Controlled exploration of chemical space by machine learning of coarse-grained representations

The size of chemical compound space is too large to be probed exhaustively. This leads high-throughput protocols to drastically subsample and results in sparse and non-uniform datasets. Rather than arbitrarily selecting compounds, we systematically explore chemical space according to the target property of interest. We first perform importance sampling by introducing a Markov chain Monte Carlo scheme across compounds. We then train an ML model on the sampled data to expand the region of chemical space probed. Our boosting procedure enhances the number of compounds by a factor 2 to 10, enabled by the ML model's coarse-grained representation, which both simplifies the structure-property relationship and reduces the size of chemical space. The ML model correctly recovers linear relationships between transfer free energies. These linear relationships correspond to features that are global to the dataset, marking the region of chemical space up to which predictions are reliable---a more robust alternative to the predictive variance. Bridging coarse-grained simulations with ML gives rise to an unprecedented database of drug-membrane insertion free energies for 1.3 million compounds.Comment: 9 pages, 5 figure

In silico screening of drug-membrane thermodynamics reveals linear relations between bulk partitioning and the potential of mean force

The partitioning of small molecules in cell membranes---a key parameter for pharmaceutical applications---typically relies on experimentally-available bulk partitioning coefficients. Computer simulations provide a structural resolution of the insertion thermodynamics via the potential of mean force, but require significant sampling at the atomistic level. Here, we introduce high-throughput coarse-grained molecular dynamics simulations to screen thermodynamic properties. This application of physics based models in a large-scale study of small molecules establishes linear relationships between partitioning coefficients and key features of the potential of mean force. This allows us to predict the structure of the insertion from bulk experimental measurements for more than 400,000 compounds. The potential of mean force hereby becomes an easily accessible quantity---already recognized for its high predictability of certain properties, e.g., passive permeation. Further, we demonstrate how coarse graining helps reduce the size of chemical space, enabling a hierarchical approach to screening small molecules.Comment: 8 pages, 6 figures. Typos fixed, minor correction

A comparative study of outcome of the absorbable suture polydioxanone and nonabsorbable suture polypropylene in laparotomy wound closure

Background: Abdominal wound closure is one of the common operations for a general surgeon. Prevention of complications is important to reduce post-operative morbidity and mortality. Post-operative wound pain, wound infection, wound dehiscence, suture sinus formation; palpable knots and incisional hernia are the parameters are to be studied.  Therefore, the present study was undertaken to compare polydioxanone and polypropylene suture material for abdominal fascial closure regarding morbidity in terms of post-operative wound complications.Methods: Patients admitted in the department of surgery, who undergo laparotomy operations, with midline abdominal incisions were included in the study. The recruited subjects were divided into Group-A, whom abdominal incisions are closed with non-absorbable suture material polypropylene and Group-B whom abdominal incisions are closed with absorbable suture material polydioxanone. Data was expressed as percentages.Results: The incidence of wound pain was observed in all the patients in both immediate and delayed post-operative period in the polypropylene suture material compared to polydioxanone.  The incidence of wound infection was higher in polypropylene (24%) compared to PDS (2%). There were 4% cases of wound dehiscence in the present study. The incidence of suture sinus formation was higher in the polypropylene suture material (9%) compared to the polydioxanone suture material (2%) in the delayed postoperative period. The incidence of palpable knots was higher in the polypropylene suture material (23%) compared to the polydioxanone suture material. No cases of incisional hernia were reported with polydioxanone suture material.Conclusions: The overall morbidity from abdominal closure was considerably reduced in the Polydioxanone group. We encountered reduction in wound complications like burst abdomen, wound infection, wound pain, suture sinus formation, palpable knots and incisional hernia. Therefore, polydioxanone can be employed rewardingly in emergency situations where closure can be carried out safely and rapidly.

Study of Eclipsing Binary and Multiple Systems in OB Associations II. The Cygnus OB Region: V443 Cyg, V456 Cyg and V2107 Cyg

Three presumably young eclipsing binary systems in the direction of the Cygnus OB1, OB3 and OB9 associations are studied. Component spectra are reconstructed and their orbits are determined using light curves and spectra disentangling techniques. V443 Cyg and V456 Cyg have circular orbits, while the light curve of V2107\,Cyg imposes a slightly eccentric orbit ($e=0.045\pm0.03)$. V443 Cyg harbours F-type stars, and not young early-A stars as previously suggested in the literature based on photometry solely. It appears to be situated in the foreground (distance $0.6\pm0.2$ kpc) of the young stellar populations in Cygnus. V456 Cyg, at a distance of $0.50\pm0.03$ kpc consists of a slightly metal-weak A--type and an early--F star. The age of both systems, on or very near to the main sequence, remains uncertain by an order of magnitude. V2107 Cyg is a more massive system ($8.9\pm2$ and $4.5\pm1.2 M_\odot$) at $1.5\pm0.5$ kpc and, also kinematically, a strong candidate-member of Cyg OB1. The more massive component is slightly evolved and appears to undergo non-radial $\beta Cep$-type pulsations. The Doppler signal of the secondary is barely detectable. A more extensive study is important to fix masses more precisely, and an asteroseismological study would then become appropriate. Nevertheless, the position of the primary in the HR-diagram confines the age already reasonably well to $20\pm5$ Myr, indicating for Cyg OB1 a similar extent of star formation history as established for Cyg OB2.Comment: 27 pages, including 9 figures and 6 tables, accepted for publication in Astronomical Journa

Legal, Technical, and Economic Challenges in Integrating Renewable Power Generation Into the Electricity Grid

This Article addresses the legal, technical, and economic challenges of integrating high levels of renewable power generation into electrical grid system operation. Part II shows that the primary integration challenge is reducing the total costs of integration and allocating the costs of integration in a hybrid regulatory structure, which presents different institutional impediments than traditional cost-of-service ratemaking or rate-of-return regulation. We demonstrate that the primary impediment to improved integration is a failure to make the critical policy choice about how such costs will be allocated. Part III describes and analyzes the BPA-wind dispute in order to evaluate the adequacy of the existing legal regime to address this policy issue. Part IV describes and analyzes a suite of strategies proposed by the Western Governors’ Association (WGA) to reduce the cost of integrating renewable generation. Finally, Part V demonstrates that FERC Order No. 764 is only a first step toward improved integration because it does not address the fundamental policy decision regarding the distribution of integration costs and methods for cost recovery. We then offer recommendations for action by FERC, state regulators, state legislatures, and Congress to promote improved integration of renewable generation. Throughout the Article, we distinguish between four distinct (but interrelated) integration problems: (1) the technical challenges of integrating variability; (2) the economic costs of integrating variability; (3) the policy choice regarding distribution of integration costs; and (4) the legal framework for implementing that policy. Proper analysis of the technical, economic, and legal issues depends on the critical policy choice regarding cost allocation. Resolution of the cost allocation policy decision is therefore essential to development of a new institutional structure that will promote high levels of renewable generation