Relationship of Fungal Vaginitis Therapy to Prior Antibiotic Exposure

Objective: To address the putative association of antibiotic use and subsequent yeast vaginitis in a population of non-pregnant women. Methods: Three hundred and sixteen women who received medical care in rural family medicine clinics enrolled in this study. Participants were pre-menopausal and non-pregnant and were followed until they used a course of antifungal therapy for vaginitis, became pregnant or moved from the catchment area. At entry subjects were free of vaginitis symptoms and had taken no antibiotics for 30 days. Patients were followed by repeated review of clinic records, hospital records and telephone or personal interviews. Data collection included documentation of episodes of antifungal treatment for vulvovaginal candidiasis and confirmed antibiotic treatment or credible history of antibiotic use prior to the use of antifungal therapy. Physician-reported uses of antibiotic and antifungal as well as patient-reported uses of these were recorded. Results: There were four reported cases of antifungal therapy following within a month of antibiotic use, in contrast to 484 antibiotic uses not followed by antifungal use. If time of observation was extended to 6 months from antibiotic use, there were 13 uses of antifungal therapy after antibiotics and 475 uses of antibiotics not followed by antifungal therapy. Conclusion: Our results cast doubt on the association of antibiotics as a putative cause of yeast vulvovaginitis

Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin

The four R-spondin (Rspo) proteins are secreted agonists of Wnt signalling in vertebrates, functioning in embryogenesis and adult stem cell biology. Through ubiquitination and degradation of Wnt receptors, the transmembrane E3 ubiquitin ligase ZNRF3 and related RNF43 antagonize Wnt signalling. Rspo ligands have been reported to inhibit the ligase activity through direct interaction with ZNRF3 and RNF43. Here we report multiple crystal structures of the ZNRF3 ectodomain (ZNRF3ecto), a signalling-competent Furin1–Furin2 (Fu1–Fu2) fragment of Rspo2 (Rspo2Fu1–Fu2), and Rspo2Fu1–Fu2 in complex with ZNRF3ecto, or RNF43ecto. A prominent loop in Fu1 clamps into equivalent grooves in the ZNRF3ecto and RNF43ecto surface. Rspo binding enhances dimerization of ZNRF3ecto but not of RNF43ecto. Comparison of the four Rspo proteins, mutants and chimeras in biophysical and cellular assays shows that their signalling potency depends on their ability to recruit ZNRF3 or RNF43 via Fu1 into a complex with LGR receptors, which interact with Rspo via Fu2

High-bone-mass causing mutant LRP5 receptors are resistant to endogenous inhibitors in vivo

Certain missense mutations affecting LRP5 cause high bone mass (HBM) in humans. Based on in vitro evidence, HBM LRP5 receptors are thought to exert their effects by providing resistance to binding/inhibition of secreted LRP5 inhibitors such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). We previously reported the creation of two Lrp5 HBM knock-in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous Lrp5 locus. To determine whether HBM knock-in mice are resistant to SOST- or DKK1-induced osteopenia, we bred Lrp5 HBM mice with transgenic mice that overexpress human SOST in osteocytes ((8kb) Dmp1-SOST) or mouse DKK1 in osteoblasts and osteocytes ((2.3kb) Col1a1-Dkk1). We observed that the (8kb) Dmp1-SOST transgene significantly lowered whole-body bone mineral density (BMD), bone mineral content (BMC), femoral and vertebral trabecular bone volume fraction (BV/TV), and periosteal bone-formation rate (BFR) in wild-type mice but not in mice with Lrp5 p.G171V and p.A214V alleles. The (2.3kb) Col1a1-Dkk1 transgene significantly lowered whole-body BMD, BMC, and vertebral BV/TV in wild-type mice and affected p.A214V mice more than p.G171V mice. These in vivo data support in vitro studies regarding the mechanism of HBM-causing mutations, and imply that HBM LRP5 receptors differ in their relative sensitivity to inhibition by SOST and DKK1

Strengthening the Cohomological Crepant Resolution Conjecture for Hilbert-Chow morphisms

Given any smooth toric surface S, we prove a SYM-HILB correspondence which relates the 3-point, degree zero, extended Gromov-Witten invariants of the n-fold symmetric product stack [Sym^n(S)] of S to the 3-point extremal Gromov-Witten invariants of the Hilbert scheme Hilb^n(S) of n points on S. As we do not specialize the values of the quantum parameters involved, this result proves a strengthening of Ruan's Cohomological Crepant Resolution Conjecture for the Hilbert-Chow morphism from Hilb^n(S) to Sym^n(S) and yields a method of reconstructing the cup product for Hilb^n(S) from the orbifold invariants of [Sym^n(S)].Comment: Revised versio

Crystal Model for the Closed Topological Vertex Geometry

The topological string partition function for the neighbourhood of three spheres meeting at one point in a Calabi-Yau threefold, the so-called 'closed topological vertex', is shown to be reproduced by a simple Calabi-Yau crystal model which counts plane partitions inside a cube of finite size. The model is derived from the topological vertex formalism. This derivation can be understood as 'moving off the strip' in the terminology of hep-th/0410174, and offers a possibility to simplify topological vertex techniques to a broader class of Calabi-Yau geometries. To support this claim a flop transition of the closed topological vertex is considered and the partition function of the resulting geometry is computed in agreement with general expectations.Comment: 26 pages, 7 figures; references added, classical part of flop analysis corrected and expande

Can electron distribution functions be derived through the Sunyaev-Zel'dovich effect?

Measurements of the Sunyaev-Zel'dovich (hereafter SZ) effect distortion of the cosmic microwave background provide methods to derive the gas pressure and temperature of galaxy clusters. Here we study the ability of SZ effect observations to derive the electron distribution function (DF) in massive galaxy clusters. Our calculations of the SZ effect include relativistic corrections considered within the framework of the Wright formalism and use a decomposition technique of electron DFs into Fourier series. Using multi-frequency measurements of the SZ effect, we find the solution of a linear system of equations that is used to derive the Fourier coefficients; we further analyze different frequency samples to decrease uncertainties in Fourier coefficient estimations. We propose a method to derive DFs of electrons using SZ multi-frequency observations of massive galaxy clusters. We found that the best frequency sample to derive an electron DF includes high frequencies $\nu$=375, 600, 700, 857 GHz. We show that it is possible to distinguish a Juttner DF from a Maxwell-Bolzman DF as well as from a Juttner DF with the second electron population by means of SZ observations for the best frequency sample if the precision of SZ intensity measurements is less than 0.1%. We demonstrate by means of 3D hydrodynamic numerical simulations of a hot merging galaxy cluster that the morphologies of SZ intensity maps are different for frequencies $\nu$=375, 600, 700, 857 GHz. We stress that measurements of SZ intensities at these frequencies are a promising tool for studying electron distribution functions in galaxy clusters.Comment: 11 pages, 12 figures, published in Astronomy and Astrophysic

Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling

LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller-EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites. © 2011 Elsevier Inc

Dissecting Molecular Differences between Wnt Coreceptors LRP5 and LRP6

Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6) serve as Wnt co-receptors for the canonical β-catenin pathway. While LRP6 is essential for embryogenesis, both LRP5 and LRP6 play critical roles for skeletal remodeling, osteoporosis pathogenesis and cancer formation, making LRP5 and LRP6 key therapeutic targets for cancer and disease treatment. LRP5 and LRP6 each contain in the cytoplasmic domain five conserved PPPSPxS motifs that are pivotal for signaling and serve collectively as phosphorylation-dependent docking sites for the scaffolding protein Axin. However existing data suggest that LRP6 is more effective than LRP5 in transducing the Wnt signal. To understand the molecular basis that accounts for the different signaling activity of LRP5 and LRP6, we generated a series of chimeric receptors via swapping LRP5 and LRP6 cytoplasmic domains, LRP5C and LRP6C, and studied their Wnt signaling activity using biochemical and functional assays. We demonstrate that LRP6C exhibits strong signaling activity while LRP5C is much less active in cells. Recombinant LRP5C and LRP6C upon in vitro phosphorylation exhibit similar Axin-binding capability, suggesting that LRP5 and LRP6 differ in vivo at a step prior to Axin-binding, likely at receiving phosphorylation. We identified between the two most carboxyl PPPSPxS motifs an intervening “gap4” region that appears to account for much of the difference between LRP5C and LRP6C, and showed that alterations in this region are sufficient to enhance LRP5 PPPSPxS phosphorylation and signaling to levels comparable to LRP6 in cells. In addition we provide evidence that binding of phosphorylated LRP5 or LRP6 to Axin is likely direct and does not require the GSK3 kinase as a bridging intermediate as has been proposed. Our studies therefore uncover a new and important molecular tuning mechanism for differential regulation of LRP5 and LRP6 phosphorylation and signaling activity

Patient and general practitioner attitudes to taking medication to prevent cardiovascular disease after receiving detailed information on risks and benefits of treatment: a qualitative study

Abstract Background There are now effective drugs to prevent cardiovascular disease and guidelines recommend their use. Patients do not always choose to accept preventive medication at levels of risk reduction recommended in guidelines. The purpose of the study was to identify and explore the attitudes of patients and general practitioners towards preventative medication for cardiovascular disease (CVD) after they have received information about it; to identify implications for practice and prescribing. Methods Qualitative interviews with GPs and patients following presentation of in depth information about CVD risks and the absolute effects of medication. Setting: GP practices in Birmingham, United Kingdom. Results In both populations: wide variation on attitudes to preventative medication; concerns about unnecessary drug taking & side effects; preferring to consider lifestyle changes first. In patient population: whatever their attitudes to medication were, the vast majority explained that they would ultimately do what their GP recommended; there was some misunderstanding of the distinction between curative and preventative medication. A common theme was the degree of trust in their doctors' judgement and recommendations, which contrasted with scepticism of the role of pharmaceutical companies and academics. Scepticism in guidelines was also common among doctors although many nevertheless recommended treatment for their patients Conclusions A guideline approach to prescribing preventative medication could be against the interests and preferences of the patient. GPs must take extra care to explain what preventative medication is and why it is recommended, attempt to discern preferences and make recommendations balancing these potentially conflicting concerns.</p