Structural States of Hdm2 and HdmX: X-ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes

Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53–Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Herein we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds (including the worldwide highest resolutions for Hdm2 and HdmX, at 1.13 and 1.20 Å, respectively). We also reveal the key additive 18-crown-ether, which we discovered to enable HdmX crystallization and show its stabilization of various Lys residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insight into the possible adaptations and structural states of Hdm2 (e.g., flip of F55, flip of Y67, reorientation of H96) and HdmX (e.g., flip of H55, dimer induction), enabling key binding interactions for different compound classes. To facilitate comparisons, we used the same numbering for Hdm2 (as in Q00987) and HdmX (as in O15151, but minus 1). Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors.     

INTEGRAL EQUATION APPEOACH FOZ SIHULATION-OF - HEAT AND MASS TRANSFER PROCESSES

An integral equation approach was recommended for modelling and simulation of heat and mass transfer processes. It was shown that several mixing models that have been dealt with up to now dlfferently, can be unified in a single integral equation. An effective numerical method was developed for the solution of non-linear integral equation. A construction method for the source and kernel functions were lntroduced in connection with the simulation and control of heat treatlng processes taking place in tunnel kiln and heat and mass transfer processes in tunnel dryer.

We have concluded that our method is advantageous If the slmulated process 1s slgnlficantly affected by the degree of mixing and/or the kernel function can be determined by direct measurement of the streaming phases including feedback, recirculation etc.     

Detection and identification of microcystins in the drinking water of Haimen City, China

The main method of classification of chronic viral hepatitis is now by cause, and the old histology-based classification is no longer considered appropriate. However, liver biopsy remains an important part of patient assessment and, in the context of clinical trials, biopsy findings are often scored in a semiquantitative manner. The concepts of grading and staging, borrowed from tumour pathology, have been introduced, representing the severity of the necroinflammatory lesion and the extent of its structural consequences respectively. The pathology of the individual forms of viral hepatitis A to G shows more similarities than differences. However, some pathological features are commonly associated with specific viruses. The combination of portal lymphoid follicles, bile duct damage, lobular activity and steatosis give chronic hepatitis C a characteristic histological profile. Very similar appearances have been noted in the limited number of biopsies so far reported from patients with known combined hepatitis C and G virus infection.     

Surface segregation in FeTi and its catalytic effect on the hydrogenation

We explain the irreversible change of the magnetic properties of FeTi upon hydrogenation, the activation process and some surface properties of FeTi by surface segregation. In a surface layer Ti diffuses to the surface and Fe forms magnetic precipitations which probably catalyze the hydrogenation. The catalytically active surface is renewed with each cycle of hydrogenation.     

Assessment of adherence with multiple informants in pre-adolescents with spina bifida: initial development of a multidimensional, multitask parent-report questionnaire

Long-term acute care and subacute care facilities (also transitional care facilities) have evolved from the need to decrease costs associated with acute care in the hospital. As the length of stay in many medical centers has been reduced, patients are admitted to transitional care facilities to continue recovery and rehabilitation. Rehabilitation and recovery can be enhanced with the provision of optimal medical nutrition therapy. Nutrition screening is essential in identifying patients who are at risk of malnutrition or are malnourished. Nutrition assessment verifies the risk or presence of malnutrition followed by the development, implementation, and monitoring of nutrition intervention. Nutrition screening and intervention promote recovery from illness, minimize morbidity and mortality, and enhance quality of life. The goals of nutrition support are to prevent starvation-associated malnutrition, preserve lean tissue mass, support metabolic functions, and improve clinical outcomes. Oral nutrition is the preferred method of nourishment; however, specialized nutrition support is considered for patients unable to meet their nutrient requirements adequately. Enteral nutrition support is recommended when providing nutrition support however, parenteral nutrition support is used when the gastrointestinal tract can not be safely used. With appropriate intention, administration, and monitoring, nutrition support can be safely administered.     

Plasma Treatment of Polyacetal-Copolymer, Polycarbonate, Polybutylene terephthalate and Nylon 6, 6 Surfaces to Improve the Adhesion of Ink

Polyacetal-copolymer (POMB), polycarbonate (PC), polybutylene terephthalate (PBT), and nylon 6, 6 (PA6, 6) have been treated in an electron cyclotron resonance (ECR) plasma chamber to improve their adhesion properties towards ink. The chemical composition, the surface free energy, and the macroscopic adhesion have been studied by X-ray photoelectron spectroscopy (XPS), contact angle measurements, cross-cut tests, and the Scotch Tape test. Their dependence on the neutral gas, the treatment time, the pressure, and the ageing in air have been investigated. The XPS results reveal that the plasma treatment allows one to clean the surface and, if reactive gases are used, to incorporate new chemical species. The static and dynamic contact angles decrease with the plasma treatment and continue to decrease after contact with air. Very slow hydrophobic recovery is visible in the advancing contact angle, whereas the receding contact angle remains non-measurable even after more than a week of air exposure. Lower pressures and longer treatment times (120 s) lead to better macroscopic adhesion and reproducibility. For optimal treatment conditions (0.5 Pa, 120s N₂ plasma treatment time), the improvement of the adhesion remains excellent after seven days exposure of the sample in air.