A Structural Rationale for N-Methylbicuculline Acting as a Promiscuous Competitive Antagonist of Inhibitory Pentameric Ligand-Gated Ion Channels

Bicuculline, a valued chemical tool in neurosciences research, is a competitive antagonist of specific GABA_A receptors and affects other pentameric ligand-gated ion channels including the glycine, nicotinic acetylcholine and 5-hydroxytryptamine type 3 receptors. We used a fluorescence-quenching assay and isothermal titration calorimetry to record low-micromolar dissociation constants for N-methylbicuculline interacting with acetylcholine-binding protein and an engineered version called glycine-binding protein (GBP), which provides a surrogate for the heteromeric interface of the extracellular domain of the glycine receptor (GlyR). The 2.4 Å resolution crystal structure of the GBP:N-methylbicuculline complex, sequence and structural alignments reveal similarities and differences between GlyR and the GABA_A receptor–bicuculline interactions. N-methylbicuculline displays a similar conformation in different structures, but adopts distinct orientations enforced by interactions and steric blocks with key residues and plasticity in the binding sites. These features explain the promiscuous activity of bicuculline against the principal inhibitory pentameric ligand-gated ion channels in the CNS.     

Applying a socially inspired technique (tags) to improve cooperation in P2P networks

In this paper, we focus on the problem of maintaining significant levels of cooperation in peer-to-peer (P2P) networks of selfish adaptive peers. We propose a simple algorithm that maintains high levels of cooperation in such a network while performing the collective task of file sharing. The algorithm is adapted from novel "tag" models of cooperation that do not rely on explicit reciprocity, reputation or trust mechanisms. A sequence of three simulation models is presented-starting with an abstract model of tag-based cooperation (TagWorld) and finishing with a P2P file-sharing model (FileWorld) that puts the technique to work. From analysis of extensive computer simulations, we demonstrate the technique to be scalable, robust, and decentralized; it requires no central servers or authorities. The algorithm is relatively simple: peers do not need to store additional trust information about other nodes or to perform significant additional processing.     

Compositional changes due to the removal of one constituent in an alloy by a surface reaction

The depletion of an alloy by the selective removal of one element is considered when various rate laws apply. Duhamel's technique has been employed to obtain analytical solutions for the change in alloy composition with time. The effect of the depletion of the matrix by selective oxidation on the subsequent oxidation behavior of the alloy is discussed in terms of operating temperature of the alloy.Notation C concentration of solute (g cm^–3) - C _m bulk concentration of solute (g cm^–3) - C(x, t) concentration of solute at distancex from surface after timet(g cm^–3) - t time - x distance - W _o increase in weight due to takeup of oxygen - W _m change in weight due to metal entering the oxide - M _o molecular weight of anion - M _m molecular weight of cation - Z valency of cation - 2M _m/M _o - k _l linear rate constant (g cm^–2 sec^–1) - k _p andk _p parabolic rate constants (g² cm^–4 sec^–1) - k _e andk _e logarithmic rate constants - D diffusion coefficients of solute in metal     

The influence of metal lattice vacancies on the oxidation of high temperature materials

When an oxide scale grows on a metal by the outward diffusion of cations, it is anticipated theoretically that lattice vacancies will be injected into the metal substrate. Experiments are reviewed which provide direct evidence for vacancy injection, including X-ray and electron microscope observations of the growth of vacancy dislocation loops and optical microscopy of voids. The influence of a vacancy supersaturation on the kinetics of oxidation is discussed in detail, but the effects are shown to be small in practical cases. The main consequence of vacancy injection is shown to be the eventual breakdown of the initial scale and subsequent growth of a duplex porous oxide. In some cases, this transition has undesirable consequences such as carburization/decarburization of the underlying metal and “breakaway” oxidation.     

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer.     

Fetal growth and hyperinsulinaemia in adult life

To explore the relation between reduced fetal growth and impaired glucose tolerance in adult life, an oral glucose tolerance test (75 g glucose) was carried out on 218 men and women, now aged around 50 years, who had been measured in detail at birth. Measurements of plasma concentrations of glucose and insulin were made at 0, 30, and 120 min. Fasting plasma concentrations of proinsulin and 32-33 split proinsulin were also measured. People in the highest category of birthweight tended to have the lowest plasma concentrations of insulin as adults at both 0 and 120 min, though both these relations were weak. Plasma insulin concentrations in adult life were more strongly related to abdominal circumference at birth than to birthweight. After adjusting for sex and body mass index, mean insulin concentrations at 0 min fell from 50 pmol l-1 to 46 pmol l-1 (p = 0.04) and at 120 min from 235 pmol l-1 to 144 pmol l-1 (p = 0.003) between people whose abdominal circumference at birth had been less than 11.5 in and those who abdominal circumference had been greater than 13 in. Plasma glucose concentrations at 120 min also fell with increasing abdominal circumference at birth. Because abdominal circumference at birth is an indicator of the growth of the liver in fetal life, one interpretation of these findings is that the sensitivity of the liver to insulin is permanently reduced if the intrauterine development of this organ is impaired.     

Whatever happened to scholarly discourse? A reply to B. F. Skinner.

Comments that B. F. Skinner (see record 1988-00027-001) has presented an egregiously inaccurate characterization of humanistic psychology. The authors note that Skinnerian radical behaviorism emphasizes behavior, science, and technology, while humanistic psychologies emphasize human beings. (PsycINFO Database Record (c) 2010 APA, all rights reserved)