Absolute configuration and conformation of the pure opioid antagonist (+)-2,9 alpha-dimethyl-5-(m-hydroxyphenyl)morphan.

(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program.     

Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta

In the large arteries, it is believed that elastin provides the resistance to stretch at low pressure, while collagen provides the resistance to stretch at high pressure. It is also thought that elastin is responsible for the low energy loss observed with cyclic loading. These tenets are supported through experiments that alter component amounts through protease digestion, vessel remodeling, normal growth, or in different artery types. Genetic engineering provides the opportunity to revisit these tenets through the loss of expression of specific wall components. We used newborn mice lacking elastin (Eln^−/−) or two key proteins (lysyl oxidase, Lox^−/−, or fibulin-4, Fbln4^−/−) that are necessary for the assembly of mechanically-functional elastic fibers to investigate the contributions of elastic fibers to large artery mechanics. We determined component content and organization and quantified the nonlinear and viscoelastic mechanical behavior of Eln^−/−, Lox^−/−, and Fbln4^−/− ascending aorta and their respective controls. We confirmed that the lack of elastin, fibulin-4, or lysyl oxidase leads to absent or highly fragmented elastic fibers in the aortic wall and a 56–97% decrease in crosslinked elastin amounts. We found that the resistance to stretch at low pressure is decreased only in Eln^−/− aorta, confirming the role of elastin in the nonlinear mechanical behavior of the aortic wall. Dissipated energy with cyclic loading and unloading is increased 53–387% in Eln^−/−, Lox^−/−, and Fbln4^−/− aorta, indicating that not only elastin, but properly assembled and crosslinked elastic fibers, are necessary for low energy loss in the aorta.     

Simulation of protein misfolding using a lattice model

The structure of the tightly bound complex of the globular myosin head with F-actin is the key to understanding important details of the mechanism of how the actin-myosin motor functions. The current notion on this complex is based on the docking of known atomic structures of constituent proteins into low-resolution electron-density maps. The atomic structure of the complex was refined by the molecular mechanics method, which consists in minimizing the energy of molecular interaction and which makes it possible to optimize not only the relative position of protein backbones as rigid bodies, but also the position of side chains on the protein interface. The structure calculated using ICM-Pro software, on the one hand, is close to the model obtained using electron microscopy; on the other hand, it ensures the best calculated interaction energy and accounts for the results of mutagenesis experiments. On the basis of the structure obtained, we can suggest the molecular mechanisms underlying the actin-activated release of ATP hydrolysis products from myosin and the decrease in the affinity of myosin for actin upon binding of nucleotides.     

Ankle and knee moment and power adaptations are elicited through load carriage conditioning in males

Soldiers routinely conduct load carriage and physical training to meet occupational requirements. These tasks are physically arduous and are believed to be the primary cause of musculoskeletal injury. Physical training can help mitigate injury risk when specifically designed to address injury mechanisms and meet task demands. This study aimed to assess lower-limb biomechanics and neuromuscular adaptations during load carriage walking in response to a 10-week evidence-based physical training program. Thirteen male civilian participants donned 23 kg and completed 5 km of load carriage treadmill walking, at 5.5 km h⁻¹ before and after a 10-week physical training program. Three-dimensional motion capture and force plate data were acquired in over-ground walking trials before and after treadmill walking. These data were inputs to a musculoskeletal model which estimated lower-limb joint kinematics and kinetics (i.e., moments and powers) using inverse kinematics and dynamics, respectively. A two-way analysis of variance revealed significant main effect of training for kinematic and kinetics parameters at the knee and ankle joints (p < 0.05). Post-Hoc comparisons demonstrated a significant decrease (4.2%) in total negative knee power between pre- and post-March 5 km measures after training (p < 0.05). Positive power contribution shifted distally after training, increasing at the post-march measure from 39.9% to 43.6% at the ankle joint (p < 0.05). These findings demonstrate that a periodised training program may reduce injury risk through favourable ankle and knee joint adaptations.     

Pay attention to membrane tension: Mechanobiology of the cell surface

The cell surface is a mechanobiological unit that encompasses the plasma membrane, its interacting proteins, and the complex underlying cytoskeleton. Recently, attention has been directed to the mechanics of the plasma membrane, and in particular membrane tension, which has been linked to diverse cellular processes such as cell migration and membrane trafficking. However, how tension across the plasma membrane is regulated and propagated is still not completely understood. Here, we review recent efforts to study the interplay between membrane tension and the cytoskeletal machinery and how they control cell form and function. We focus on factors that have been proposed to affect the propagation of membrane tension and as such could determine whether it can act as a global or local regulator of cell behavior. Finally, we discuss the limitations of the available tool kit as new approaches that reveal its dynamics in cells are needed to decipher how membrane tension regulates diverse cellular processes.     

An Algorithm for Calculation of n-Dimensional Nonlinear Dependencies – Behaviour Tests on Rats

The evaluation of the data obtained during the behaviour tests always leads to the problem of multiple correlation, very often with non-linear dependencies on the target. All mathematical and statistical procedures that have been used so far are based on the assumption of an equation for the desired correlation for which parameters and related statistical equivalents are determined eventually. The MODAK system applied here (MODAK = algorithms of modelling for the calculation of multi-dimensional non-linear mathematical models) breaks down a complex correlation into individual dependencies in a mathematical and statistical way and selects suitable equations for each of them independently and determines the corresponding parameters. The numerical example evaluates data of behaviour tests on rats. First results obtained on the correlations of various behaviour tests indicate both the possibility of selecting suitable tests independent of each other and a better interpretation of the observed patterns of behaviour taking into account the interrelations between the tests. In addition, MODAK is a method which can be applied as a matter of course in a general way to all cases which call for the reduction and analysis of data occurring in process and system analysis and in the evaluation of test results requiring statistical modelling. So far, MODAK applications range from engineering sciences to medicine.     

Assessment of Optimal Selected Prognostic Factors

The identification and assessment of prognostic factors is one of the major tasks in clinical research. The assessment of one single prognostic factor can be done by recently established methods for using optimal cutpoints. Here, we suggest a method to consider an optimal selected prognostic factor from a set of prognostic factors of interest. This can be viewed as a variable selection method and is the underlying decision problem at each node of various tree building algorithms. We propose to use maximally selected statistics where the selection is defined over the set of prognostic factors and over all cutpoints in each prognostic factor. We demonstrate that it is feasible to compute the approximate null distribution. We illustrate the new variable selection test with data of the German Breast Cancer Study Group and of a small study on patients with diffuse large B‐cell lymphoma. Using the null distribution for a p‐value adjusted regression trees algorithm, we adjust for the number of variables analysed at each node as well. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Detection of native-like models for amino acid sequences of unknown three-dimensional structure in a data base of known protein conformations.

We present an approach which can be used to identify native-like folds in a data base of protein conformations in the absence of any sequence homology to proteins in the data base. The method is based on a knowledge-based force field derived from a set of known protein conformations. A given sequence is mounted on all conformations in the data base and the associated energies are calculated. Using several conformations and sequences from the globin family we show that the native conformation is identified correctly. In fact the resolution of the force field is high enough to discriminate between a native fold and several closely related conformations. We then apply the procedure to several globins of known sequence but unknown three dimensional structure. The homology of these sequences to globins of known structures in the data base ranges from 49 to 17%. With one exception we find that for all globin sequences one of the known globin folds is identified as the most favorable conformation. These results are obtained using a force field derived from a data base devoid of globins of known structure. We briefly discuss useful applications in protein structural research and future development of our approach.     

Nonlever action of the mandible

This study considers the current concept of the mandible as a lever of the third order. The concept requires a fulcrum, and this function has been ascribed to the condyle region, but it tends to be overlooked that the fulcrum of a third-order lever in this case would sometimes have to bear a considerable stress. Certain changes, attributed to stress, have been observed in anatomical components of the articulation, but they cannot be explained in terms of the lever concept. They are accounted for by the changing anatomical relations in the working and contralateral sides during mandibular function. They arise from minor stress, especially when dental conditions indicate a period of abnormal function.