Mesoscope: A Web-based Tool for Mesoscale Data Integration and Curation.

Interest is growing for 3D models of the biological mesoscale, the intermediate scale between the nanometer scale of molecular structure and micrometer scale of cellular biology. However, it is currently difficult to gather, curate and integrate all the data required to define such models. To address this challenge we developed Mesoscope (mesoscope.scripps.edu/beta), a web-based data integration and curation tool. Mesoscope allows users to begin with a listing of molecules (such as data from proteomics), and to use resources at UniProt and the PDB to identify, prepare and validate appropriate structures and representations for each molecule, ultimately producing a portable output file used by CellPACK and other modeling tools for generation of 3D models of the biological mesoscale. The availability of this tool has proven essential in several exploratory applications, given the high complexity of mesoscale models and the heterogeneity of the available data sources.

Doing a good job and getting something good out of it: on stress and well-being in anaesthesia.

The anaesthetist's work, aimed at giving safe anaesthesia to patients, can do both harm and good to the anaesthetist. Research on stress in anaesthesia has traditionally focused on how the negative effects of stress can be avoided and much effort has been put into improving anaesthetists' work environment to reduce the level of stress. In this review, however, we give attention instead to what the individual anaesthetist can do to improve his or her well-being at work. Stress is, and will remain, an inevitable aspect of the anaesthetist's occupation but, as for any professional working in a stressful environment, adaptive coping can make a big difference in outcome. The choice between construing a difficult clinical situation as threat or challenge is important here because of the difference in the resulting stress response. The anaesthetist can reduce the stress effect of a potentially stressful situation by thinking of it in a new way, by redefining it through reappraisal. We describe here some lines of thought that experienced anaesthetists use to buffer the effects of work stress on physical health and mental well-being. By reframing a situation, they can reduce its stress content even if the problem at hand cannot be successfully solved. Trainee anaesthetists, who experience much stress at work and are at risk of burnout, would benefit from learning about these coping strategies.

Exchanging spare parts or becoming a new person? People's attitudes toward receiving and donating organs.

The present study explored the public's feelings and ideas about receiving organs, and how this influenced their attitudes toward accepting a transplant themselves. Also the willingness to donate was examined in order to provide a complementary perspective. The main aim was to identify consistent attitude patterns that would include attitudes toward both receiving and donating organs and the motives behind this. Sixty-nine individuals with varying socio-demographic background, selected from samples who had responded to a questionnaire on receiving and donating organs and tissues, were interviewed in-depth. The approach to analyse the interviews was hermeneutic. Seven typical attitude patterns emerged. By an 'attitude pattern' was meant a specific set of attitudes and motives, that formed a consistent picture that was logical and psychologically meaningful. In the discussion, two different conceptions of the body were focused. One of them meant that the body was easily objectified and conceived as machine-like, and did not represent the self. This machine model paved the way for the understanding that body parts needed to be replaced by spare parts. The other conception meant that a new organ would transfer the donor's qualities, i.e. influence the identity of the recipient with regard to behaviour, appearance, and personality. This belief may be explained by 'analogy thinking' based on our everday experience of how mixed entities take on the qualities of all components. Another explanation would be a kind of magical thinking and 'the law of contagion', which is often connected to oral incorporation. The consequences of these conceptions when patients are confronted with the factual situation of a transplantation, were discussed.

People's feelings and ideas about receiving transplants of different origins--questions of life and death, identity, and nature's border.

The aim of this study was to explore the public's feelings and ideas with regard to receiving transplants of different origins. Sixty-nine individuals with varying sociodemographic background, selected from samples who had responded to a questionnaire on receiving and donating organs, were interviewed in-depth. A wide variety of reactions was displayed. The feelings and ideas about receiving organs were summarized in ten categories: 1) the emergency situation; 2) the functioning of the transplant; 3) the influence of transplants on personality, behaviour, and appearance; 4) the influence of transplants on body image; 5) disgust; 6) cannibalism; 7) trespassing nature's border; 8) tradition; 9) ethical considerations; and 10) the debt of gratitude. Most individuals were willing to accept at least one organ. Animal organs were the least preferred. The hierarchy of organ preferences--with organs from a relative at the top and animal organs at the bottom was explained in terms of rational, magical, and analogy thinking. Finally, the consequences for the encounter between health care personnel and transplantation candidates were briefly discussed.

Integrating computation and visualization for biomolecular analysis: an example using python and AVS.

One of the challenges in biocomputing is to enable the efficient use of a wide variety of fast-evolving computational methods to simulate, analyze, and understand the complex properties and interactions of molecular systems. Our laboratory investigates several areas including molecular visualization, protein-ligand docking, protein-protein docking, molecular surfaces, and the derivation of phenomenological potentials. In this paper we present an approach based on the Python programming language to achieve a high level of integration between these different computational methods and our primary visualization system AVS. This approach removes many limitations of AVS while increasing dramatically the inter-operability of our computational tools. Several examples are shown to illustrate how this approach enables a high level of integration and inter-operability between different tools, while retaining modularity and avoiding the creation of a large monolithic package that is difficult to extend and maintain.

The discovery of steroids and other novel FKBP inhibitors using a molecular docking program.

The molecular docking computer program SANDOCK was used to screen small molecule three-dimensional databases in the hunt for novel FKBP inhibitors. Spectroscopic measurements confirmed binding of over 20 compounds to the target protein, some with dissociation constants in the low micromolar range. The discovery that FK506 binding protein is a steroid binding protein may be of wider biological significance. Two-dimensional NMR was used to determine the steroid binding mode and confirmed the interactions predicted by the docking program.

Giving and taking--to whom and from whom? People's attitudes toward transplantation of organs and tissue from different sources.

The aims of the study were: 1) to describe the willingness of the public to receive material of different origins in one's own body; 2) to compare the willingness to donate and receive body material; 3) to compare the willingness to donate while alive and after death; 4) to compare the willingness to donate to a next-of-kin and unknown recipients. A random sample of 1500 inhabitants, 18 to 70 yr old, in the county of Uppsala, Sweden, were sent a questionnaire asking about their opinion on transplantation and transfusion issues. The response rate was 71%. Ninety-five percent accepted to receive blood transfusion, 89% bone-marrow transplantation, and 85% transplantation of a solid organ. Organs from living donors were preferred (77%), then organs from decreased donors (69%), then artificial organs (63%), and last animal organs (40%). More than half of those accepting transplants made exceptions for some types of organs. The youngest and those with higher education were more positive toward receiving all types of organs than the older ones and those with lower education. Women were less prepared than men to accept animal organs. Those who accepted organs from animals usually also accepted all other types of organs, and were willing to donate organs and tissue more often than those who did not accept to receive animal organs. The readiness to support a sick family member by giving bone-marrow and even a kidney was considerable, 89 and 81%, respectively. The attitudes were less positive with regard to giving blood and bone-marrow to unknown recipients, 54 and 41%, respectively. Sixty-one percent of the respondents were positive toward donating their own organs after death. Of those who were positive, 10% made exceptions for special organs that they did not want to donate, mostly heart, eyes, and brain. Individuals with higher education and young people were more often positive than those with lower education and old people regarding donation of blood and organs, and bone-marrow donation to a relative. Women were somewhat more accepting to donate while alive than males. Thirty-one percent, more often women than men, had signed a donor card and/or registered with the Swedish Organ Donation Registry. The results with regard to receiving organs and tissue are discussed in terms of two different sets of explanations, which can be seen as different sides of the same coin, and mutually strengthening the reactions. The great readiness to donate to a family member as well as the discrepancy between giving in life and after death is commented upon.

[Deaths at an emergency hospital. Circumstances around the cases as described by physicians and relatives]. / Döden på akutsjukhuset. Förhållanden kring dödsfall skildrade av läkare och anhöriga.

Cases of death occurring at University Hospital (Akademiska sjukhuset), Uppsala, during a four-month period were studied by means of interviews (n = 258) with the attending physicians and questionnaires answered by relatives (191) of the deceased. In half the cases death was unexpected and the preceding treatment period short. In most cases the family was present at the time of death, one of several signs that family participation has increased. The question of autopsy was raised in 70 per cent of cases, autopsy being performed in 53 per cent. Great importance was attached to relatives' attitudes toward autopsy, which were negative in only about one case in four. Shortcomings remain in the information provided to families, although there was improvement in this respect as compared with findings in earlier studies.

The discovery of potent and selective dopamine D4 receptor antagonists.

The identification of a novel dopamine receptor subtype, referred to as the D4 receptor, which binds the atypical antipsychotic drug clozapine with high potency, has led to the initiation of a drug discovery program that aims to find novel inhibitors of this receptor subtype. A selective screening strategy was utilized, in which 4500 compounds chosen on the basis of structural similarities to known biogenic amine receptor antagonists were tested against both the D4 and D2 dopamine receptor subtypes. A potent D4-selective compound was discovered.

Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition.

Recent evidence suggests that the dopamine D4 receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1-5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D4-selective compounds, CP-293,019 (5.6-17.8 mg/kg), U-101,387 (3-30 mg/kg) and L-745,870 (1-10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D4 dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D2 receptor antagonists.

Synthesis, SAR and pharmacology of CP-293,019: a potent, selective dopamine D4 receptor antagonist.

A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.

Residue-residue mean-force potentials for protein structure recognition.

We present two new sets of energy functions for protein structure recognition, given the primary sequence of amino acids along the polypeptide chain. The first set of potentials is based on the positions of alpha- and the second on positions of beta- and alpha-carbon atoms of amino acid residues. The potentials are derived using a theory of Boltzmann-like statistics of protein structure. The energy terms incorporate both long-range interactions between residues remote along a chain and short-range interactions between near neighbors. Distance dependence is approximated by a piecewise constant function defined on intervals of equal size. The size of the interval is optimized to preserve as much detail as possible without introducing excessive error due to limited statistics. A database of 214 non-homologous proteins was used both for the derivation of the potentials, and for the 'threading' test originally suggested by Hendlich et al. (1990) J. Mol. Biol., 216, 167-180. Special care is taken to avoid systematic error in this test. For threading, we used 100 non-homologous protein chains of 60-205 residues. The energy of each of the native structures was compared with the energy of 43,000 to 19,000 alternative structures generated by threading. Of these 100 native structures, 92 have the lowest energy with alpha-carbon-based potentials and, even more, 98 of these 100 structures, have the lowest energy with the beta- and alpha-carbon based potentials.

Registered bone marrow donors' views on bodily donations.

The attitudes of 463 potential bone marrow donors toward blood donation, kidney donation in life, organ donation after death, autopsy, and donation of the whole body for anatomic dissection were surveyed, using a questionnaire that had previously been employed for assessing the attitudes of the public. The response rate was 96%. Three quarters of the respondents were blood donors and recruited via the blood center. The proportion that accepted the procedures varied between 24% for anatomic dissection and 97% for autopsy. Differences were small between individuals with positive attitudes and individuals who had also actively taken steps to activate these attitudes. Compared with the public, the bone marrow donors were more positive to all kinds of bodily donations. The conclusion is that if one is prepared to give from the body in life, one is also prepared to give after death. The results may indicate less death anxiety and fear of physical injury, and less fear of chaos either with or without altruism compared to the public.

Accurate mean-force pairwise-residue potentials for discrimination of protein folds.

We present two new sets of energy functions for protein structure recognition. The first set of potentials is based on the positions of alpha- and the second on positions of beta-carbon atoms of amino acid residues. The potentials are derived using a theory of Boltzmann-like statistics of protein structure by Finkelstein et al. The energy terms incorporate both long-range interactions between residues remote along a chain and short-range interactions between near neighbors. Distance-dependence is approximated by a piecewise constant function defined on intervals of equal size. The size of this interval is optimized. A database of 222 non-homologous proteins was used both for the derivation of the potentials, and for the "threading" test originally suggested by Hendlich et al. For threading, we used 102 non-homologous protein chains of 60 to 200 residues. The energy of each of the native structures was compared with the energy of 45 to 20 thousand alternative structures generated by threading. Of these 102 native structures 94 have the lowest energy with alpha-carbon-based potentials, and even more, 100 of these 102 structures, have the lowest energy with the beta-carbon-based potentials.

Real time surface reconstruction for moving molecular fragments.

Recently we introduced the Reduced Surface as an efficient tool to built molecular surfaces. We describe here how this geometric construct can be used to efficiently reconstruct the solvent excluded surface of a protein for which the coordinates of a subset of atoms are changing. We show that, the complexity of that operation is not dependent upon the size of the molecule and is in O[tlog(t)] where t is the maximum of the number of probes and atoms involved in the reconstruction of the surface. The algorithms described here have been implemented and tested on several proteins. The triangulation of the solvent excluded surface of proteins in which a side chain was changing conformation could be updated at rates ranging from 7 to 22 frames per second. We also applied this method to compute the surface area fluctuation of the FIV protease undergoing a constrained molecular dynamics simulation (16 mobile residues). Rate of 6 frames per second were obtained in this case.

Recognition of protein structure on coarse lattices with residue-residue energy functions.

We suggest and test potentials for the modeling of protein structure on coarse lattices. The coarser the lattice, the more complete and faster is the exploration of the conformational space of a molecule. However, there are inevitable energy errors in lattice modeling caused by distortions in distances between interacting residues; the coarser the lattice, the larger are the energy errors. It is generally believed that an improvement in the accuracy of lattice modelling can be achieved only by reducing the lattice spacing. We reduce the errors on coarse lattices with lattice-adapted potentials. Two methods are used: in the first approach, 'lattice-derived' potentials are obtained directly from a database of lattice models of protein structure; in the second approach, we derive 'lattice-adjusted' potentials using our previously developed method of statistical adjustment of the 'off-lattice' energy functions for lattices. The derivation of off-lattice Calpha atom-based distance-dependent pairwise potentials has been reported previously. The accuracy of 'lattice-derived', 'lattice-adjusted' and 'off-lattice' potentials is estimated in threading tests. It is shown that 'lattice-derived' and 'lattice-adjusted' potentials give virtually the same accuracy and ensure reasonable protein fold recognition on the coarsest considered lattice (spacing 3.8 A), however, the 'off-lattice' potentials, which efficiently recognize off-lattice folds, do not work on this lattice, mainly because of the errors in short-range interactions between neighboring residues.

Adjusting potential energy functions for lattice models of chain molecules.

Lattice models of proteins can approximate off-lattice structure to arbitrary precision with RMS (root mean squared) deviations roughly equal to half the lattice spacing (Rykunov et al., Proteins 22:100-109, 1995; Reva et al., J. Comp. Biol., 1996). However, even small distortions in the positions of chain links lead to significant errors in lattice-based energy calculations (Reva et al., J. Comp. Chem., 1996). These errors arise mainly from rigid interactions (such as steric repulsion) which change their energies considerably at a range which is much smaller than the usual accuracy of lattice modeling (> 1.0 A). To reduce this error, we suggest a procedure of adjusting energy functions to a given lattice. The general approach is illustrated with energy calculations based on pairwise potentials by Kolinski et al. (J. Chem. Phys. 98:1-14, 1993). At all the lattice spacings, from 0.5-3.8 A, the lattice-adjusted potentials improve the accuracy of lattice-based energy calculations and increase the correlations between off-lattice and lattice energies.