Structure of the human histamine H1 receptor complex with doxepin

The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp?428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys?191(5.39) and/or Lys?179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.     

First episode psychosis with extrapyramidal signs prior to antipsychotic drug treatment

Extrapyramidal movement disorders are common in chronic schizophrenia, and may be an intrinsic feature of the illness as well as related to antipsychotic drug treatment. Similar dysfunctions at illness onset may have implications for outcome, and for under- standing the mechanisms of illness. The objectives were to examine the clinical correlates of pre-treatment movement disorders at first episode of psychosis, and determine associations with neuropsychological function and striatal structure. Never medicated subjects were recruited from consecutive admissions to Early Psychosis Programs with defined catchment areas in Hong Kong, China, and Halifax, Canada. Standardized clinical, neuropsychological and brain imaging assessments were carried out at baseline and following acute and long term treatment with typical or atypical antipsychotic drugs. At the Hong Kong site, we studied 84 subjects with first episode psychosis (n = 10 with EPS). At the Halifax site, we studied 40 subjects with first episode psychosis (n = 17 with EPS), and 23 healthy comparison subjects. Subjects with movement disorders prior to treatment (EPS+) had higher total PANSS scores at baseline (mean elevation 19.9% Hong Kong, P = 0.016; 14.7% Halifax, P = 0.049). In subjects treated with atypical antipsychotics (all Halifax), EPS+ status at baseline predicted more movement disorders at long term follow up (P = 0.0005). In both cohorts, EPS+ subjects had poorer acute symptomatic treatment response assessed with the PANSS (Hong Kong P = 0.005; Halifax P = 0.017). Neuropsychological impairment related to executive dysfunction appeared greater in a small sam- ple of EPS+ subjects (Hong Kong, effect size 0.26-0.27, P < 0.05). Caudate volumes were 4.5% larger in EPS+ compared with EPS-subjects (Halifax P = 0.042), and correlations between striatal volumes and age were different in the EPS+ group. In conclu- sion, pre-treatment EPS is present in a substantial minority of subjects with first episode psychosis, appears to persist at long term follow up, and is associated with poorer response of symptoms to treatment. Selective impairment of executive function and stria- tal enlargement provides evidence of abnormalities of brain function and structure associated with this aspect of early psychosis.     

The type Ia supernova SNLS-03D3bb from a super-Chandrasekhar-mass white dwarf star

The accelerating expansion of the Universe, and the need for dark energy, were inferred from observations of type Ia supernovae. There is a consensus that type Ia supernovae are thermonuclear explosions that destroy carbon-oxygen white dwarf stars that have accreted matter from a companion star, although the nature of this companion remains uncertain. These supernovae are thought to be reliable distance indicators because they have a standard amount of fuel and a uniform trigger: they are predicted to explode when the mass of the white dwarf nears the Chandrasekhar mass of 1.4 solar masses (M(o)). Here we show that the high-redshift supernova SNLS-03D3bb has an exceptionally high luminosity and low kinetic energy that both imply a super-Chandrasekhar-mass progenitor. Super-Chandrasekhar-mass supernovae should occur preferentially in a young stellar population, so this may provide an explanation for the observed trend that overluminous type Ia supernovae occur only in 'young' environments. As this supernova does not obey the relations that allow type Ia supernovae to be calibrated as standard candles, and as no counterparts have been found at low redshift, future cosmology studies will have to consider possible contamination from such events.     

An integrated view of the chemistry and mineralogy of martian soils

The mineralogical and elemental compositions of the martian soil are indicators of chemical and physical weathering processes. Using data from the Mars Exploration Rovers, we show that bright dust deposits on opposite sides of the planet are part of a global unit and not dominated by the composition of local rocks. Dark soil deposits at both sites have similar basaltic mineralogies, and could reflect either a global component or the general similarity in the compositions of the rocks from which they were derived. Increased levels of bromine are consistent with mobilization of soluble salts by thin films of liquid water, but the presence of olivine in analysed soil samples indicates that the extent of aqueous alteration of soils has been limited. Nickel abundances are enhanced at the immediate surface and indicate that the upper few millimetres of soil could contain up to one per cent meteoritic material.     

Detection of Design Fault in Dart Placement - intersecting Dart

It is easy to apply lines in design drawings to create different styles, however, there is no guarantee that all the style lines drawn are able to be manufactured. In this paper, we focus on one undeliverable style to enhance our understanding of the relationship between the design sketch and the pattern design process. In order to evidence that such style is unworkable, a systematic display of pattern development, and to be reinforced by mathematical evaluation, will be introduced and addressed. When one can easily detect design fault, waste of product development time can be minimized.