Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis

BackgroundObservational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.ConclusionsThis IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.     

Inhibition of P-glycoprotein-mediated multidrug efflux by aminomethylene and ketomethylene analogs of reversins

Several aminomethylene analogs and a ketomethylene analog of reversins were synthesized in order to evaluate their ability to inhibit P-glycoprotein-mediated drug efflux in K562/R7 human leukemic cells overexpressing P-glycoprotein. These analogs retained good activity compared to cyclosporin A and the original reversins.     

Microwave expedited synthesis of 5-aminocamptothecin analogs: Inhibitors of hypoxia inducible factor HIF-1alpha

A series of 5-aminosubstituted camptothecin analogs were prepared from the corresponding 5-hydroxycamptothecin using microwave irradiation. The analogs were assayed for ability to inhibit the action of hypoxia inducible factors (HIF-1alpha and HIF-2alpha). The 5-fluoroethyl analog showed potent inhibitory activity and is now the focus of ongoing pathway analysis and potential as an antiproliferative agent.     

Transmitting tissue architecture in basal-relictual angiosperms: Implications for transmitting tissue origins

Carpel transmitting tissue is a major floral innovation that is essential for angiosperm success. It facilitates the rapid adhesion, hydration, and growth of the male gametophyte to the female gametophyte. As well, it functions as a molecular screen to promote male gametophytic competition and species-specific recognition and compatibility. Here, we characterize the transmitting tissue extracellular matrix (ECM) and pollen tube growth in basal-relictual angiosperms and test the hypothesis that a freely flowing ECM (wet stigma) was ancestral to a cuticle-bound ECM (dry stigma). We demonstrate that the most recent common ancestor of extant angiosperms produced an ECM that was structurally and functionally equivalent to a dry stigma. Dry stigmas are composed of a cuticle and primary wall that contains compounds that facilitate the adhesion and growth of the male gametophyte. These compounds include methyl-esterified homogalacturonans, arabinogalactan-proteins, and lipids. We propose that transmitting tissue evolved in concert with an increase in cuticle permeability that resulted from modifications in the biosynthesis and secretion of fatty acids needed for cuticle construction. Increased cuticle permeability exposed the male gametophyte to pre-existing molecules that enabled rapid male gametophyte adhesion, hydration, and growth as well as species-specific recognition and compatibility.     

"Ring pledget": a new concept for secure apex closure during transapical aortic valve implantation

Transapical aortic valve implantation requires puncture of the left ventricle apex and insertion of a 32-French delivery sheath. A critical step in the procedure consists of secure closure of the ventricular apex. We describe 2 cases of apical rupture of 42 transapical aortic valve implantations. Furthermore, we describe the use of a newly designed single circular Teflon pledget that can help to avoid this complication. This pledget provides a more secure and uniform shrinkage of the entire apex to close the defect left by the delivery sheath.     

Xanthidae MacLeay, 1838 (Decapoda: Brachyura: Xanthoidea) systematics: A multi-gene approach with support from adult and zoeal morphology

Currently, 13 subfamilies are recognised in the brachyuran family Xanthidae: Actaeinae, Antrocarcininae, Chlorodiellinae, Cymoinae, Etisinae, Euxanthinae, Kraussiinae, Liomerinae, Polydectinae, Speocarcininae, Xanthinae, Zalasiinae and Zosiminae. This classification has been based on shared adult features like a transversely ovate carapace, well defined dorsal carapace regions, usually with lateral dentition, stout chelipeds and relatively short ambulatory legs. Such characters are now considered to be convergent. Consequently a number of higher xanthid taxa may be artifical and not monophyletic. A broad sample of 147 xanthid species representing 75 out of 124 genera from all 13 xanthid subfamilies were sampled in a multi-gene analysis. Four markers (three mitochondrial and one nuclear) were used and yielded a tree with ca. 30 xanthid clades. Monophyletic support was demonstrated for the Antrocarcininae (although substantially redefined), Cymoinae, and Polydectinae. Almost every other subfamily was para- or polyphyletic. Furthermore, the two other families of the Xanthoidea, Pseudorhombilidae and Panopeidae, were found nested within the Xanthidae. The molecular results were consistent with phylogenetic relationships implied by a suite of novel and/or neglected “ventral” adult characters including sternal characters, position of genital openings and morphology of the first zoea, instead of “dorsal” characters traditionally used to infer xanthid relationships.     

Extracellular production of Streptomyces lividans acetyl xylan esterase A in Escherichia coli for rapid detection of activity

Acetyl xylan esterase A (AxeA) from Streptomyces lividans belongs to a large family of industrially relevant polysaccharide esterases. AxeA and its truncated form containing only the catalytically competent domain, AxeA(tr), catalyze both the deacetylation of xylan and the N-deacetylation of chitosan. This broad substrate specificity lends additional interest to their characterization and production. Here, we report three systems for extracellular production of AxeA(tr): secretion from the native host S. lividans with the native signal peptide, extracellular production in Escherichia coli with the native signal peptide, and in E. coli with the OmpA signal peptide. Over five to seven days of a shake flask culture, the native host S. lividans with the native signal peptide secreted AxeA(tr) into the extracellular medium in high yield (388 mg/L) with specific activity of 19 U/mg corresponding to a total of 7000 U/L. Over one day of shake flask culture, E. coli with the native secretion signal peptide produced 84-fold less in the extracellular medium (4.6 mg/L), but the specific activity was higher (100 U/mg) corresponding to a total of 460 U/L. A similar E. coli culture using the OmpA signal peptide, produced 10mg/L with a specific activity of 68 U/mg, corresponding to a total of 680 U/L. In 96-well microtiter plates, extracellular production with E. coli gave approximately 30 and approximately 86 microg/mL in S. lividans. Expression in S. lividans with the native signal peptide is best for high level production, while expression in E. coli using the OmpA secretion signal peptide is best for high-throughput expression and screening of variants in microtiter plate format.     

Hyperlipidemia affects multiscale structure and strength of murine femur

To improve bone strength prediction beyond limitations of assessment founded solely on the bone mineral component, we investigated the effect of hyperlipidemia, present in more than 40% of osteoporotic patients, on multiscale structure of murine bone. Our overarching purpose is to estimate bone strength accurately, to facilitate mitigating fracture morbidity and mortality in patients. Because (i) orientation of collagen type I affects, independently of degree of mineralization, cortical bone?s micro-structural strength; and, (ii) hyperlipidemia affects collagen orientation and μCT volumetric tissue mineral density (vTMD) in murine cortical bone, we have constructed the first multiscale finite element (mFE), mouse-specific femoral model to study the effect of collagen orientation and vTMD on strength in Ldlr^−/−, a mouse model of hyperlipidemia, and its control wild type, on either high fat diet or normal diet. Each µCT scan-based mFE model included either element-specific elastic orthotropic properties calculated from collagen orientation and vTMD (collagen-density model) by experimentally validated formulation, or usual element-specific elastic isotropic material properties dependent on vTMD-only (density-only model). We found that collagen orientation, assessed by circularly polarized light and confocal microscopies, and vTMD, differed among groups and that microindentation results strongly correlate with elastic modulus of collagen-density models (r²=0.85, p=10⁻⁵). Collagen-density models yielded (1) larger strains, and therefore lower strength, in simulations of 3-point bending and physiological loading; and (2) higher correlation between mFE-predicted strength and 3-point bending experimental strength, than density-only models. This novel method supports ongoing translational research to achieve the as yet elusive goal of accurate bone strength prediction.     

Coordinate regulation of the mother centriole component nlp by nek2 and plk1 protein kinases

Mitotic entry requires a major reorganization of the microtubule cytoskeleton. Nlp, a centrosomal protein that binds gamma-tubulin, is a G(2)/M target of the Plk1 protein kinase. Here, we show that human Nlp and its Xenopus homologue, X-Nlp, are also phosphorylated by the cell cycle-regulated Nek2 kinase. X-Nlp is a 213-kDa mother centriole-specific protein, implicating it in microtubule anchoring. Although constant in abundance throughout the cell cycle, it is displaced from centrosomes upon mitotic entry. Overexpression of active Nek2 or Plk1 causes premature displacement of Nlp from interphase centrosomes. Active Nek2 is also capable of phosphorylating and displacing a mutant form of Nlp that lacks Plk1 phosphorylation sites. Importantly, kinase-inactive Nek2 interferes with Plk1-induced displacement of Nlp from interphase centrosomes and displacement of endogenous Nlp from mitotic spindle poles, while active Nek2 stimulates Plk1 phosphorylation of Nlp in vitro. Unlike Plk1, Nek2 does not prevent association of Nlp with gamma-tubulin. Together, these results provide the first example of a protein involved in microtubule organization that is coordinately regulated at the G(2)/M transition by two centrosomal kinases. We also propose that phosphorylation by Nek2 may prime Nlp for phosphorylation by Plk1.