Effect of Ions and Sequence Variants on the Antagonist Binding Properties of the Histamine H1 Receptor

The histamine H₁ receptor (H₁R) is a G protein-coupled receptor (GPCR) and represents a main target in the treatment of allergic reactions as well as inflammatory reactions and depressions. Although the overall effect of antagonists on H₁ function has been extensively investigated, rather little is known about the potential modulatory effect of ions or sequence variants on antagonist binding. We investigated the dynamics of a phosphate ion present in the crystal structure and of a sodium ion, for which we determined the position in the allosteric pocket by metadynamics simulations. Both types of ions exhibit significant dynamics within their binding site; however, some key contacts remain stable over the simulation time, which might be exploited to develop more potent drugs targeting these sites. The dynamics of the ions is almost unaffected by the presence or absence of doxepin, as also reflected in their small effect (less than 1 kcal·mol⁻¹) on doxepin binding affinity. We also examined the effect of four H₁R sequence variants observed in the human population on doxepin binding. These variants cause a reduction in doxepin affinity of up to 2.5 kcal·mol⁻¹, indicating that personalized medical treatments that take into account individual mutation patterns could increase precision in the dosage of GPCR-targeting drugs.     

AUTOMATIC DELINEATION OF FUNCTIONAL RIVER REACH BOUNDARIES FOR RIVER RESEARCH AND APPLICATIONS

The river reach is a pervasive term within contemporary river research and applications. Yet, despite its prevalence, there is a notable lack of consistency in its definition. This paper identifies the presence of two broad types of reach definition within the academic literature, operational and functional, and argues that a functional definition is more suitable for applications within river research and management. A range of sequence zonation algorithms that were originally derived for geological well‐log analysis were compared for their ability to automatically identify functional reach boundaries. An analysis of variance‐based global boundary hunting algorithm was identified as the most suitable. To demonstrate the potential practical applications of automatic reach delineation methods, two case studies where functional reach boundaries have been identified were described: first, in a sequence of predicted sediment transport capacities for use in a reach‐based sediment transport model; and second, in a sequence of RHS Habitat Quality Assessment scores for identification of lengths of channel in need of habitat restoration efforts. Finally, the paper discusses how this type of functional reach identification procedure might be applied in other areas of river research and applications and how a multivariate version of a statistical zonation algorithm might prove useful in facilitating integrated catchment management by identifying reach boundaries common across all variables of interest in the system. Copyright © 2011 John Wiley & Sons, Ltd.     

Effect of radiographic positioning on interpretation of cubital joint congruity in dogs

OBJECTIVE: To ascertain effects of x-ray beam centering and limb position on apparent congruity of a normal cubital joint (elbow). ANIMALS: 6 skeletally mature male Treeing Walker Coonhounds without physical, radiographic, or gross evidence of elbow abnormalities. PROCEDURE: Relative movement among humerus, radius, and ulna and measured joint space width on mediolateral and craniocaudal radiographic views was compared, using various x-ray beam centering and limb positions. RESULTS: Highest agreement and greatest certainty on subjective determination of congruity was for the flexed 90 degrees mediolateral radiographic view with the x-ray beam centered on the elbow. Distortion artifact of the proximal ulnar measurements was significant when the x-ray beam was centered on the midpoint of the radius. On the mediolateral view, the humeroradial joint space became significantly wide when the elbow was flexed. On the craniocaudal view, maximal humeroradial joint space width was obtained when the x-ray beam bisected the angle of the joint or was angled +30 degrees toward the humerus. CONCLUSIONS: Artifact distortion of joint width affected objective and subjective assessment of elbow congruity when the limb was placed in extreme flexion or extension or when the x-ray beam was not centered over the area of interest. Optimal visualization of the humeroradial joint space on the craniocaudal view was achieved when the x-ray beam bisected the angle of the elbow or was slightly angled toward the humerus. CLINICAL RELEVANCE: Elbow congruity was best assessed on the flexed 90 degrees lateral radiographic view with the x-ray beam centered on the joint.     

The HLD (CalMod) index and the index question

Twenty free-ranging guanaco (Lama guanicoe) in Chubut Province, Argentina, were immobilized for health evaluations. All but two animals appeared to be in good condition. Hematology, serum chemistry, and vitamin and mineral levels were measured, and feces were evaluated for parasites. Serology tests included bluetongue, brucellosis, bovine respiratory syncitial virus, bovine viral diarrhea/mucosal disease, equine herpesvirus 1, infectious bovine rhinotracheitis, Johne's disease (Mycobacterium paratuberculosis), foot and mouth disease, leptospirosis (17 serovars), parainfluenza-3, and vesicular stomatitis. Blood samples from 20 domestic sheep (Ovis aries) maintained in the same reserve with the guanaco were also collected at the same time for serology tests. No guanaco had positive serologic tests. Sheep were found to have antibody titers to bovine respiratory syncytial virus, Johne's disease, leptospirosis, and parainfluenza-3. There was no apparent difference in external appearance or condition, or statistical difference in blood test values, between the animals that were positive or negative for parasite ova.     

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses

In an in-vitro preparation of gastric mucosae of Rana pipiens, the effect of adding melittin to a concentration of 5x10-6 M in the secretory solution on the transepithelial potential difference (PD), resistance (R) and short-circuit current (Isc) was studied. In 20 min, melittin decreased the PD by 9.3 mV and R by 148 ohm cm2. These changes can be explained by a decrease in the resistance, RP, of the paracellular pathway. To determine whether specific-ion pathways were responsible for the decrease in R, the effect of melittin on the partial conductances of Cl-, K+ and Na+ was also studied using the ion substitution method. Melittin decreased the PD response to changes in nutrient Na+, K+ and Cl- and the PD response to changes in secretory Cl-, but did not affect PD responses to changes in secretory Na+ or K+. Therefore, melittin decreased the nutrient membrane partial conductances of Cl-, K+ and Na+ and secretory membrane partial conductance of Cl-, without affecting the secretory partial conductances of Na+ or K+. Initially, melittin increased Isc in regular and Cl--free but not in Na+-free solutions. There was a delayed decrease in Isc. The results indicate that melittin decreases RP, increases the Na+ conductance of the secretory membrane and inhibits, eventually, the Na+/K+-ATPase pump.     

Influence of bearing stiffness on the static properties of a planetary gear system with manufacturing errors

Hybrid finite element analysis was used to analyze the influence of bearing stiffness on the static properties of a planetary gear system with manufacturing errors. The effects of changes in stiffness were similar for most of the manufacturing errors. State variables were most affected by the stiffness of the planet bearings. Floating either the sun or carrier helps to equal load sharing and minimizes the critical tooth stress. The effects of a floating sun and carrier are similar, but it is not recommended that both float, because this can induce greater critical tooth stress. Planet bearing stiffness should be optimized. Both load sharing and critical tooth stress should be considered to determine optimal bearing stiffness.     

Lubricants and lubricant additives: I. Performance characteristics of N-mono and N,N-Disubstituted fatty amides and modified fatty amides

A number of N-mono and N,N-disubstituted amides of substituted and unsubstituted C₁₈ fatty acids have been prepared and evaluated as base lubricants and lubricant additives. The neat epithioamides possess extreme pressure lubricant characteristics and are noncorrosive at normal temperatures. The epithioamides also frequently function as extreme pressure additives and antiwear agents for paraffinic or diester base oils, sometimes in both capacities for both base oils. The intensiveness of these properties correlated directly with the degree of thiirane substitution in the compound. Performance in both these capacities at the same levels of epithioation was dependent upon the N- or N,N-substituent groups present. One of 12 papers presented in the symposium “Novel Uses of Agricultural Oils” at the AOCS Spring Meeting, New Orleans, April 1973. ARS, USDA.     

Effect of Pre-coated Vs. Added Coupling Agents on the Vulcanization of Silica-filled Polyisoprene

Solid-state ¹³C NMR was utilized in analysis of the crosslink structure in silica-filled polyisoprene. Samples containing either a pre-coated coupling agent, a coupling agent added in the mixing process, or polyethylene glycol (PEG) were vulcanized and the type and density of crosslinking determined. The precoated coupling agent sample gave lower %swelling, lower extraction amounts, and a lower T ₂ relaxation than the mixed coupling agent, indicating increased crosslinking or increased filler –rubber interaction. The precoated also showed less cis –trans isomerization than the mixed, which may be due to its more uniform coating effect on the silica. The PEG sample yielded a ¹³C spectrum similar to an unfilled sample indicating decreased silica adsorption of vulcanization agents. Neither coupling agent significantly decreased the total sulfurization nor the percent monosulfidic crosslinks from that of a silica-filled sample without coupling agent.