BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology.

BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel discrimination, and support vector machine methods. Specialized data sets are also available, such as binding data for hundreds of congeneric series of ligands, drawn from BindingDB and organized for use in validating drug design methods. BindingDB offers several forms of programmatic access, and comes with extensive background material and documentation. Here, we provide the first update of BindingDB since 2007, focusing on new and unique features and highlighting directions of importance to the field as a whole

Statistical mechanics of geomagnetic orientation in sediment bacteria

Also published as: Biological Bulletin 159 (1980): 459-460Last year we reported on time-of-transit experiments in which magnetically orienting bacteria crossed a 1-mm stretch in the direction of a uniform magnetic field. The bacteria were found to behave as tiny self-propelled compass needles subject both to magnetic field alignment and to the randomizing effect of thermal agitation. In strong fields, magnetic bacteria are held in tight aligment; in weaker fields, their swimming paths meander more and transit times are greater. Paul Langevin derived an expression for the distribution of orientation in an ensemble of free-moving dipole particles as a function of ambient field strength. His theory becomes applicable to our experiments when bacterial migration is analyzed as a sequence of short steps during each of which the cell swims in a direction randomly selected from the Langevin distribution . The duration of each step, Δt, is actually a time constant of the cell's loss of directionality due to thermal agitation. By thus treating the migration as a process of random walk with drift, we are able to predict the mean and variance of the time of transit across a 1-mm stretch.Prepared for the Office of Naval Research under Contract N00014-79-C-0071

Charge as a Selection Criterion for Translocation through the Nuclear Pore Complex

Nuclear pore complexes (NPCs) are highly selective filters that control the exchange of material between nucleus and cytoplasm. The principles that govern selective filtering by NPCs are not fully understood. Previous studies find that cellular proteins capable of fast translocation through NPCs (transport receptors) are characterized by a high proportion of hydrophobic surface regions. Our analysis finds that transport receptors and their complexes are also highly negatively charged. Moreover, NPC components that constitute the permeability barrier are positively charged. We estimate that electrostatic interactions between a transport receptor and the NPC result in an energy gain of several kBT, which would enable significantly increased translocation rates of transport receptors relative to other cellular proteins. We suggest that negative charge is an essential criterion for selective passage through the NPC.Merck Research LaboratoriesNational Science Foundation (U.S.) (Division of Mathematical Sciences)Kavli Institute for Bionano Science & Technology at Harvard UniversityNational Centers for Systems Biology (U.S.) (NIGMS grant GM068763)National Institute of General Medical Sciences (U.S.

Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate.

Type IIA topoisomerases (Top2s) manipulate the handedness of DNA crossovers by introducing a transient and protein-linked double-strand break in one DNA duplex, termed the DNA-gate, whose opening allows another DNA segment to be transported through to change the DNA topology. Despite the central importance of this gate-opening event to Top2 function, the DNA-gate in all reported structures of Top2-DNA complexes is in the closed state. Here we present the crystal structure of a human Top2 DNA-gate in an open conformation, which not only reveals structural characteristics of its DNA-conducting path, but also uncovers unexpected yet functionally significant conformational changes associated with gate-opening. This structure further implicates Top2's preference for a left-handed DNA braid and allows the construction of a model representing the initial entry of another DNA duplex into the DNA-gate. Steered molecular dynamics calculations suggests the Top2-catalyzed DNA passage may be achieved by a rocker-switch-type movement of the DNA-gate

Civil society and international governance: the role of non-state actors in the EU, Africa, Asia and Middle East

Structures and processes occurring within and between states are no longer the only – or even the most important - determinants of those political, economic and social developments and dynamics that shape the modern world. Many issues, including the environment, health, crime, drugs, migration and terrorism, can no longer be contained within national boundaries. As a result, it is not always possible to identify the loci for authority and legitimacy, and the role of governments has been called into question. \ud \ud Civil Society anf International Governance critically analyses the increasing impact of nongovernmental organisations and civil society on global and regional governance. Written from the standpoint of advocates of civil society and addressing the role of civil society in relation to the UN, the IMF, the G8 and the WTO, this volume assess the role of various non-state actors from three perspectives: theoretical aspects, civil society interaction with the European Union and civil society and regional governance outside Europe, specifically Africa, East Asia and the Middle East. It demonstrates that civil society’s role has been more complex than one defined in terms, essentially, of resistance and includes actual participation in governance as well as multi-facetted contributions to legitimising and democratising global and regional governance

Membraneless flow battery leveraging flow-through heterogeneous porous media for improved power density and reduced crossover

We propose and demonstrate a novel flow battery architecture that replaces traditional ion-exchange membranes with less expensive heterogeneous flow-through porous media. Compared to previous membraneless systems, our prototype exhibits significantly improved power density (0.925 W cm[superscript -2]), maximum current density (3 A cm[suprescript -2]), and reactant crossover, shown by the proposed experimentally-validated crossover model

Brief of Corporate Law Professors as Amici Curie in Support of Respondents

The Supreme Court has looked to the rights of corporate shareholders in determining the rights of union members and non-members to control political spending, and vice versa. The Court sometimes assumes that if shareholders disapprove of corporate political expression, they can easily sell their shares or exercise control over corporate spending. This assumption is mistaken. Because of how capital is saved and invested, most individual shareholders cannot obtain full information about corporate political activities, even after the fact, nor can they prevent their savings from being used to speak in ways with which they disagree. Individual shareholders have no “opt out” rights or practical ability to avoid subsidizing corporate political expression with which they disagree. Nor do individuals have the practical option to refrain from putting their savings into equity investments, as doing so would impose damaging economic penalties and ignore conventional financial guidance for individual investors

Hepatitis B serological markers and plasma DNA concentrations.

OBJECTIVES: To examine hepatitis B (HBV) serological markers and plasma DNA concentrations in a large group of untreated HBV/HIV-coinfected individuals in two sub-Saharan settings. DESIGN: Baseline analysis of a randomized controlled trial. METHODS: DART was a large trial of treatment monitoring practices in HIV-infected adults with advanced disease starting antiretroviral therapy at centres in Kampala or Entebbe, Uganda (n = 2317) and Harare, Zimbabwe (n = 999). HBV serological markers [antibody to HBV core antigen, HBV surface antigen (HBsAg), antibody to HBV surface antigen, HBV 'e' antigen (HBeAg), and antibody to hepatitis B 'e' antigen] and plasma HBV DNA viral load were measured retrospectively on stored baseline samples. Logistic regression was used to examine associations with baseline demographic and clinical factors. RESULTS: The rate of HBsAg positivity was significantly higher in Zimbabwe than Uganda (12.2 vs. 7.7%, adjusted odds ratio = 1.54, P < 0.001) despite a similar prevalence of antibody to HBV core antigen (56.3 vs. 52.4%) in the two settings. Overall, HBsAg positivity was associated with male sex (adjusted odds ratio = 1.54, P < 0.001) but not with age, WHO disease stage, or CD4 cell count. HBeAg was detected among 37% of HBsAg-positive patients, with higher rates among those with advanced WHO stage (P = 0.02). Also in HBsAg-positive patients, HBV DNA was undetectable in 21%, detectable but below the level of quantification in 14%, and quantifiable in 65%. A total of 96% of HBeAg-positive and 70% of HBeAg-negative patients had detectable HBV DNA; 92 and 28% of patients, respectively, had HBV DNA viral load more than 2000 IU/ml. CONCLUSION: High rates of HBV coinfection were observed, highlighting the importance of ensuring that coinfected patients receive an antiretroviral regimen, whether first-line or not, that is active against both viruses