A flexible approach for understanding protein stability.

A distance constraint model (DCM) is presented that identifies flexible regions within protein structure consistent with specified thermodynamic condition. The DCM is based on a rigorous free energy decomposition scheme representing structure as fluctuating constraint topologies. Entropy non-additivity is problematic for naive decompositions, limiting the success of heat capacity predictions. The DCM resolves non-additivity by summing over independent entropic components determined by an efficient network-rigidity algorithm. A minimal 3-parameter DCM is demonstrated to accurately reproduce experimental heat capacity curves. Free energy landscapes and quantitative stability-flexibility relationships are obtained in terms of global flexibility. Several connections to experiment are made.

Network rigidity at finite temperature: relationships between thermodynamic stability, the nonadditivity of entropy, and cooperativity in molecular systems.

A statistical mechanical distance constraint model (DCM) is presented that explicitly accounts for network rigidity among constraints present within a system. Constraints are characterized by local microscopic free-energy functions. Topological rearrangements of thermally fluctuating constraints are permitted. The partition function is obtained by combining microscopic free energies of individual constraints using network rigidity as an underlying long-range mechanical interaction, giving a quantitative explanation for the nonadditivity in component entropies exhibited in molecular systems. Two exactly solved two-dimensional toy models representing flexible molecules that can undergo conformational change are presented to elucidate concepts, and to outline a DCM calculation scheme applicable to many types of physical systems. It is proposed that network rigidity plays a central role in balancing the energetic and entropic contributions to the free energy of biopolymers, such as proteins. As a demonstration, the distance constraint model is solved exactly for the alpha-helix to coil transition in homogeneous peptides. Temperature and size independent model parameters are fitted to Monte Carlo simulation data, which includes peptides of length 10 for gas phase, and lengths 10, 15, 20, and 30 in water. The DCM is compared to the Lifson-Roig model. It is found that network rigidity provides a mechanism for cooperativity in molecular structures including their ability to spontaneously self-organize. In particular, the formation of a characteristic topological arrangement of constraints is associated with the most probable microstates changing under different thermodynamic conditions.

Withholding and withdrawing life-sustaining therapy in a Canadian intensive care unit.

The purpose of this study was to document the rationale and procedures for withholding and withdrawing life-sustaining treatment in critically ill patients. A prospective observational study was conducted over 12 mo in a Canadian academic intensive care unit. Of the 110 intensive care unit patients who died during the study period, 71 (64.5%) died after treatment was withheld or withdrawn. Compared with the other 39 patients who died despite full therapy, these patients were found to have a longer hospital and ICU stay, more organ systems failed, and a higher rate of malignancy. Intensivists rated poor prognosis for survival and poor quality of life should the patient survive as being the two most important factors when making a decision to withhold or withdraw treatment, while patient age and physical health prior to hospital admission were the two least important factors. There was a consistent approach to withdrawing therapy in 68 of the 71 patients who had treatment either withheld or withdrawn. In these 68 patients, the first step was to write a do-not-resuscitate order, vasopressor drugs were then stopped and, lastly, the patient was weaned from mechanical ventilation and the trachea was extubated. The results of this study demonstrate that life-supporting treatment is commonly withdrawn in critically ill patients when continued therapy is thought to be unlikely to restore the patient to health.

Religious content in the DSM-III-R glossary of technical terms.

The authors reviewed Appendix C of DSM-III-R, Glossary of Technical Terms, for its references to religion. Religion was referred to more frequently in this glossary than it is in psychiatric research. The authors conclude that although the Glossary uses religion in constructive or cautionary reminders, the high rate of illustrative case examples of psychopathology that involve religion in the Glossary indicates cultural insensitivity in interpreting religion.

Seeing/believing/seeing: perception-correcting and cognitive skills.

Some people believe only what they can see with their own eyes. For them, seeing is believing. But often people are deceived by their eyes into seeing one thing when something else actually is there. In these instances, believing is seeing. They see what they expect to see, have learned to see, or want to see. After a theoretical discussion of perception and cognition, 10 skills are identified for correcting perceptual and cognitive processes involved in dealing with incoming stimuli. The authors propose that these skills will increase social workers' accuracy in making observations and interpretations.