476 research outputs found

    In Vivo Structures of the Helicobacter pylori cag Type IV Secretion System

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    The type IV secretion system (T4SS) is a versatile nanomachine that translocates diverse effector molecules between microbes and into eukaryotic cells. Here, using electron cryotomography, we reveal the molecular architecture of the Helicobacter pylori cag T4SS. Although most components are unique to H. pylori, the cag T4SS exhibits remarkable architectural similarity to other T4SSs. Our images revealed that, when H. pylori encounters host cells, the bacterium elaborates membranous tubes perforated by lateral ports. Sub-tomogram averaging of the cag T4SS machinery revealed periplasmic densities associated with the outer membrane, a central stalk, and peripheral wing-like densities. Additionally, we resolved pilus-like rod structures extending from the cag T4SS into the inner membrane, as well as densities within the cytoplasmic apparatus corresponding to a short central barrel surrounded by four longer barrels. Collectively, these studies reveal the structure of a dynamic molecular machine that evolved to function in the human gastric niche

    \u3cem\u3eIn Vivo\u3c/em\u3e Structures of the \u3cem\u3eHelicobacter pylori cag\u3c/em\u3e Type IV Secretion System

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    The type IV secretion system (T4SS) is a versatile nanomachine that translocates diverse effector molecules between microbes and into eukaryotic cells. Here, using electron cryotomography, we reveal the molecular architecture of the Helicobacter pylori cag T4SS. Although most components are unique to H. pylori, the cag T4SS exhibits remarkable architectural similarity to other T4SSs. Our images revealed that, when H. pylori encounters host cells, the bacterium elaborates membranous tubes perforated by lateral ports. Sub-tomogram averaging of the cag T4SS machinery revealed periplasmic densities associated with the outer membrane, a central stalk, and peripheral wing-like densities. Additionally, we resolved pilus-like rod structures extending from the cag T4SS into the inner membrane, as well as densities within the cytoplasmic apparatus corresponding to a short central barrel surrounded by four longer barrels. Collectively, these studies reveal the structure of a dynamic molecular machine that evolved to function in the human gastric niche

    Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration

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    Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely

    Kinetic and Structural Analysis of Substrate Specificity in Two Copper Amine Oxidases from Hansenula polymorpha

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    The structural underpinnings of enzyme substrate specificity are investigated in a pair of copper amine oxidases (CAOs) from Hansenula polymorpha (HPAO-1 and HPAO-2). The X-ray crystal structure (to 2.0 Å resolution) and steady state kinetic data of the second copper amine oxidase (HPAO-2) are presented for comparison to HPAO-1. Despite 34 % sequence identity and superimposable active site residues implicated in catalysis, the enzymes vary considerably in their substrate entry channel. The previously studied CAO, HPAO-1, has a narrow substrate channel. In contrast HPAO-2 has a wide funnel-shaped substrate channel, which also contains a side-chamber. In addition, there are a number of amino acid changes within the channels of HPAO-2 and HPAO-1 that may sterically impact the ability of substrates to form covalent Schiff base catalytic intermediates and to initiate chemistry. These differences can partially explain the greatly different substrate specificities as characterized by kcat/Km value differences: in HPAO-1, the kcat/Km for methylamine is 330-fold greater than for benzylamine, whereas in HPAO-2 it is benzylamine that is the better substrate by 750-fold. In HPAO-2 an inflated Dkcat/Km(methylamine) in relation to Dkcat/Km(benzylamine) indicates that proton abstraction has been impeded more than substrate release. In HPAO-1, Dkcat/Km(S) changes little with the slow substrate, and indicates a similar increase in the energy barriers that control both substrate binding and subsequent catalysis. In neither case is kcat/Km for the second substrate, O2, significantly altered. These results reinforce the modular nature of the active sites of CAOs and show that multiple factors contribute to substrate specificity and catalytic efficiency. In HPAO-1, the enzyme with the smaller substrate binding pocket, both initial substrate binding and proton loss are affected by an increase in substrate size, while in HPAO-2, the enzyme with the larger substrate binding pocket, the rate of proton loss is differentially affected when a phenyl substituent in substrate is reduced to the size of a methyl group

    Effect of learning resources on Mendeley user adoption and productivity

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    Poster PresentationThis study was done to understand the user adoption pattern of a reference management tool such as Mendeley. Libraries can improve usage of reference management tools if they adopt a mix of learning support services. The study also found that structured support is more effective than ‘just-in-time’ support. Finally, support for early career researchers is more effective than for seasoned researchers. The results obtained from different Schools across North America were presented as a poster at the Special Libraries Association's Annual Library Conference in Boston in 2015.Special Libraries Association Annual Conference 201

    Synaptic Innervation Density Is Regulated by Neuron-Derived BDNF

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    AbstractIn this report, we have examined the role of neuron-derived BDNF at an accessible synapse, that of preganglionic neurons onto their sympathetic neuron targets. Developing and mature sympathetic neurons synthesize BDNF, and preganglionic neurons express the full-length BDNF/TrkB receptor. When sympathetic neuron-derived BDNF is increased 2- to 4-fold in transgenic mice, preganglionic cell bodies and axons hypertrophy, and the synaptic innervation to sympathetic neurons is increased. Conversely, when BDNF synthesis is eliminated in BDNF −/− mice, preganglionic synaptic innervation to sympathetic neurons is decreased. Together these results indicate that variations in neuronal neurotrophin synthesis directly regulate neuronal circuitry by selectively modulating synaptic innervation density

    Use of Mobile Learning by Resident Physicians in Botswana

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    With the growth of mobile health in recent years, learning through the use of mobile devices (mobile learning [mLearning]) has gained recognition as a potential method for increasing healthcare providers\u27 access to medical information and resources in resource-limited settings. In partnership with the University of Botswana School of Medicine (SOM), we have been exploring the role of smartphone-based mLearning with resident (physicians in specialty training) education. The SOM, which admitted its first class of medical students and residents in 2009, is committed to providing high-level on-site educational resources for resident physicians, even when practicing in remote locations. Seven residents were trained to use an Android-based myTouch 3G smartphone equipped with data-enabled subscriber identity module (SIM) cards and built-in camera. Phones contained locally loaded point-of-care and drug information applications, a telemedicine application that allows for the submission of cases to local mentors, and e-mail/Web access. Surveys were administered at 4 weeks and 8 weeks following distribution of phones. We found that smartphones loaded with point-of-care tools are effectively utilized by resident physicians in resource-limited settings, both for accessing point-of-care medical information at the bedside and engaging in self-directed learning at home

    Addressing the Future Burden of Cancer and Its Impact on the Oncology Workforce: Where Is Cancer Prevention and Control?

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    The need for cancer professionals has never been more urgent than it is today. Reports project serious shortages by 2020 of oncology health care providers. Although many plans have been proposed, no role for prevention has been described. In response, a 2-day symposium was held in 2009 at The University of Texas MD Anderson Cancer Center to capture the current status of the cancer prevention workforce and begin to identify gaps in the workforce. Five working groups were organized around the following topic areas: (a) health policy and advocacy; (b) translation to the community; (c) integrating cancer prevention into clinical practice; (d) health services infrastructure and economics; and (e) discovery, research, and technology. Along with specific recommendations on these topics, the working groups identified two additional major themes: the difficulty of defining areas within the field (including barriers to communication) and lack of sufficient funding. These interdependent issues synergistically impede progress in preventing cancer; they are explored in detail in this synthesis, and recommendations for actions to address them are presented. Progress in cancer prevention should be a major national and international goal. To achieve this goal, ensuring the health of the workforce in cancer prevention and control is imperative
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