SwissParam: a fast force field generation tool for small organic molecules.

The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy estimation, both of which require force field parameterization for many drug candidates. Here, we present a fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field. Output files can be used with CHARMM or GROMACS. The topologies and parameters generated by SwissParam are used by the docking software EADock2 and EADock DSS to describe the small molecules to be docked, whereas the protein is described by the CHARMM force field, and allow them to reach success rates ranging from 56 to 78%. We have also developed a rapid binding free energy estimation approach, using SwissParam for ligands and CHARMM22/27 for proteins, which requires only a short minimization to reproduce the experimental binding free energy of 214 ligand-protein complexes involving 62 different proteins, with a standard error of 2.0 kcal mol(-1), and a correlation coefficient of 0.74. Together, these results demonstrate the relevance of using SwissParam topologies and parameters to describe small organic molecules in computer-aided drug design applications, together with a CHARMM22/27 description of the target protein. SwissParam is available free of charge for academic users at www.swissparam.ch.

FRAX(®) Clinical Task Force of the 2010 Joint International Society for Clinical Densitometry & International Osteoporosis Foundation Position Development Conference.

The World Health Organization fracture risk assessment tool, FRAX(®), is an advance in clinical care that can assist in clinical decision-making. However, with increasing clinical utilization, numerous questions have arisen regarding how to best estimate fracture risk in an individual patient. Recognizing the need to assist clinicians in optimal use of FRAX(®), the International Osteoporosis Foundation (IOF) in conjunction with the International Society for Clinical Densitometry (ISCD) assembled an international panel of experts that ultimately developed joint Official Positions of the ISCD and IOF advising clinicians regarding FRAX(®) usage. As part of the process, the charge of the FRAX(®) Clinical Task Force was to review and synthesize data surrounding a number of recognized clinical risk factors including rheumatoid arthritis, smoking, alcohol, prior fracture, falls, bone turnover markers and glucocorticoid use. This synthesis was presented to the expert panel and constitutes the data on which the subsequent Official Positions are predicated. A summary of the Clinical Task Force composition and charge is presented here.

Like Man, Like Woman: Roman Women, Gender Qualities and Conjugal Relationships at the Turn of the First Century

Modern scholarship often discusses Roman women in terms of their difference from their male counterparts, frequently defining them as 'other'. This book shows how Roman male writers at the turn of the first century actually described women as not so different from men: the same qualities and abilities pertaining to the domains of parenthood, intellect and morals are ascribed by writers to women as well as to men. There are two voices, however: a traditional, ideal voice and an individual, realistic voice. This creates a duality of representations of women, which recurs across literary genres and reflects a duality of mentality. How can we interpret the paradoxical information about Roman women given by the male-authored texts? How does this duality of mentality inform us about gender roles and gender hierarchy? This work analyses well-known, as well as overlooked, passages from the writings of Pliny the Younger, Tacitus, Suetonius, Quintilian, Statius, Martial and Juvenal and sheds new light on Roman views of women and their abilities, on the notions of private and public and on conjugal relationships. In the process, the famous sixth satire of Juvenal is revisited and its topic reassessed, providing further insights into the complex issues of gender roles, marriage and emotions. By contrasting representations of women across a broad spectrum of literary genres, this book provides consistent findings that have wide significance for the study of Latin literature and the social history of the late first and early second centuries.

Effects of a 5-h hilly running on ankle plantar and dorsal flexor force and fatigability

This study aimed to examine the effects of a 5-h hilly run on ankle plantar (PF) and dorsal flexor (DF) force and fatigability. It was hypothesised that DF fatigue/fatigability would be greater than PF fatigue/fatigability. Eight male trail long distance runners (42.5 ± 5.9 years) were tested for ankle PF and DF maximal voluntary isokinetic contraction strength and fatigue resistance tests (percent decrement score), maximal voluntary and electrically evoked isometric contraction strength before and after the run. Maximal EMG root mean square (RMS(max)) and mean power frequency (MPF) values of the tibialis anterior (TA), gastrocnemius lateralis (GL) and soleus (SOL) EMG activity were calculated. The peak torque of the potentiated high- and low-frequency doublets and the ratio of paired stimulation peak torques at 10 Hz over 100 Hz (Db10:100) were analysed for PF. Maximal voluntary isometric contraction strength of PF decreased from pre- to post-run (-17.0 ± 6.2%; P < 0.05), but no significant decrease was evident for DF (-7.9 ± 6.2%). Maximal voluntary isokinetic contraction strength and fatigue resistance remained unchanged for both PF and DF. RMS(max) SOL during maximal voluntary isometric contraction and RMS(max) TA during maximal voluntary isokinetic contraction were decreased (P < 0.05) after the run. For MPF, a significant decrease for TA (P < 0.05) was found and the ratio Db10:100 decreased for PF (-6.5 ± 6.0%; P < 0.05). In conclusion, significant isometric strength loss was only detected for PF after a 5-h hilly run and was partly due to low-frequency fatigue. This study contradicted the hypothesis that neuromuscular alterations due to prolonged hilly running are predominant for DF.

Mothers' and fathers' views of the interdependence of their relationships with their infant: a systems perspective on early family relationships.

This study examined the interrelatedness of mother-infant and father-infant relationships as they develop over the first 4 months postpartum as well as the dynamics used by the couple to balance these relationships. First-time mother-father couples (n = 18) were interviewed separately at 1, 6, and 16 weeks postpartum using the Parent-Infant Relationship Interview. The data were analyzed using in-depth qualitative strategies. The parents' core themes of their early family relationships ranged from an undifferentiated unit at 1 week, to being a highly disorganized unit at 6 weeks, to a more integrated unit at 16 weeks. These results suggest that one should be thinking of early family relationships and parenting in terms of "messy processes" out of which new ways of being together are created. This disorganization plays a fundamental role in the establishment of early family relationships and warrants further empirical and clinical attention.

Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes

Several population pharmacokinetic (PPK) analyses of the anticancer drug imatinib have been performed to investigate different patient populations and covariate effects. The present analysis offers a systematic qualitative and quantitative summary and comparison of those. Its primary objective was to provide useful information for evaluating the expectedness of imatinib plasma concentration measurements in the frame of therapeutic drug monitoring. The secondary objective was to review clinically important concentration-effect relationships to provide help in evaluating the potential suitability of plasma concentration values. Nine PPK models describing total imatinib plasma concentration were identified. Parameter estimates were standardized to common covariate values whenever possible. Predicted median exposure (Cmin) was derived by simulations and ranged between models from 555 to 1388 ng/mL (grand median: 870 ng/mL and interquartile "reference" range: 520-1390 ng/mL). Covariates of potential clinical importance (up to 30% change in pharmacokinetic predicted by at least 1 model) included body weight, albumin, α1 acid glycoprotein, and white blood cell count. Various other covariates were included but were statistically not significant or seemed clinically less important or physiologically controversial. Concentration-response relationships had more importance below the average reference range and concentration-toxicity relationships above. Therapeutic drug monitoring-guided dosage adjustment seems justified for imatinib, but a formal predictive therapeutic range remains difficult to propose in the absence of prospective target concentration intervention trials. To evaluate the expectedness of a drug concentration measurement in practice, this review allows comparison of the measurement either to the average reference range or to a specific range accounting for individual patient characteristics. For future research, external PPK model validation or meta-model development should be considered.

Analysis of micro- and nano-structures of the corneal surface of Drosophila and its mutants by atomic force microscopy and optical diffraction.

Drosophila melanogaster is a model organism instrumental for numerous biological studies. The compound eye of this insect consists of some eight hundred individual ommatidia or facets, ca. 15 µm in cross-section. Each ommatidium contains eighteen cells including four cone cells secreting the lens material (cornea). High-resolution imaging of the cornea of different insects has demonstrated that each lens is covered by the nipple arrays--small outgrowths of ca. 200 nm in diameter. Here we for the first time utilize atomic force microscopy (AFM) to investigate nipple arrays of the Drosophila lens, achieving an unprecedented visualization of the architecture of these nanostructures. We find by Fourier analysis that the nipple arrays of Drosophila are disordered, and that the seemingly ordered appearance is a consequence of dense packing of the nipples. In contrast, Fourier analysis confirms the visibly ordered nature of the eye microstructures--the individual lenses. This is different in the frizzled mutants of Drosophila, where both Fourier analysis and optical imaging detect disorder in lens packing. AFM reveals intercalations of the lens material between individual lenses in frizzled mutants, providing explanation for this disorder. In contrast, nanostructures of the mutant lens show the same organization as in wild-type flies. Thus, frizzled mutants display abnormal organization of the corneal micro-, but not nano-structures. At the same time, nipples of the mutant flies are shorter than those of the wild-type. We also analyze corneal surface of glossy-appearing eyes overexpressing Wingless--the lipoprotein ligand of Frizzled receptors, and find the catastrophic aberration in nipple arrays, providing experimental evidence in favor of the major anti-reflective function of these insect eye nanostructures. The combination of the easily tractable genetic model organism and robust AFM analysis represents a novel methodology to analyze development and architecture of these surface formations.