1,383 research outputs found

    Synthesis and Characterization of Naphthalenediimide-Functionalized Flavin Derivatives

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    Two acceptor–acceptor dyads have been synthesized featuring a flavin moiety and a naphthalenediimide (NDI) unit. The NDI unit is linked to the flavin through a short spacer group via either the N(3) or N(10) positions of the flavin. We have investigated the UV-Vis and redox properties of these multi-electron accepting systems which indicate that these materials display the collective properties of their component systems. Fluorescence spectroscopy measurements have revealed that their emission properties are dominated by the flavin unit

    Interplay between attenuation- and virulence-factors of Babesia Bovis and their contribution to the establishment of persistent infections in cattle

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    Bovine babesiosis is an acute and persistent tick-borne global disease caused mainly by the intraerythrocytic apicomplexan parasites Babesia bovis and B. bigemina. B. bovis infected erythrocytes sequester in blood capillaries of the host (cytoadhesion), causing malaria-like neurological signs. Cytoadhesion and antigenic variation in B. bovis are linked to the expression of members of the Variant Erythrocyte Surface Antigen (VESA) gene family. Animals that survive acute B. bovis infection and those vaccinated with attenuated strains remain persistently infected, suggesting that B. bovis parasites use immune escape mechanisms. However, attenuated B. bovis parasites do not cause neurological signs in vaccinated animals, indicating that virulence or attenuation factors play roles in modulating parasite virulence phenotypes. Artificial overexpression of the SBP2t11 protein, a defined attenuation factor, was associated with reduced cytoadhesion, suggesting a role for this protein as a key modulator of virulence in the parasite. Hereby, we propose a model that might be functional in the modulation of B. bovis virulence and persistence that relies on the interplay among SBP2t, VESA proteins, cytoadhesion, and the immune responses of the host. Elucidation of mechanisms used by the parasite to establish persistent infection will likely contribute to the design of new methods for the control of bovine babesiosis

    Plasmodium falciparum FIKK Kinase Members Target Distinct Components of the Erythrocyte Membrane

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    BACKGROUND: Modulation of infected host cells by intracellular pathogens is a prerequisite for successful establishment of infection. In the human malaria parasite Plasmodium falciparum, potential candidates for erythrocyte remodelling include the apicomplexan-specific FIKK kinase family (20 members), several of which have been demonstrated to be transported into the erythrocyte cytoplasm via Maurer's clefts. METHODOLOGY: In the current work, we have knocked out two members of this gene family (Pf fikk7.1 and Pf fikk12), whose products are localized at the inner face of the erythrocyte membrane. Both mutant parasite lines were viable and erythrocytes infected with these parasites showed no detectable alteration in their ability to adhere in vitro to endothelial receptors such as chondroitin sulfate A and CD36. However, we observed sizeable decreases in the rigidity of infected erythrocytes in both knockout lines. Mutant parasites were further analyzed using a phospho-proteomic approach, which revealed distinct phosphorylation profiles in ghost preparations of infected erythrocytes. Knockout parasites showed a significant reduction in the level of phosphorylation of a protein of approximately 80 kDa for FIKK12-KO in trophozoite stage and a large protein of about 300 kDa for FIKK7.1-KO in schizont stage. CONCLUSIONS: Our results suggest that FIKK members phosphorylate different membrane skeleton proteins of the infected erythrocyte in a stage-specific manner, inducing alterations in the mechanical properties of the parasite-infected red blood cell. This suggests that these host cell modifications may contribute to the parasites' survival in the circulation of the human host

    Interval Management Display Design Study

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    In 2012, the Federal Aviation Administration (FAA) estimated that U.S. commercial air carriers moved 736.7 million passengers over 822.3 billion revenue-passenger miles. The FAA also forecasts, in that same report, an average annual increase in passenger traffic of 2.2 percent per year for the next 20 years, which approximates to one-and-a-half times the number of today's aircraft operations and passengers by the year 2033. If airspace capacity and throughput remain unchanged, then flight delays will increase, particularly at those airports already operating near or at capacity. Therefore it is critical to create new and improved technologies, communications, and procedures to be used by air traffic controllers and pilots. National Aeronautics and Space Administration (NASA), the FAA, and the aviation industry are working together to improve the efficiency of the National Airspace System and the cost to operate in it in several ways, one of which is through the creation of the Next Generation Air Transportation System (NextGen). NextGen is intended to provide airspace users with more precise information about traffic, routing, and weather, as well as improve the control mechanisms within the air traffic system. NASA's Air Traffic Management Technology Demonstration-1 (ATD-1) Project is designed to contribute to the goals of NextGen, and accomplishes this by integrating three NASA technologies to enable fuel-efficient arrival operations into high-density airports. The three NASA technologies and procedures combined in the ATD-1 concept are advanced arrival scheduling, controller decision support tools, and aircraft avionics to enable multiple time deconflicted and fuel efficient arrival streams in high-density terminal airspace

    Correction: Zainalabdeen, N., et al., Synthesis and Characterization of Naphthalenediimide-Functionalized Flavin Derivatives. Int. J. Mol. Sci. 2013, 14, 7468–7479.

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    Note: In lieu of an abstract, this is an excerpt from the first page. In the original version of the manuscript [1] some of the analytical data for compounds 1 and 2 were incorrect. The correct NMR data are presented below. The authors apologize for any inconvenience this may have caused to the readers of this journal. Compound 1: 1H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.73 (s, 4H), 8.57 (d, J = 1.4 Hz, 1H), 8.16 (dd, J = 8.9, 1.4 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.9 Hz, 1H), 4.08 (t, J = 7.0 Hz, 2H), 3.28 (m, 2H), 1.69 (quin, J = 7.0 Hz, 2H), 1.33 (m, 8H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 162.6 (2xC = 0), 162.3 (2xC = 0), 158.9, 155.1, 151.9, 140.8, 136.6, 136.1, 135.2, 133.7, 131.1 (2xC), 130.5 (4xC), 130.3 (q, J = 4 Hz), 128.6 (q, J = 4 Hz), 128.4 (2xC), 126.6, 126.5 (2xC), 126.4 (q, J = 31 Hz), 126.3 (2xC), 126.2, 123.2 (q, J = 271 Hz), 117.8, 39.9, 30.9, 28.5, 28.3, 27.1, 26.3, 21.9, 13.7. Compound 2: 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 4H), 8.58 (d, J = 1.4 Hz, 1H), 8.03 (dd, J = 9.1, 1.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 5.37 (s, 2H), 4.61 (br s, 2H), 4.19 (t, 2H), 2.47 (sept, J = 6.7 Hz, 1H), 1.74 (m, 2H), 1.47–1.23 (m, 10H), 1.07 (d, J = 6.7 Hz, 6H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 163.1 (2xC = O), 162.9 (2xC = O), 159.0, 155.0, 149.9, 138.9, 137.5, 135.2, 134.9, 134.3, 131.7 (2xC), 131.5 (2xC), 131.2 (q, J = 4 Hz), 131.1 (4xC), 130.9 (q, J = 4 Hz), 128.6 (2xC), 127.1 (2xC), 127.0 (q, J = 28 Hz), 126.8 (2xC), 123.1 (q, J = 270 Hz), 116.9, 51.5, 44.9, 41.2, 31.9, 29.4, 29.3, 28.2, 27.6, 27.2, 22.8, 20.2 (2xC), 14.2

    Unravelling the cellular and molecular pathogenesis of bovine babesiosis: is the sky the limit?

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    The global impact of bovine babesiosis caused by the tick-borne apicomplexan parasites Babesia bovis, Babesia bigemina and Babesia divergens is vastly underappreciated. These parasites invade and multiply asexually in bovine red blood cells (RBCs), undergo sexual reproduction in their tick vectors (Rhipicephalus spp. for B. bovis and B. bigemina, and Ixodes ricinus for B. divergens) and have a transovarial mode of transmission. Babesia parasites can cause acute and persistent infections to adult naïve cattle that can occur without evident clinical signs, but infections caused by B. bovis are associated with more severe disease and increased mortality, and are considered to be the most virulent agent of bovine babesiosis. In addition, babesiosis caused by B. divergens has an important zoonotic potential. The disease caused by B. bovis and B. bigemina can be controlled, at least in part, using therapeutic agents or vaccines comprising live-attenuated parasites, but these methods are limited in terms of their safety, ease of deployability and long-term efficacy, and improved control measures are urgently needed. In addition, expansion of tick habitats due to climate change and other rapidly changing environmental factors complicate efficient control of these parasites. While the ability to cause persistent infections facilitates transmission and persistence of the parasite in endemic regions, it also highlights their capacity to evade the host immune responses. Currently, the mechanisms of immune responses used by infected bovines to survive acute and chronic infections remain poorly understood, warranting further research. Similarly, molecular details on the processes leading to sexual reproduction and the development of tick-stage parasites are lacking, and such tick-specific molecules can be targets for control using alternative transmission blocking vaccines. In this review, we identify and examine key phases in the life-cycle of Babesia parasites, including dependence on a tick vector for transmission, sexual reproduction of the parasite in the midgut of the tick, parasite-dependent invasion and egression of bovine RBCs, the role of the spleen in the clearance of infected RBCs (IRBCs), and age-related disease resistance in cattle, as opportunities for developing improved control measures. The availability of integrated novel research approaches including "omics" (such as genomics, transcriptomics, and proteomics), gene modification, cytoadhesion assays, RBC invasion assays and methods for in vitro induction of sexual-stage parasites will accelerate our understanding of parasite vulnerabilities. Further, producing new knowledge on these vulnerabilities, as well as taking full advantage of existing knowledge, by filling important research gaps should result in the development of next-generation vaccines to control acute disease and parasite transmission. Creative and effective use of current and future technical and computational resources are needed, in the face of the numerous challenges imposed by these highly evolved parasites, for improving the control of this disease. Overall, bovine babesiosis is recognised as a global disease that imposes a serious burden on livestock production and human livelihood, but it largely remains a poorly controlled disease in many areas of the world. Recently, important progress has been made in our understanding of the basic biology and host-parasite interactions of Babesia parasites, yet a good deal of basic and translational research is still needed to achieve effective control of this important disease and to improve animal and human health

    Assessment of Babesia bovis 6cys A and 6cys B as components of transmission blocking vaccines for babesiosis

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    Background: Babesia bovis reproduces sexually in the gut of its tick vector Rhipicephalus microplus, which involves expression of 6cys A and 6cys B proteins. Members of the widely conserved 6cys superfamily are candidates for transmission blocking vaccines (TBV), but intricacies in the immunogenicity of the 6cys proteins in the related Plasmodium parasites required the identification of transmission blocking domains in these molecules for vaccine design. Hereby, the immunogenic efficacy of recombinant (r) B. bovis 6cys A and B proteins as a TBV formulation was studied. Methods: The immunogenicity of r6cys A and 6cys B proteins expressed in a eukaryotic system was evaluated in a cattle immunization trial (3 immunized and 3 control calves). A B. bovis sexual stage induction in vitro inhibition assay to assess the ability of antibodies to block the production of sexual forms by the parasite was developed. Results: Immunized cattle generated antibodies against r6cys A and r6cys B that were unable to block sexual reproduction of the parasite in ticks. Additionally, these antibodies also failed in recognizing native 6cys A and 6cys B and peptides representing 6cys A and 6cys B functional domains and in inhibiting the development of sexual forms in an in vitro induction system. In contrast, rabbit antibodies generated against synthetic peptides representing predicted B-cell epitopes of 6cys A and 6cys B recognized recombinant and native forms of both 6cys proteins as well as peptides representing 6cys A and 6cys B functional domains and were able to neutralize development of sexual forms of the parasite in vitro. Conclusions: These data, combined with similar work performed on Plasmodium 6cys proteins, indicate that an effective 6cys protein-based TBV against B. bovis will require identifying and targeting selected regions of proteins containing epitopes able to reduce transmission

    Evaluating causes of error in landmark-based data collection using scanners

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    In this study, we assess the precision, accuracy, and repeatability of craniodental landmarks (Types I, II, and III, plus curves of semilandmarks) on a single macaque cranium digitally reconstructed with three different surface scanners and a microCT scanner. Nine researchers with varying degrees of osteological and geometric morphometric knowledge landmarked ten iterations of each scan (40 total) to test the effects of scan quality, researcher experience, and landmark type on levels of intra- and interobserver error. Two researchers additionally landmarked ten specimens from seven different macaque species using the same landmark protocol to test the effects of the previously listed variables relative to species-level morphological differences (i.e., observer variance versus real biological variance). Error rates within and among researchers by scan type were calculated to determine whether or not data collected by different individuals or on different digitally rendered crania are consistent enough to be used in a single dataset. Results indicate that scan type does not impact rate of intra- or interobserver error. Interobserver error is far greater than intraobserver error among all individuals, and is similar in variance to that found among different macaque species. Additionally, experience with osteology and morphometrics both positively contribute to precision in multiple landmarking sessions, even where less experienced researchers have been trained in point acquisition. Individual training increases precision (although not necessarily accuracy), and is highly recommended in any situation where multiple researchers will be collecting data for a single project

    Solvatochromic probes for detecting hydrogen-bond-donating solvents

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    Hydrogen bonding heavily influences conformations, rate of reactions, and chemical equilibria. The development of a method to monitor hydrogen bonding interactions independent of polarity is challenging as both are linked. We have developed two solvatochromic dyes that detect hydrogen-bond-donating solvents. The unique solvatochromism of the triazine architecture has allowed the development of probes that monitor hydrogen-bond-donating species including water

    Harnessing Mycobacterium bovis BCG Trained Immunity to Control Human and Bovine Babesiosis

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    Babesiosis is a disease caused by tickborne hemoprotozoan apicomplexan parasites of the genus Babesia that negatively impacts public health and food security worldwide. Development of effective and sustainable vaccines against babesiosis is currently hindered in part by the absence of definitive host correlates of protection. Despite that, studies in Babesia microti and Babesia bovis, major causative agents of human and bovine babesiosis, respectively, suggest that early activation of innate immune responses is crucial for vertebrates to survive acute infection. Trained immunity (TI) is defined as the development of memory in vertebrate innate immune cells, allowing more efficient responses to subsequent specific and non-specific challenges. Considering that Mycobacterium bovis bacillus Calmette-Guerin (BCG), a widely used anti-tuberculosis attenuated vaccine, induces strong TI pro-inflammatory responses, we hypothesize that BCG TI may protect vertebrates against acute babesiosis. This premise is supported by early investigations demonstrating that BCG inoculation protects mice against experimental B. microti infection and recent observations that BCG vaccination decreases the severity of malaria in children infected with Plasmodium falciparum, a Babesia-related parasite. We also discuss the potential use of TI in conjunction with recombinant BCG vaccines expressing Babesia immunogens. In conclusion, by concentrating on human and bovine babesiosis, herein we intend to raise awareness of BCG TI as a strategy to efficiently control Babesia infection
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