bluuebunny/crossref_metadata_2025 huggingface dataset:
Delphinidin and cyanidin inhibit PDGFAB‐induced VEGF release in vascular smooth muscle cells by preventing activation of p38 MAPK and JNK
Authors: Oak M‐H , Bedoui J E , Madeira S V F , Chalupsky K , Schini‐Kerth V B
Published: August 2006

Background and purpose:

Red wine polyphenols (RWPs) inhibit the expression of vascular endothelial growth factor (VEGF), a major pro‐angiogenic and pro‐atherosclerotic factor, in vascular smooth muscle cells (VSMCs). The aim of this study was to identify which red wine polyphenols were inhibitory and to determine the mechanism underlying the inhibitory effects.

Experimental approach:

Release of VEGF stimulated by platelet derived growth factorAB (PDGFAB), from human aortic VSMCs was measured by immunoassay and phosphorylation of kinases by Western blot analysis. The direct antioxidant properties of polyphenols were determined by electron paramagnetic resonance and the cellular formation of reactive oxygen species (ROS) by dichlorofluorescein.

Key results:

The inhibitory effect of RWPs on PDGFAB‐induced release of VEGF was mimicked by delphinidin but not by quercetin, catechins, resveratrol, gallic acid or caffeic acid. In the anthocyanin class, not only delphinidin but also cyanidin prevented VEGF release whereas malvidin and peonidin were without effect. RWPs, delphinidin and cyanidin directly scavenged ROS and prevented the PDGFAB‐induced formation of ROS in VSMCs. Malvidin and peonidin did not scavenge ROS but prevented the cellular formation of ROS. Although the p38 MAPK, ERK1/2 and JNK pathways have been involved in the PDGFAB‐induced expression of VEGF, in our experiments, only phosphorylation of p38 MAPK and JNK was inhibited by RWPs, delphinidin and cyanidin.

Conclusions and implications:

Anthocyanins presenting a hydroxyl residue at position 3′ are able to inhibit PDGFAB‐induced VEGF expression by preventing activation of p38 MAPK and JNK in VSMCs.

British Journal of Pharmacology (2006) 149, 283–290. doi:10.1038/sj.bjp.0706843
Greater antiarrhythmic activity of acute 17β‐estradiol in female than male anaesthetized rats: correlation with Ca2+ channel blockade
Authors: Philp K L , Hussain M , Byrne N F , Diver M J , Hart G , Coker S J
Published: August 2006

Background and purpose:

Female sex hormones may protect pre‐menopausal women from sudden cardiac death. We therefore investigated the effects of the main female sex hormone, 17β‐estradiol, on ischaemia‐induced cardiac arrhythmias and on the L‐type Ca2+ current (ICaL).

Experimental approach:

In vivo experiments were performed in pentobarbital‐anaesthetized rats subjected to acute coronary artery occlusion. ICaL was measured by the whole‐cell patch‐clamp technique, in rat isolated ventricular myocytes.

Key results:

Acute intravenous administration of 17β‐estradiol as a bolus dose followed by a continuous infusion, commencing 10 min before coronary artery occlusion, had dose‐dependent antiarrhythmic activity. In female rats 300 ng kg‐1 + 30 ng kg−1 min−1 17β‐estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17β‐estradiol was required to cause similar effects in male rats. In vitro 17β‐estradiol reduced peak ICaL in a concentration‐dependent manner. The EC50 was ten‐fold higher in male myocytes (0.66 μM) than in females (0.06 μM).

Conclusions and implications:

These results indicate that 17β‐estradiol has marked dose‐dependent antiarrhythmic activity that is greater in female rats than in males. A similar differential potency in blocking ICaL in myocytes from female and male rats can account for this effect. This provides an explanation for the antiarrhythmic activity of 17β‐estradiol and gender‐selective protection against sudden cardiac death.

British Journal of Pharmacology (2006) 149, 233–242. doi:10.1038/sj.bjp.0706850
Sex hormones and arrhythmia in myocardial ischemia
Authors: Korte T , Grohé C
Published: August 2006

The mechanisms by which gender affects cardiac electrophysiological parameters and alters the predisposition to certain arrhythmias are not well understood, although differences in the expression and function of ion channels and in the activation of the autonomic nervous system may contribute. In their study Philp and coworkers address the issue of the effect of 17β‐estradiol on ventricular vulnerability in a rat model of ischemia. Their data show that there is a dose‐dependent antiarrhythmic activity of 17β‐estradiol administration with suppression ventricular premature beats, ventricular tachycardia and ventricular fibrillation during ischemia. Furthermore they show a dose‐dependent blockage of ICaL by 17β‐estradiol which is again stronger in female than in male mice. They postulate that the shown gender‐selective, concentration‐dependent inhibition of ICaL is sufficient to account for the reduction in ischaemia‐induced arrhythmia. With this data they have added important information on the influence of sex hormones on cardiac electrophysiology under pathophysiological conditions.

British Journal of Pharmacology (2006) 149, 227–228. doi:10.1038/sj.bjp.0706851
Pretreatment with simvastatin reduces myocardial no‐reflow by opening mitochondrial KATP channel
Authors: Zhao J‐L , Yang Y‐J , Cui C‐J , You S‐J , Gao R‐L
Published: August 2006

Background and purpose:

Simvastatin, a cholesterol‐lowering agent, can protect against endothelial dysfunction. However, the effects of simvastatin treatment on the restoration of blood flow to ischemic myocardium are not known. This study sought to assess such effects of simvastatin on an experimental model of myocardial no‐reflow and to explore possible mechanisms.

Experimental approach:

Coronary ligation area and area of no‐reflow were determined by myocardial contrast echocardiography in vivo and by histology in mini‐pigs randomized into 7 study groups: controls, pretreated with simvastatin for 2 days, treated with 5‐hydroxydecanoate (5‐HD, the selective mitochondrial KATP channel blocker), treated with simvastatin+5‐HD, treated with HMR 1883 (the selective sarcolemmal KATP channel blocker), treated with simvastatin+HMR 1883 and a sham‐operated group. The myocardial no‐reflow model was induced with 3 h occlusion of the left anterior descending coronary artery followed by 2 h reperfusion.

Key results:

Compared with the control group, simvastatin significantly increased coronary blood flow, decreased the area of no‐reflow assessed echocardiographically and reduced the necrotic area, by histology. There was no significant difference in these outcomes between simvastatin and simvastatin+HMR 1883 groups. In contrast, 5‐HD abolished the effect of simvastatin.

Conclusions and implications:

Simvastatin can reduce the area and myocardial no‐reflow after ischaemia and reperfusion. This beneficial effect is due to its activation of mitochondrial KATP channels.

British Journal of Pharmacology (2006) 149, 243–249. doi:10.1038/sj.bjp.0706862
Statin therapy and myocardial no‐reflow
Authors: Calvert J W , Lefer D J
Published: August 2006

HMG‐CoA reductase inhibitors (statins) have now become one of the most powerful pharmacological strategies in the treatment of cardiovascular diseases. Originally, the cardioprotective effects of statins were thought to be mediated through lipid lowering actions. However, it has now become increasingly clear that the beneficial effects of statins are not related to the lipid lowering effects, but rather to a number of pleiotropic actions. Of particular interest, statins have been shown to increase bioavailability of nitric oxide and protect against vascular inflammation and cardiac cell death in a number of cardiovascular disease states. In this present issue of the British Journal of Pharmacology, Zhao and colleagues provide a novel mechanism of action for statins with the observation that simvastatin reduces myocardial ‘no‐reflow’ after ischemia and reperfusion by activating the mitochondrial KATP channel. The findings of the present study have very profound implications for the treatment of cardiovascular disease. This commentary discusses the implications of these findings and how they relate to the established cardioprotective actions of statins.

British Journal of Pharmacology (2006) 149, 229–231. doi:10.1038/sj.bjp.0706863
Evaluation of the pharmacological activity of the major mexiletine metabolites on skeletal muscle sodium currents
Authors: De Bellis M , De Luca A , Rana F , Cavalluzzi M M , Catalano A , Lentini G , Franchini C , Tortorella V , Conte Camerino D
Published: August 2006

Background and purpose:

Mexiletine (Mex), an orally effective antiarrhythmic agent used to treat ventricular arrhythmias, has also been found to be effective for myotonia and neuropathic pain. It is extensively metabolized in humans but little information exists about the pharmacodynamic properties of its metabolites.

Experimental approach:

To determine their contribution to the clinical activity of Mex,p‐hydroxy‐mexiletine (PHM), hydroxy‐methyl‐mexiletine (HMM),N‐hydroxy‐mexiletine (NHM) (phase I reaction products) andN‐carbonyloxyβ‐D‐glucuronide (NMG) (phase II reaction product) were tested on sodium currents (INa) of frog skeletal muscle fibres. Sodium currents were elicited with depolarizing pulses from different holding potentials (HP=−140, −100, −70 mV) and stimulation frequencies (0.25, 0.5, 1, 2, 5, 10 Hz) using the vaseline‐gap voltage‐clamp method.

Key results:

All the hydroxylated derivatives blocked the sodium channel in a voltage‐ and use‐dependent manner. The PHM, HMM and NHM metabolites were up to 10‐fold less effective than the parent compound. However, HMM showed a greater use‐dependent behaviour (10 Hz), compared to Mex and the other metabolites. Similar to Mex, these products behaved as inactivating channel blockers. Conjugation with glucuronic acid (NMG) resulted in almost complete abolition of the pharmacological activity of the parent compound.

Conclusions and Implications:

Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.

British Journal of Pharmacology(2006)149, 300–310. doi:10.1038/sj.bjp.0706867
Tramadol, but not its major metabolite (mono‐O‐demethyl tramadol) depresses compound action potentials in frog sciatic nerves
Authors: Katsuki R , Fujita T , Koga A , Liu T , Nakatsuka T , Nakashima M , Kumamoto E
Published: August 2006

Background and purpose:

Although tramadol is known to exhibit a local anaesthetic effect, how tramadol exerts this effect is not understood fully.

Experimental approach:

The effects of tramadol and its metabolite mono‐O‐demethyl‐tramadol (M1) on compound action potentials (CAPs) were examined by applying the air‐gap method to frog sciatic nerves, and the results were compared with those of other local anaesthetics, lidocaine and ropivacaine.

Key results:

Tramadol reduced the peak amplitude of the CAP in a dose‐dependent manner (IC50=2.3 mM). On the other hand, M1 (1–2 mM), which exhibits a higher affinity forμ‐opioid receptors than tramadol, did not affect CAPs. These effects of tramadol were resistant to the non‐selective opioid receptor antagonist naloxone and theμ‐opioid receptor agonist, DAMGO, did not affect CAPs. This tramadol action was not affected by a combination of the noradrenaline uptake inhibitor, desipramine, and the 5‐hydroxytryptamine uptake inhibitor, fluoxetine. Lidocaine and ropivacaine also concentration‐dependently reduced CAP peak amplitudes with IC50values of 0.74 and 0.34 mM, respectively.

Conclusions and implications:

These results indicate that tramadol reduces the peak amplitude of CAP in peripheral nerve fibres with a potency which is less than those of lidocaine and ropivacaine, whereas M1 has much less effect on CAPs. This action of tramadol was not produced by activation ofμ‐opioid receptors nor by inhibition of noradrenaline and 5‐hydroxytryptamine uptake. It is suggested that the methyl group present in tramadol but not in M1 may play an important role in producing nerve conduction block.

British Journal of Pharmacology(2006)149, 319–327. doi:10.1038/sj.bjp.0706868
Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin
Authors: Choi Y H , Lee M G
Published: August 2006

Background and purpose:

The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats.

Experimental approach:

Metformin at a dose of 100 mg kg−1was administered intravenously to rats. The rats were pretreated with CYP inducers such as 3‐methylcholanthrene, orphenadrine, isoniazid, and dexamethasone (major inducers of CYP1A1/2, 2B1/2, 2E1, and 3A1/2, respectively, in rats), or CYP inhibitors such as SKF‐525 (a non‐specific inhibitor of CYP isozymes), and sulfaphenazole, quinine, and troleandomycin (major inhibitors of CYP2C11, 2D1, and 3A1/2, respectively, in rats). The time‐averaged non‐renal clearance (CLNR) of metformin was compared with that of controls.

Key results:

In rats pretreated with dexamethasone, the CLNRwas significantly faster (57% increase) than for the controls. In rats pretreated with SKF‐525‐A, sulfaphenazole, quinine, and troleandomycin, the CLNRwas significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CLNRvalues did not significantly different in the rats pretreated with 3‐methylencholanthrene, orphenadrine, and isoniazid compared with the controls.

Conclusions and implications:

Our data suggest that metformin was metabolized mainly via CYP2C11, 2D1, and 3A1/2 in rats. This result could contribute to understanding of the possible changes in metformin pharmacokinetics in disease models where CYP2C11 and/or 3A1/2 are altered.

British Journal of Pharmacology(2006)149, 424–430. doi:10.1038/sj.bjp.0706875
Identification of Thr283 as a key determinant of P2X7 receptor function
Authors: Young M T , Pelegrin P , Surprenant A
Published: August 2006

Background and purpose:

The ATP‐gated P2X7 receptor is an unusual ion channel that couples to multiple downstream signalling cascades. We noted differences in mouse cDNA sequences that may indicate polymorphisms; the aim of this study was to compare function and expression of these mouse P2X7 receptor mutations.

Experimental approach:

There are three differences in the sequences of P2X7 cDNA cloned from mouse NTW8 microglial cells or C57 BL/6 mice: [Phe11,Ala221,Met283]P2X7 in the former and [Leu11,Thr221,Thr283]P2X7 in the latter. We expressed these receptors and measured membrane currents, ethidium uptake, calcium influx and surface membrane expression. We also carried out these assays on the previously described polymorphism observed between C57 BL/6 and Balb/c mice ([Leu451]P2X7 vs [Pro451]P2X7).

Key results:

Maximum current densities at [Phe11,Ala221,Met283]P2X7 were <12% of those at [Leu11,Thr221,Thr283]P2X7 without change in the agonist concentration‐response. Replacing methionine with threonine at residue 283 yielded a receptor whose properties were the same as [Leu11,Thr221,Thr283]P2X7. Replacing T283 in the rat P2X7 receptor with methionine yielded currents that were <10% of wildtype and no ethidium uptake was associated with its activation. Maximum current densities and agonist EC50 values were the same at mouse [Thr283,Leu451]P2X7 and [Thr283,Pro451]P2X7 but ethidium uptake and Fluo4 fluorescence were significantly reduced at the [Thr283,Leu451]P2X7 receptor. There was equivalent surface membrane expression of all P2X7 receptors.

Conclusions:

This study has revealed a residue (Thr283) in the ectodomain that is critical for P2X7 receptor function and suggests that the intracellular residue 451 alters downstream signalling independently of ion channel activity.

British Journal of Pharmacology (2006) 149, 261–268. doi:10.1038/sj.bjp.0706880
Group-theoretical approach to reflectionless potentials
Authors: Kerimov G. A. , Ventura A.
Published: August 2006

We examine the general form of potentials with zero reflection coefficient in one-dimensional Hamiltonians connected with Casimir invariants of non-compact groups.
Diffusion process and formation of super-spin-glass state in soft magnetic Fe∕Pt system
Authors: Aurongzeb D. , Holtz M. , Menon Latika
Published: August 2006

We report results on surface and micromagnetic structures of Fe thin films consisting of a Pt underlayer. We use atomic force microscopy to study the surface structure evolution of the Fe films as a function of annealing time at an annealing temperature of 800°C. Power spectral density analysis shows saturation in roughness exponent after 15min of annealing. However, lateral correlation length and roughness continue to increase for up to 45min. At high annealing temperature, the authors find two separate phase correlation lengths and a single surface correlation length indicating super-spin-glass state in the system.
Improved performance of amorphous silicon solar cells via scattering from surface plasmon polaritons in nearby metallic nanoparticles
Authors: Derkacs D. , Lim S. H. , Matheu P. , Mar W. , Yu E. T.
Published: August 2006

An engineered enhancement in short-circuit current density and energy conversion efficiency in amorphous silicon p-i-n solar cells is achieved via improved transmission of electromagnetic radiation arising from forward scattering by surface plasmon polariton modes in Au nanoparticles deposited above the amorphous silicon film. For a Au nanoparticle density of ∼3.7×108cm−2, an 8.1% increase in short-circuit current density and an 8.3% increase in energy conversion efficiency are observed. Finite-element electromagnetic simulations confirm the expected increase in transmission of electromagnetic radiation at visible wavelengths, and suggest that substantially larger improvements should be attainable for higher nanoparticle densities.
Prospective emission efficiency and in-plane light polarization of nonpolar m-plane InxGa1−xN∕GaN blue light emitting diodes fabricated on freestanding GaN substrates
Authors: Koyama T. , Onuma T. , Masui H. , Chakraborty A. , Haskell B. A. , Keller S. , Mishra U. K. , Speck J. S. , Nakamura S. , DenBaars S. P. , Sota T. , Chichibu S. F.
Published: August 2006

Prospective equivalent internal quantum efficiency (ηint) of approximately 34% at 300K was demonstrated for the blue emission peak of nonpolar m-plane (11¯00) InxGa1−xN∕GaN multiple quantum well light emitting diodes (LEDs) fabricated on freestanding m-plane GaN substrates. Although the ηint value is yet lower than that of conventional c-plane blue LEDs (>70%), the results encourage one to realize high performance green, amber, and red LEDs by reducing the concentration of nonradiative defects, according to the absence of the quantum-confined Stark effects due to the polarization fields parallel to the quantum well normal. The electric field component of the blue surface emission was polarized perpendicular to the c axis with the in-plane polarization ratio of 0.58 at 300K.
Thermodynamic properties of short-range square well fluid
Authors: López-Rendón R. , Reyes Y. , Orea P.
Published: August 2006

The interfacial properties of short-range square well fluid with λ=1.15, 1.25, and 1.375 were determined by using single canonical Monte Carlo simulations. Simulations were carried out in the vapor-liquid region. The coexistence curves of these models were calculated and compared to those previously reported in the literature and good agreement was found among them. We found that the surface tension curves for any potential model of short range form a single master curve when we plot γ* vs T∕Tc. It is demonstrated that the critical reduced second virial coefficient B2* as a function of interaction range or Tc* is not constant.
Effect of surface morphology on the fracture strength of silicon nanobeams
Authors: Alan Tuncay , Hines Melissa A. , Zehnder Alan T.
Published: August 2006

The effect of nanoscale surface morphology on the fracture strength of 190-nm-thick, doubly clamped Si beams was measured experimentally. The surface morphology was controlled through aqueous etching and characterized by atomic force microscopy. The beams fractured along the primary cleavage planes, {111}. Fracture strength was extracted using finite element simulations of the experiment. Nanobeams etched with relatively smooth morphologies (0.4nm rms) were able to sustain a tensile stress of 15.8GPa, close to theoretical strengths predicted by previous atomistic calculations. In contrast, nanobeams decorated with nanometer-high step bunches (1.5nm rms) had a 20% lower fracture strength, 12.8GPa, suggesting that careful attention to processing is necessary for maximum strength.
X-ray diffuse scattering from stacking faults in thick 3C-SiC single crystals
Authors: Boulle A. , Chaussende D. , Latu-Romain L. , Conchon F. , Masson O. , Guinebretière R.
Published: August 2006

Stacking faults in thick (001)- and (111)-oriented 3C-SiC single crystals are studied by high resolution x-ray diffraction. The authors demonstrate that the analysis of the diffuse scattering intensity distribution can be used as a nondestructive means to accurately determine the densities of Shockley-type stacking faults. The diffuse scattering intensity is simulated with a scattering model based on a difference-equation description of faulting in fcc materials. It is shown that the (001) SiC crystals exhibit an anisotropic fault distribution, whereas the (111) SiC crystals exhibit an isotropic fault distribution, in excellent quantitative agreement with transmission electron microscopy observations.
Pressure-induced structural transformations in cadmium selenide nanorods
Authors: Lee Nicholas Jabari , Kalia Rajiv K. , Nakano Aiichiro , Vashishta Priya
Published: August 2006

Pressure induced structural transformations in cadmium selenide (CdSe) nanorods are studied using parallel molecular dynamics. Nanorods (4.4nm in diameter and 4.4 to 53nm in length) are embedded in a liquid and subjected to pressure. Reversible structural transformations are observed from wurtzite to a single domain rocksalt crystal phase. The simulation results reveal a decrease in transformation pressure with rod length. The transformation mechanism involves atomic shifts within the (0001) plane of the wurtzite structure and is similar to the one observed in electronic structure calculations of pressure-induced structural transformation in bulk CdSe.
Tailoring light polarization in vertical cavity surface emitting lasers by isotropic optical feedback from an extremely short external cavity
Authors: Arizaleta Arteaga Mikel , López-Amo Manuel , Thienpont Hugo , Panajotov Krassimir
Published: August 2006

The authors experimentally show that isotropic optical feedback from an extremely short external cavity can induce switching between the two fundamental transverse modes with orthogonal linear polarization of otherwise (without optical feedback) polarization stable vertical cavity surface emitting laser. The switching currents and the hysteresis width can be widely tuned by varying the external cavity length. Moreover, by a proper choice of the optical feedback parameters, the emission can be stabilized in any of the two linearly polarized modes.
Phylogenetic placement of Echinotheridion (Araneae:Theridiidae) - do male sexual organ removal, emasculation, and sexual cannibalism in Echinotheridion and Tidarren represent evolutionary replicas?
Authors: Agnarsson Ingi
Published: August 2006

Uniquely among spiders, males of two cobweb spider (Theridiidae) genera, Tidarren Chamberlin & Ivie, 1934 and Echinotheridion Levi, 1963, voluntarily amputate one of their secondary sexual organs (the pedipalpi, modified as sperm transfer organs) before their last molt and thus have only one palp as adults. This is the first step in a fascinating sexual biology observed in both genera, which is marked by sexual dimorphism – males are tiny compared with females – and usually involves both emasculation and sexual cannibalism. To study the evolution of these striking traits it is essential to understand the phylogenetic relationship of these genera. Both morphological and molecular data place Tidarren in the subfamily Theridiinae. However, Echinotheridion has not been placed phylogenetically to date owing to rarity of specimens, and difficulty of interpreting the highly autapomorphic palpal organ, the main source of morphological characters. Here, the phylogenetic position of Echinotheridion is inferred using fragments of three nuclear (Histone 3, 18S rDNA, and 28S rDNA) and two mitochondrial (16S rDNA and COI) loci. Each matrix separately, and a combined matrix, were analysed using parsimony with gaps either treated as missing data, or as 5th state, and with Bayesian methods. Although all genes agree that Tidarren and Echinotheridion are closely related, perhaps surprisingly, none of the analyses supported their sister relationship. The sister relationship was ambiguously supported in a preliminary morphological analysis, whereas combined molecular and morphological data refuted it. This implies a more complex evolutionary history of male sexual organ removal and other bizarre sexual biology of Tidarren and Echinotheridion than previously envisioned. Many of the analyses are equally consistent with two hypotheses: a single origin, followed by a secondary loss; or independent evolution of this behaviour in the two genera. However, based on the combined molecular Bayesian phylogeny, and some of the preliminary ‘total evidence’ analyses, the latter hypothesis is better supported.
A general look at female orgasm and anorgasmia
Authors: Redelman Margaret
Published: August 2006

Male and female genital anatomy evolves from the same embryonic tissue. Is it therefore possible that males and females have the same potential for orgasmic response? Have forces external to a woman’s biology influenced her potential enjoyment of this bodily function, or is female orgasm a by-product of that early sameness and variable because it has no or very little functional or evolutionary benefit? In modern times, we continue to study the anatomy and physiology of female sexual responses. The journey now is to understand the similarities and differences between the male and female sexual responses and be respectful of both. Female sexual response models and the classification of female sexual dysfunctions direct the thoughts and treatments of sexual and relationship therapists. The ultimate aim is to allow each woman to have the best possible sex life and orgasm, namely the one she wants. The psychophysiological treatments for female orgasmic dysfunction are on the whole successful. However, in anorgasmia proven to be biological in aetiology, following menopause for example, physiological changes occur that cannot be resolved by these strategies alone. We need to be supportive of the pharmaceutical industry finding medication that we can appropriately and responsibly use for the good of women with sexual difficulties, because good sexuality is a very important quality of life issue for very many women.
Demographic predictors of circumcision status in a community-based sample of homosexual men in Sydney, Australia
Authors: Templeton David J. , Mao Limin , Prestage Garrett , Kaldor John M. , Kippax Susan , Grulich Andrew E.
Published: August 2006

Male circumcision may reduce the risk of HIV acquisition in heterosexual men. In observational studies, confounding by demographic factors could produce spurious associations between circumcision and HIV risk. To assess this possibility, cross-sectional data on self-reported circumcision status and demographic factors were collected at baseline as part of the Health in Men study. Two-thirds of 1426 subjects were circumcised, mostly in the neonatal period. In multivariate analyses, age, ethnicity and country of birth were independently associated with circumcision status. Confounding by these demographic factors must be considered in future epidemiological studies addressing circumcision and HIV acquisition.
Making sense of syphilis: beliefs, behaviours and disclosure among gay men recently diagnosed with infectious syphilis and the implications for prevention
Authors: Lambert Natalie L. , Imrie John , Fisher Martin J. , Phillips Alan , Watson Rod , Dean Gill
Published: August 2006

Background: The resurgence of syphilis in men who have sex with men (MSM) has proved remarkably resilient in the face of innovative control and prevention interventions. Understanding the determinants of the current outbreaks has been restricted by the available data. Qualitative work is needed to understand individual and community experiences of syphilis and to help guide new prevention and control efforts. Methods: An exploratory study using semi-structured interviews with a convenience sample of MSM (n = 15), recently diagnosed with infectious syphilis, attending sexual health and HIV-outpatient services in Brighton, England. Results: Analysis focussed on men’s beliefs about syphilis, their experience of testing and being given a syphilis diagnosis, mediators of ‘risky’ sexual behaviour and disclosure to social and sexual contacts. Two beliefs — ‘syphilis is rare’ and ‘syphilis is dirty’ — dominated respondents’ accounts. These beliefs coloured every aspect of respondents’ clinical and social experience of syphilis, and impeded disclosure and partner notification. They also contributed to misconceptions about behaviours with increased syphilis transmission risk, the mechanics of disease acquisition, health-seeking behaviours and risk-reduction strategies. Conclusions: The apparent failure of syphilis control measures so far may be due to our limited understanding of MSM’s views and experience of STIs other than HIV. Syphilis prevention needs to tackle MSM’s widely held beliefs about sexual communication, risk behaviour and other STIs. The most useful health education interventions are likely to be those that build on MSM’s significant knowledge base and address both the current syphilis crisis and wider sexual health promotion goals.
Lymphogranuloma venereum in Australia
Authors: Simms Ian , Ward Helen , Martin Iona , Alexander Sarah , Ison Catherine
Published: August 2006

Lymphogranuloma venereum (LGV), caused by C. trachomatis serovars L1, L2 and L3, is an invasive disease capable of causing tissue destruction with many patients experiencing complex, severe symptoms. LGV, endemic to areas of Africa, Asia, South America and the Caribbean, has emerged as a cause of significant morbidity among men who have sex with men (MSM) in more affluent nations. The high prevalence of HIV in LGV cases could suggest either that LGV is confined to a dense sexual network, or that clinicians are selectively testing HIV-positive MSM for LGV. The increase in reported LGV cases highlights the need to improve sexual health overall among MSM; experience from the recent syphilis outbreaks suggests that control could prove difficult.
Polyvalent inhibitors of anthrax toxin that target host receptors
Authors: Basha Saleem , Rai Prakash , Poon Vincent , Saraph Arundhati , Gujraty Kunal , Go Mandy Y. , Sadacharan Skanda , Frost Mia , Mogridge Jeremy , Kane Ravi S.
Published: August 2006

Resistance of pathogens to antimicrobial therapeutics has become a widespread problem. Resistance can emerge naturally, but it can also be engineered intentionally, which is an important consideration in designing therapeutics for bioterrorism agents. Blocking host receptors used by pathogens represents a powerful strategy to overcome this problem, because extensive alterations to the pathogen may be required to enable it to switch to a new receptor that can still support pathogenesis. Here, we demonstrate a facile method for producing potent receptor-directed antitoxins. We used phage display to identify a peptide that binds both anthrax-toxin receptors and attached this peptide to a synthetic scaffold. Polyvalency increased the potency of these peptides by >50,000-fold
in vitro
and enabled the neutralization of anthrax toxin
in vivo
. This work demonstrates a receptor-directed anthrax-toxin inhibitor and represents a promising strategy to combat a variety of viral and bacterial diseases.
Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)
Authors: Wideman Rhonda D. , Yu Irene L. Y. , Webber Travis D. , Verchere C. Bruce , Johnson James D. , Cheung Anthony T. , Kieffer Timothy J.
Published: August 2006

Glucagon-like peptide 1 (GLP-1) is a hormone that has received significant attention as a therapy for diabetes because of its ability to stimulate insulin biosynthesis and release and to promote growth and survival of insulin-producing β cells. While GLP-1 is produced from the proglucagon precursor by means of prohormone convertase (PC) 1/3 activity in enteroendocrine L cells, the same precursor is differentially processed by PC2 in pancreatic islet α cells to release glucagon, leaving GLP-1 trapped within a larger fragment with no known function. We hypothesized that we could induce GLP-1 production directly within pancreatic islets by means of delivery of PC1/3 and, further, that this intervention would improve the viability and function of islets. Here, we show that adenovirus-mediated expression of PC1/3 in α cells increases islet GLP-1 secretion, resulting in improved glucose-stimulated insulin secretion and enhanced survival in response to cytokine treatment. PC1/3 expression in α cells also improved performance after islet transplantation in a mouse model of type 1 diabetes, possibly by enhancing nuclear Pdx1 and insulin content of islet β cells. These results demonstrate a unique strategy for liberating GLP-1 from directly within the target organ and highlight the potential for up-regulating islet GLP-1 production as a means of treating diabetes.
Olfactory responses in a gustatory organ of the malaria vector mosquito
Anopheles gambiae
Authors: Kwon Hyung-Wook , Lu Tan , Rützler Michael , Zwiebel Laurence J.
Published: August 2006

The proboscis is an important head appendage in insects that has primarily been thought to process gustatory information during food intake. Indeed, in
Drosophila
and other insects in which they have been identified, most gustatory receptors are expressed in proboscis neurons. Our previous characterization of the expression of AgOR7, a highly conserved odorant receptor (OR) of the Afrotropical malaria vector mosquito
Anopheles gambiae
in the labellum at the tip of the proboscis was suggestive of a potential olfactory function in this mosquito appendage. To test this hypothesis, we used electrophysiological recording and neuronal tracing, and carried out a molecular characterization of candidate OR expression in the labellum of
A. gambiae
. These studies have uncovered a set of labial olfactory responses to a small spectrum of human-related odorants, such as isovaleric acid, butylamine, and several ketones and oxocarboxylic acids. Molecular analyses indicated that at least 24 conventional OR genes are expressed throughout the proboscis. Furthermore, to more fully examine AgOR expression within this tissue, we characterized the AgOR profile within a single labial olfactory sensillum. This study provides compelling data to support the hypothesis that a cryptic set of olfactory neurons that respond to a small set of odorants are present in the mouth parts of hematophagous mosquitoes. This result is consistent with an important role for the labellum in the close-range discrimination of bloodmeal hosts that directly impacts the ability of
A. gambiae
to transmit malaria and other diseases.
Dual roles for
adenomatous polyposis coli
in regulating retinoic acid biosynthesis and Wnt during ocular development
Authors: Nadauld Lincoln D. , Chidester Stephanie , Shelton Dawne N. , Rai Kunal , Broadbent Talmage , Sandoval Imelda T. , Peterson Peter W. , Manos Elizabeth J. , Ireland Chris M. , Yost H. Joseph , Jones David A.
Published: August 2006

Congenital hypertrophy/hyperplasia of the retinal pigmented epithelium is an ocular lesion found in patients harboring mutations in the
adenomatous polyposis coli
(
APC
) tumor suppressor gene. We report that Apc-deficient zebrafish display developmental abnormalities of both the lens and retina. Injection of dominant-negative Lef reduced Wnt signaling in the lens but did not rescue retinal differentiation defects. In contrast, treatment of
apc
mutants with all-trans retinoic acid rescued retinal differentiation defects but had no apparent effect on the lens. We identified Rdh5 as a retina-specific retinol dehydrogenase controlled by APC. Morpholino knockdown of Rdh5 phenocopied the
apc
mutant retinal differentiation defects and was rescued by treatment with exogenous all-trans retinoic acid. Microarray analyses of
apc
mutants and Rdh5 morphants revealed a profound overlap in the transcriptional profile of these embryos. These findings support a model wherein Apc serves a dual role in regulating Wnt and retinoic acid signaling within the eye and suggest retinoic acid deficiency as an explanation for
APC
mutation-associated retinal defects such as congenital hypertrophy/hyperplasia of the retinal pigmented epithelium.
Anomalous resonance in a nanomechanical biosensor
Authors: Gupta Amit K. , Nair Pradeep R. , Akin Demir , Ladisch Michael R. , Broyles Steve , Alam Muhammad A. , Bashir Rashid
Published: August 2006

The decrease in resonant frequency (−Δω

r

) of a classical cantilever provides a sensitive measure of the mass of entities attached on its surface. This elementary phenomenon has been the basis of a new class of bio-nanomechanical devices as sensing components of integrated microsystems that can perform rapid, sensitive, and selective detection of biological and biochemical entities. Based on classical analysis, there is a widespread perception that smaller sensors are more sensitive (sensitivity ≈ −0.5ω

r

/

m
C

, where

m
C

is the mass of the cantilever), and this notion has motivated scaling of biosensors to nanoscale dimensions. In this work, we show that the response of a nanomechanical biosensor is far more complex than previously anticipated. Indeed, in contrast to classical microscale sensors, the resonant frequencies of the nanosensor may actually decrease or increase after attachment of protein molecules. We demonstrate theoretically and experimentally that the direction of the frequency change arises from a size-specific modification of diffusion and attachment kinetics of biomolecules on the cantilevers. This work may have broad impact on microscale and nanoscale biosensor design, especially when predicting the characteristics of bio-nanoelectromechanical sensors functionalized with biological capture molecules.
Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice
Authors: Frydenlund Didrik S. , Bhardwaj Anish , Otsuka Takashi , Mylonakou Maria N. , Yasumura Thomas , Davidson Kimberly G. V. , Zeynalov Emil , Skare Øivind , Laake Petter , Haug Finn-Mogens , Rash John E. , Agre Peter , Ottersen Ole P. , Amiry-Moghaddam Mahmood
Published: August 2006

The aquaporin-4 (AQP4) pool in the perivascular astrocyte membranes has been shown to be critically involved in the formation and dissolution of brain edema. Cerebral edema is a major cause of morbidity and mortality in stroke. It is therefore essential to know whether the perivascular pool of AQP4 is up- or down-regulated after an ischemic insult, because such changes would determine the time course of edema formation. Here we demonstrate by quantitative immunogold cytochemistry that the ischemic striatum and neocortex show distinct patterns of AQP4 expression in the reperfusion phase after 90 min of middle cerebral artery occlusion. The striatal core displays a loss of perivascular AQP4 at 24 hr of reperfusion with no sign of subsequent recovery. The most affected part of the cortex also exhibits loss of perivascular AQP4. This loss is of magnitude similar to that of the striatal core, but it shows a partial recovery toward 72 hr of reperfusion. By freeze fracture we show that the loss of perivascular AQP4 is associated with the disappearance of the square lattices of particles that normally are distinct features of the perivascular astrocyte membrane. The cortical border zone differs from the central part of the ischemic lesion by showing no loss of perivascular AQP4 at 24 hr of reperfusion but rather a slight increase. These data indicate that the size of the AQP4 pool that controls the exchange of fluid between brain and blood during edema formation and dissolution is subject to large and region-specific changes in the reperfusion phase.
High-field pulsed electron–electron double resonance spectroscopy to determine the orientation of the tyrosyl radicals in ribonucleotide reductase
Authors: Denysenkov V. P. , Prisner T. F. , Stubbe J. , Bennati M.
Published: August 2006

Class I ribonucleotide reductases (RNRs) are composed of two subunits, R1 and R2. The R2 subunit contains the essential diferric cluster-tyrosyl radical (Y·) cofactor, and R1 is the site of the conversion of nucleoside diphosphates to 2′-deoxynucleoside diphosphates. It has been proposed that the function of the tyrosyl radical in R2 is to generate a transient thiyl radical (C439·) in R1 over a distance of 35 Å, which in turn initiates the reduction process. EPR distance measurements provide a tool with which to study the mechanism of radical initiation in class I RNRs. These types of experiments at low magnetic fields and frequencies (0.3 T, 9 GHz) give insight into interradical distances and populations. We present a pulsed electron–electron double resonance (PELDOR) experiment at high EPR frequency (180-GHz electron Larmor frequency) that detects the dipolar interaction between the Y·s in each protomer of RNR R2 from
Escherichia coli
. We observe a correlation between the orientation-dependent dipolar interaction and their resolved g-tensors. This information has allowed us to define the relative orientation of two radicals embedded in the active homodimeric protein in solution. This experiment demonstrates that high-field PELDOR spectroscopy is a powerful tool with which to study the assembly of proteins that contain multiple paramagnetic centers.
Neurotoxic protein expression reveals connections between the circadian clock and mating behavior in
Drosophila
Authors: Kadener Sebastian , Villella Adriana , Kula Elzbieta , Palm Kristyna , Pyza Elzbieta , Botas Juan , Hall Jeffrey C. , Rosbash Michael
Published: August 2006

To investigate the functions of circadian neurons, we added two strategies to the standard
Drosophila
behavioral genetics repertoire. The first was to express a polyglutamine-expanded neurotoxic protein (MJDtr78Q; MJD, Machado–Joseph disease) in the major
timeless
(
tim
)-expressing cells of the adult brain. These Tim-MJD flies were viable, in contrast to the use of cell-death gene expression for
tim
neuron inactivation. Moreover, they were more arrhythmic than flies expressing other neurotoxins and had low but detectable
tim
mRNA levels. The second extended standard microarray technology from fly heads to dissected fly brains. By combining the two approaches, we identified a population of Tim-MJD-affected mRNAs. Some had been previously identified as sex-specific and relevant to courtship, including mRNAs localized to brain-proximal fat-body tissue and brain courtship centers. Finally, we found a decrease in the number of neurons that expressed male-specific forms of the
fruitless
protein in the laterodorsal region of the brain. The decrease was not a consequence of toxic protein expression within these specialized cells but a likely effect of communication with neighboring TIM-expressing neurons. The data suggest a functional interaction between adjacent circadian and mating circuits within the fly brain, as well as an interaction between circadian circuits and brain-proximal fat body.
The transition state for formation of the peptide bond in the ribosome
Authors: Gindulyte Asta , Bashan Anat , Agmon Ilana , Massa Lou , Yonath Ada , Karle Jerome
Published: August 2006

Using quantum mechanics and exploiting known crystallographic coordinates of tRNA substrate located in the ribosome peptidyl transferase center around the 2-fold axis, we have investigated the mechanism for peptide-bond formation. The calculation is based on a choice of 50 atoms assumed to be important in the mechanism. We used density functional theory to optimize the geometry and energy of the transition state (TS) for peptide-bond formation. The TS is formed simultaneously with the rotatory motion enabling the translocation of the A-site tRNA 3′ end into the P site, and we estimated the magnitude of rotation angle between the A-site starting position and the place at which the TS occurs. The calculated TS activation energy,

E
a

, is 35.5 kcal (1 kcal = 4.18 kJ)/mol, and the increase in hydrogen bonding between the rotating A-site tRNA and ribosome nucleotides as the TS forms appears to stabilize it to a value qualitatively estimated to be ≈18 kcal/mol. The optimized geometry corresponds to a structure in which the peptide bond is being formed as other bonds are being broken, in such a manner as to release the P-site tRNA so that it may exit as a free molecule and be replaced by the translocating A-site tRNA. At TS formation the 2′ OH group of the P-site tRNA A76 forms a hydrogen bond with the oxygen atom of the carboxyl group of the amino acid attached to the A-site tRNA, which may be indicative of its catalytic role, consistent with recent biochemical experiments.
Population-wide lineage frequencies predict genetic load in the seed-harvester antPogonomyrmex
Authors: Anderson Kirk E. , Hölldobler Bert , Fewell Jennifer H. , Mott Brendon M. , Gadau Jürgen
Published: August 2006

Many populations of the seed-harvester antPogonomyrmex barbatusexhibit genetic caste determination (GCD) generated by the interbreeding of two distinct yet interdependent lineages. Same-lineage matings are genetically predestined to become female reproductives (gynes) whereas alternate-lineage matings become workers. The perpetuation of this system requires that reproductives of both lineages are available for mating and are thus part of the effective population. We label these dependent lineage populations, because each lineage depends on the alternate lineage for worker production. Here we investigate the potential costs associated with GCD in a population with highly skewed lineage frequencies. We reared colonies using newly mated queens from a GCD population and an ecologically equivalentPogonomyrmex rugosuspopulation with environmental caste determination. GCD founding queens suffer a genetic load from mating randomly and produce fewer brood with advanced development compared with environmental caste determination queens. Our results indicate that GCD queens acquiring a high proportion of same-lineage sperm are unlikely to found a colony successfully. Given model parameters of random mating and founding queens mating with three males on average, there was a close fit between theoretical expectations of variation in colony worker production based on mating and lineage frequencies and empirical deficits in worker production. As expected, severely decreased worker production was specific to the common lineage, suggesting that negative frequency-dependent selection acts to stabilize a dependent lineage system.