608 research outputs found
Synthesis, Structure and Stereodynamics of Atropisomeric <em>N</em>‑Chloroamides
Atropisomeric N-chloroamides were efficiently accessed by electrophilic halogenation of ortho-substituted secondary anilides. The stereodynamics of atropisomerism in these novel scaffolds was interrogated by detailed experimental and computational studies, revealing that racemization is correlated with amide isomerization. The stereoelectronic nature of the amide was shown to significantly influence racemization rates, with potentially important implications for other C-N atropisomeric scaffolds
Rectal Transmission of Transmitted/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice
Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1(JRCSF) or the MSM-derived transmitted/founder (T/F) virus HIV-1(THRO) within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1(JRCSF) and HIV-1(THRO), respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1(JRCSF) and 0% (0/6; log rank p = 0.02) for HIV-1(THRO). This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides
Cardiorespiratory fitness is associated with hard and light intensity physical activity but not time spent sedentary in 10–14 year old schoolchildren: the HAPPY study
Sedentary behaviour is a major risk factor for developing chronic diseases and is associated with low cardiorespiratory fitness in adults. It remains unclear how sedentary behaviour and different physical activity subcomponents are related to cardiorespiratory fitness in children. The purpose of this study was to assess how sedentary behaviour and different physical activity subcomponents are associated with 10–14 year-old schoolchildren's cardiorespiratory fitness
The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.
Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex
Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets
<div><p>Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway <i>i</i>.<i>e</i>., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3–38 times <i>vs</i>. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation.</p></div
High nutrient-use efficiency during early seedling growth in diverse Grevillea species (Proteaceae)
Several hypotheses have been proposed to explain the rich floristic diversity in regions characterised by nutrient-impoverished soils; however, none of these hypotheses have been able to explain the rapid diversification over a relatively short evolutionary time period of Grevillea, an Australian plant genus with 452 recognised species/subspecies and only 11 million years of evolutionary history. Here, we hypothesise that the apparent evolutionary success of Grevillea might have been triggered by the highly efficient use of key nutrients. The nutrient content in the seeds and nutrient-use efficiency during early seedling growth of 12 species of Grevillea were compared with those of 24 species of Hakea, a closely related genus. Compared with Hakea, the Grevillea species achieved similar growth rates (root and shoot length) during the early stages of seedling growth but contained only approximately half of the seed nutrient content. We conclude that the high nutrient-use efficiency observed in Grevillea might have provided a selective advantage in nutrient-poor ecosystems during evolution and that this property likely contributed to the evolutionary success in Grevillea
A Topical Microbicide Gel Formulation of CCR5 Antagonist Maraviroc Prevents HIV-1 Vaginal Transmission in Humanized RAG-hu Mice
For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field
The impact of pre-exposure prophylaxis (PrEP) on HIV epidemics in Africa and India: A simulation study
Background: Pre-exposure prophylaxis (PrEP) is a promising new HIV prevention method, especially for women. An urgent demand for implementation of PrEP is expected at the moment efficacy has been demonstrated in clinical trials. We explored the long-term impact of PrEP on HIV transmission in different HIV epidemics. Methodology/Principal Findings: We used a mathematical model that distinguishes the general population, sex workers and their clients. PrEP scenarios varying in effectiveness, coverage and target group were modeled in the epidemiological settings of Botswana, Nyanza Province in Kenya, and Southern India. We also studied the effect of condom addition or condom substitution during PrEP use. Main outcome was number of HIV infections averted over ten years of PrEP use. PrEP strategies with high effectiveness and high coverage can have a substantial impact in African settings. In Southern India, by contrast, the number of averted HIV infections in different PrEP scenarios would be much lower. The impact of PrEP may be strongly diminished or even reversed by behavioral disinhibition, especially in scenarios with low coverage and low effectiveness. However, additional condom use during low coverage and low effective PrEP doubled the amount of averted HIV infections. Conclusions/Significance: The public health impact of PrEP can be substantial. However, this impact may be diminished, or even reversed, by changes in risk behavior. Implementation of PrEP strategies should therefore come on top of current condom campaigns, not as a substitution
Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)
This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and
Technology (CICYT), the
Spanish National Parks agency, the European Commission, the
Spanish Ministry of Science, and the European
Social Fund
Revealing the last 13,500 years of environmental history from the multiproxy record of a mountain lake (Lago Enol, northern Iberian Peninsula)
This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s10933-009-9387-7.We present the Holocene sequence from Lago Enol (43°16′N, 4°59′W, 1,070 m a.s.l.), Cantabrian Mountains, northern Spain. A multiproxy analysis provided comprehensive information about regional humidity and temperature changes. The analysis included sedimentological descriptions, physical properties, organic carbon and carbonate content, mineralogy and geochemical composition together with biological proxies including diatom and ostracod assemblages. A detailed pollen study enabled reconstruction of variations in vegetation cover, which were interpreted in the context of climate changes and human impact. Four distinct stages were recognized for the last 13,500 years: (1) a cold and dry episode that includes the Younger Dryas event (13,500–11,600 cal. year BP); (2) a humid and warmer period characterizing the onset of the Holocene (11,600–8,700 cal. year BP); (3) a tendency toward a drier climate during the middle Holocene (8,700–4,650 cal. year BP); and (4) a return to humid conditions following landscape modification by human activity (pastoral activities, deforestation) in the late Holocene (4,650–2,200 cal. year BP). Superimposed on relatively stable landscape conditions (e.g. maintenance of well established forests), the typical environmental variability of the southern European region is observed at this site.The Spanish Inter-Ministry Commission of Science and
Technology (CICYT), the
Spanish National Parks agency, the European Commission, the
Spanish Ministry of Science, and the European
Social Fund
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