found to take up a helical structure in fibrils. We find that this domain not only becomes structured, but that it also engages in tertiary or quaternary packing interactions. The existence of spin-spin interactions in this region suggests that such contacts could be made between N-terminal domains from different molecules. In contrast, the C-terminal domain is dynamic, contains polyproline II structure, and lacks pronounced packing interactions. This region must be facing away from the core of the fibrils. Collectively, these data provide new constraints for building structural models of HDx1 fibrils.

Characterisation of the passive permeability barrier of nuclear pore complexes.

Nuclear pore complexes (NPCs) restrict uncontrolled nucleocytoplasmic fluxes of inert macromolecules but permit facilitated translocation of nuclear transport receptors and their cargo complexes. We probed the passive barrier of NPCs and observed sieve-like properties with a dominating mesh or channel radius of 2.6 nm, which is narrower than proposed earlier. A small fraction of diffusion channels has a wider opening, explaining the very slow passage of larger molecules. The observed dominant passive diameter approximates the distance of adjacent hydrophobic clusters of FG repeats, supporting the model that the barrier is made of FG repeat domains cross-linked with a spacing of an FG repeat unit length. Wheat germ agglutinin and the dominant-negative importin beta(45-462) fragment were previously regarded as selective inhibitors of facilitated NPC passage. We now observed that they do not distinguish between the passive and the facilitated mode. Instead, their inhibitory effect correlates with the size of the NPC-passing molecule. They have little effect on small species, inhibit the passage of green fluorescent protein-sized objects >10-fold and virtually block the translocation of larger ones. This suggests that passive and facilitated NPC passage proceed through one and the same permeability barrier.

Annexin B12 is a sensor of membrane curvature and undergoes major curvature-dependent structural changes.

The regulation of membrane curvature plays an important role in many membrane trafficking and fusion events. Recent studies have begun to identify some of the proteins involved in controlling and sensing the curvature of cellular membranes. A mechanistic understanding of these processes is limited, however, as structural information for the membrane-bound forms of these proteins is scarce. Here, we employed a combination of biochemical and biophysical approaches to study the interaction of annexin B12 with membranes of different curvatures. We observed selective and Ca(2+)-independent binding of annexin B12 to negatively charged vesicles that were either highly curved or that contained lipids with negative intrinsic curvature. This novel curvature-dependent membrane interaction induced major structural rearrangements in the protein and resulted in a backbone fold that was different from that of the well characterized Ca(2+)-dependent membrane-bound form of annexin B12. Following curvature-dependent membrane interaction, the protein retained a predominantly alpha-helical structure but EPR spectroscopy studies of nitroxide side chains placed at selected sites on annexin B12 showed that the protein underwent inside-out refolding that brought previously buried hydrophobic residues into contact with the membrane. These structural changes were reminiscent of those previously observed following Ca(2+)-independent interaction of annexins with membranes at mildly acidic pH, yet they occurred at neutral pH in the presence of curved membranes. The present data demonstrate that annexin B12 is a sensor of membrane curvature and that membrane curvature can trigger large scale conformational changes. We speculate that membrane curvature could be a physiological signal that induces the previously reported Ca(2+)-independent membrane interaction of annexins in vivo.

Critical appraisal of primary systemic endocrine therapy in receptor-positive postmenopausal breast cancer: an update.

Even in elderly patients, greater consideration is now being given to tumor volume reduction in locally advanced breast cancer, with increased subsequent breast-conserving surgery. Neoadjuvant endocrine therapy offers the possibility of testing therapeutic efficacy in vivo, which is of great importance for optimal adjuvant treatment. Resulting therapy modifications can be expected to increase disease-free as well as overall survival. Recent results indicate that remission rates with primary chemotherapy are significantly lower in receptor-positive than in receptor-negative breast cancer and that efficacy parameters in receptor-positive tumors tend to favor primary endocrine therapy, highlighting the increased importance of this type of treatment. Aromatase inhibitors are superior to tamoxifen in terms of clinical response as well as breast conservation rate. Results from a small number of studies suggest that prolonged preoperative aromatase inhibitor therapy for up to 12 months can increase the rate of clinical and pathological complete remissions. In conclusion, primary endocrine therapy is a valid therapeutic option for postmenopausal patients with locally advanced hormone receptor-positive breast cancer and significant comorbidity, increased risk of complications with regard to anesthesia and surgery, desire for breast-conserving surgery and/or reduced suitability for chemotherapy, as well as in very old patients.

Ca2+-myristoyl switch in the neuronal calcium sensor recoverin requires different functions of Ca2+-binding sites.

Recoverin is an EF-hand Ca(2+)-binding protein that is suggested to control the activity of the G-protein-coupled receptor kinase GRK-1 or rhodopsin kinase in a Ca(2+)-dependent manner. It undergoes a Ca(2+)-myristoyl switch when Ca(2+) binds to EF-hand 2 and 3. We investigated the mechanism of this switch by the use of point mutations in EF-hand 2 (E85Q) and 3 (E121Q) that impair their Ca(2+) binding. EF-hand 2 and 3 display different properties and serve different functions. Binding of Ca(2+) to recoverin is a sequential process, wherein EF-hand 3 is occupied first followed by the filling of EF-hand 2. After EF-hand 3 bound Ca(2+), the subsequent filling of EF-hand 2 triggers the exposition of the myristoyl group and in turn binding of recoverin to membranes. In addition, EF-hand 2 controls the mean residence time of recoverin at membranes by decreasing the dissociation rate of recoverin from membranes by 10-fold. We discuss this mechanism as one critical step for inhibition of rhodopsin kinase by recoverin.