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Sample records for brucei causative agent

  1. Helicobacter pylori : the causative agent of peptic ulcer ...

    African Journals Online (AJOL)

    This review examines Helicobacter pylori as an organism and as the causative agent of peptic ulcers. The review also examined the classification of ulcers, ... Elimination of Helicobacter pylori by treatment with antibiotics in peptic ulcer patients resulted in the healing of the ulcer. Prevention of Helicobacter pylori infections is ...

  2. Identification of fungal causative agents of rhinosinusitis from Mashhad, Iran

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    Mohammad Javad Najafzadeh

    2017-09-01

    Full Text Available Background and Purpose: Rhinosinusitis is a common disorder, influencing approximately 20% of the population at some time of their lives. It was recognized and reported with expanding recurrence over the past two decades worldwide. Undoubtedly, correct diagnosis of fungi in patients with fungal rhinosinusitis affects the treatment planning and prognosis of the patients. Identification of the causative agents using the standard mycological procedures remains difficult and time-consuming. Materials and Methods: Based on clinical and radiological parameters, 106 patients suspected of fungal rhinosinusitis were investigated in this cross-sectional prospective study from April 2012 to March 2016 at an otorhinolaryngology department. In this study, internal transcribed spacer (ITS and calmodulin (CaM sequencing were respectively validated as reliable techniques for the identification of Mucorales and Aspergillus to species level (both agents of fungal rhinosinusitis. Results: Of these, 63 (59.4% patients were suspected of allergic fungal rhinosinusitis (AFRS, 40 (37.7% patients suspected of acute invasive fungal rhinosinusitis (AIFRS, and 3 (2.8% patients suspected of fungus ball. In patients suspected of AFRS, AIFRS, and fungus ball only 7, 29, and 1 had positive fungal culture, respectively. After ITS and CaM sequencing, Aspergillus flavus was the most common species isolated from non-invasive forms, and A. flavus and Rhizopus oryzae were more frequently isolated from invasive forms. Conclusion: Aspergillus flavus is the most common agent of fungal rhinosinusitis in Iran, unlike most other reports from throughout the world stating that A. fumigatus is the most frequent causative agent of this disease.

  3. Genome sequence of Yersinia pestis, the causative agent of plague.

    Science.gov (United States)

    Parkhill, J; Wren, B W; Thomson, N R; Titball, R W; Holden, M T; Prentice, M B; Sebaihia, M; James, K D; Churcher, C; Mungall, K L; Baker, S; Basham, D; Bentley, S D; Brooks, K; Cerdeño-Tárraga, A M; Chillingworth, T; Cronin, A; Davies, R M; Davis, P; Dougan, G; Feltwell, T; Hamlin, N; Holroyd, S; Jagels, K; Karlyshev, A V; Leather, S; Moule, S; Oyston, P C; Quail, M; Rutherford, K; Simmonds, M; Skelton, J; Stevens, K; Whitehead, S; Barrell, B G

    2001-10-04

    The Gram-negative bacterium Yersinia pestis is the causative agent of the systemic invasive infectious disease classically referred to as plague, and has been responsible for three human pandemics: the Justinian plague (sixth to eighth centuries), the Black Death (fourteenth to nineteenth centuries) and modern plague (nineteenth century to the present day). The recent identification of strains resistant to multiple drugs and the potential use of Y. pestis as an agent of biological warfare mean that plague still poses a threat to human health. Here we report the complete genome sequence of Y. pestis strain CO92, consisting of a 4.65-megabase (Mb) chromosome and three plasmids of 96.2 kilobases (kb), 70.3 kb and 9.6 kb. The genome is unusually rich in insertion sequences and displays anomalies in GC base-composition bias, indicating frequent intragenomic recombination. Many genes seem to have been acquired from other bacteria and viruses (including adhesins, secretion systems and insecticidal toxins). The genome contains around 150 pseudogenes, many of which are remnants of a redundant enteropathogenic lifestyle. The evidence of ongoing genome fluidity, expansion and decay suggests Y. pestis is a pathogen that has undergone large-scale genetic flux and provides a unique insight into the ways in which new and highly virulent pathogens evolve.

  4. The Human Ureaplasma Species as Causative Agents of Chorioamnionitis.

    Science.gov (United States)

    Sweeney, Emma L; Dando, Samantha J; Kallapur, Suhas G; Knox, Christine L

    2017-01-01

    The human Ureaplasma species are the most frequently isolated microorganisms from the amniotic fluid and placentae of women who deliver preterm and are also associated with spontaneous abortions or miscarriages, neonatal respiratory diseases, and chorioamnionitis. Despite the fact that these microorganisms have been habitually found within placentae of pregnancies with chorioamnionitis, the role of Ureaplasma species as a causative agent has not been satisfactorily explained. There is also controversy surrounding their role in disease, particularly as not all women infected with Ureaplasma spp. develop chorioamnionitis. In this review, we provide evidence that Ureaplasma spp. are associated with diseases of pregnancy and discuss recent findings which demonstrate that Ureaplasma spp. are associated with chorioamnionitis, regardless of gestational age at the time of delivery. Here, we also discuss the proposed major virulence factors of Ureaplasma spp., with a focus on the multiple-banded antigen (MBA), which may facilitate modulation/alteration of the host immune response and potentially explain why only subpopulations of infected women experience adverse pregnancy outcomes. The information presented within this review confirms that Ureaplasma spp. are not simply "innocent bystanders" in disease and highlights that these microorganisms are an often underestimated pathogen of pregnancy. Copyright © 2016 American Society for Microbiology.

  5. Biological agents and respiratory infections: Causative mechanisms and practice management.

    Science.gov (United States)

    Takayanagi, Noboru

    2015-09-01

    Biological agents are increasingly being used to treat patients with immune-mediated inflammatory disease. In Japan, currently approved biological agents for patients with rheumatoid arthritis (RA) include tumor necrosis factor inhibitors, interleukin-6 receptor-blocking monoclonal antibody, and T-cell costimulation inhibitor. Rheumatologists have recognized that safety issues are critical aspects of treatment decisions in RA. Therefore, a wealth of safety data has been gathered from a number of sources, including randomized clinical trials and postmarketing data from large national registries. These data revealed that the most serious adverse events from these drugs are respiratory infections, especially pneumonia, tuberculosis, nontuberculous mycobacteriosis, and Pneumocystis jirovecii pneumonia, and that the most common risk factors associated with these respiratory infections are older age, concomitant corticosteroid use, and underlying respiratory comorbidities. Because of this background, in 2014, the Japanese Respiratory Society published their consensus statement of biological agents and respiratory disorders. This review summarizes this statement and adds recent evidence, especially concerning respiratory infections in RA patients, biological agents and respiratory infections, and practice management of respiratory infections in patients treated with biological agents. To decrease the incidence of infections and reduce mortality, we should know the epidemiology, risk factors, management, and methods of prevention of respiratory infections in patients receiving biological agents. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  6. [MANIFESTATIONS OF EPIDEMIC PROCESS AND TRANSMISSION ROUTES OF CAUSATIVE AGENT OF ENTEROVIRUS SEROUS MENINGITIS].

    Science.gov (United States)

    Sergevnin, V I; Tryasolobova, M A; Kudrevatykh, E V; Kuzovnikova, E Zh

    2015-01-01

    Study the manifestations of epidemic process and leading transmission routes of causative agents of enterovirus serous meningitis (SM) by results of laboratory studies and epidemiologic examination of epidemic nidi. During 2010 - 2014 a study for enterovirus was carried out in cerebrospinal fluid in 743 patients, hospitalized into medical organizations of Perm with primary diagnosis "serous meningitis", feces of 426 individuals, that had communicated with patients with SM of enterovirus etiology; 827 water samples from the distribution network, 295 water samples from open water and 57 washes from surface of vegetables and fruits. All the samples were studied in polymerase chain reaction, part--by a virological method. Epidemiologic examination of 350 epidemic nidi of SM was carried out. Enterovirus and (or) its RNA were detected in 62.0% of patients and 61.9% of individuals that had communicated with patients with enteroviris SM. ECHO 6 serotype enterovirus dominated among the causative agents. Maximum intensity of epidemic process of enterovirus SM, based on data from laboratory examination of patients, was detected in a group of organized pre-school and school age children during summer-autumn period. . Examination of epidemic nidi and laboratory control of environmental objects have shown that CV causative agent transmission factors are, in particular, unboiled water from decentralized sources (boreholes, wells, springs), water from open waters during bathing, as well as fresh vegetables, fruits, berries and meals produced from them. .

  7. [Formation of microbial biofilms in causative agents of acute and chronic pyelonephritis].

    Science.gov (United States)

    Lagun, L V; Atanasova, Iu V; Tapal'skiĭ, D V

    2013-01-01

    Study the intensity of formation of microbial biofilms by Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus strains isolated during various forms of pyelonephritis. 150 clinical isolates of microorganisms isolated from urine ofpatientswith acute and chronic pyelonephritiswere included into the study. Determination of intensity of film-formation was carried out by staining of the formed biofilms by crystal violet with consequent extraction of the dye and measurement of its concentration in washout solution. Among causative agents ofpyelonephritis P. aeruginosa isolates had the maximum film-forming ability. The intensity of biofilm formation of these isolates was 2-3 time higher than staphylococcus and enterobacteria strains. Strains isolated from patients with chronic pyelonephritis by ability to form biofilms significantly surpassed strains isolated from acute pyelonephritis patients. A higher ability to form microbial biofilms for microorganisms--causative agents of pyelonephritis progressing against the background ofurolithiasis was noted. The ability to form biofilms is determined by both causative agent species and character of the infectious process in which this microorganism participates. Intensive formation of biofilms by E. coli, P. aeruginosa, K. pneumoniae, S. aureus clinical isolates may be an important factor of chronization of urinary tract infections.

  8. Observational goals for Max '91 to identify the causative agent for impulsive bursts

    International Nuclear Information System (INIS)

    Batchelor, D.A.

    1989-01-01

    Recent studies of impulsive hard x ray and microwave bursts suggest that a propagating causative agent with a characteristic velocity of the order of 1000 km/s is responsible for these bursts. The results of these studies are summarized and observable distinguishing characteristics of the various possible agents are highlighted, with emphasis on key observational goals for the Max '91 campaigns. The most likely causative agents suggested by the evidence are shocks, thermal conduction fronts, and propagating modes of magnetic reconnection in flare plasmas. With new instrumentation planned for Max '91, high spatial resolution observations of hard x ray sources have the potential to identify the agent by revealing detailed features of source spatial evolution. Observations with the Very Large Array and other radio imaging instruments are of great importance, as well as detailed modeling of coronal loop structures to place limits on their density and temperature profiles. With the combined hard x ray and microwave imaging observations, aided by loop model results, the simplest causative agent to rule out would be the propagating modes of magnetic reconnection. To fit the observational evidence, reconnection modes would need to travel at approximately the same velocity (the Alfven velocity) in different coronal structures that vary in length by a factor of 10(exp 3). Over such a vast range in loop lengths, it is difficult to believe that the Alfven velocity is constant. Thermal conduction fronts would be suggested by sources that expand along the direction of B and exhibit relatively little particle precipitation. Particle acceleration due to shocks could produce more diverse radially expanding source geometries with precipitation at loop footprints

  9. Causative Agents of Aspergillosis Including Cryptic Aspergillus Species and A. fumigatus.

    Science.gov (United States)

    Toyotome, Takahito

    2016-01-01

    Aspergillosis is an important deep mycosis. The causative agents are Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus, of which A. fumigatus is the most prevalent. Cryptic Aspergillus spp., which morphologically resemble representative species of each Aspergillus section, also cause aspergillosis. Most of the cryptic species reveal different susceptibility patterns and/or different secondary metabolite profiles, also called exometabolome in this manuscript, from those representative species. On the other hand, azole-resistant A. fumigatus strains in clinical specimens and in the environment have been reported. Therefore, it is imperative to precisely identify the species, including cryptic Aspergillus spp., and evaluate the susceptibility of isolates.In this manuscript, some of the causative cryptic Aspergillus spp. are briefly reviewed. In addition, the exometabolome of Aspergillus section Fumigati is described. Finally, azole resistance of A. fumigatus is also discussed, in reference to several studies from Japan.

  10. ANTIBACTERIAL PROPERTIES OF HOLMIUM TO CAUSATIVE AGENTS OF SUPPURATIVE -INFLAMMATORY COMPLICATIONS IN PATIENTS WITH TRAUMA

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    Poddubnaya H. N.

    2012-06-01

    Full Text Available Article denotes to determination of antibacterial action of polyoxometalate holmium to causative agents of suppurative-inflammatory process in wounds of patients, which were suffered from trauma. Method of serial dilutions was used for determination of minimal inhibiting concentration (MIC of holmium to staphylococci, enterococci and E. coli. Registration of holmium action shows the strong antibacterial influence to staphylococci and enterococci (MIC of holmium action to staphylococcal and enterococcal strains same 1 10 M, to strains of E.coli – 2,5 10 M. Solutions of holmium don’t have antibacterial action to strains of E.coli.

  11. Pacific Broad Tapeworm Adenocephalus pacificus as a Causative Agent of Globally Reemerging Diphyllobothriosis

    Science.gov (United States)

    Serrano-Martínez, Marcus Enrique; Scholz, Tomas

    2015-01-01

    The Pacific broad tapeworm Adenocephalus pacificus (syn. Diphyllobothrium pacificum) is the causative agent of the third most common fish-borne cestodosis among humans. Although most of the nearly 1,000 cases among humans have been reported in South America (Peru, Chile, and Ecuador), cases recently imported to Europe demonstrate the potential for spread of this tapeworm throughout the world as a result of global trade of fresh or chilled marine fish and travel or migration of humans. We provide a comprehensive survey of human cases of infection with this zoonotic parasite, summarize the history of this re-emerging disease, and identify marine fish species that may serve as a source of human infection when eaten raw or undercooked. PMID:26402440

  12. Prevalence and causative agents of superficial mycoses in a textile factory in Adana, Turkey.

    Science.gov (United States)

    Celik, E; Ilkit, M; Tanir, F

    2003-09-01

    This study was carried out in a textile factory settled in the city center of Adana, Turkey. The workers were evaluated for the presence of superficial mycoses and the interaction of their working environment or working condition. A total of 431 textile workers were included in the study, with a male to female ratio of 378 (87.7%) to 53 (12.3%) and an age range of 19-52 (mean: 33.7 +/- 6.8). Direct examination and/or culture revealed superficial mycoses in 73 (16.9%) workers, among them 56 (76.7%) were classified as dermatophytoses, 8 (11.0%) as Pityriasis versicolor while in nine (12.3%) of the cases, no causative agent could be determined. Trichophyton rubrum (57.1%) and T. mentagrophytes (42.9%) were the two species isolated on culture. This study emphasized that textile workers should be admitted as a risk group for superficial mycoses, especially tinea pedis.

  13. Are Abeta and its derivatives causative agents or innocent bystanders in AD?

    Science.gov (United States)

    Robakis, Nikolaos K

    2010-01-01

    Alzheimer's disease (AD) is characterized by neurodegeneration in neocortical regions of the brain. Currently, Abeta-based theories, including amyloid depositions and soluble Abeta, form the basis of most therapeutic approaches to AD. It remains unclear, however, whether Abeta and its derivatives are the primary causative agents of neuronal loss in AD. Reported studies show no significant correlations between brain amyloid depositions and either degree of dementia or loss of neurons, and brain amyloid loads similar to AD are often found in normal individuals. Furthermore, behavioral abnormalities in animal models overexpressing amyloid precursor protein seem independent of amyloid depositions. Soluble Abeta theories propose toxic Abeta42 or its oligomers as the agents that promote cell death in AD. Abeta peptides, however, are normal components of human serum and CSF, and it is unclear under what conditions these peptides become toxic. Presently, there is little evidence of disease-associated abnormalities in soluble Abeta and no toxic oligomers specific to AD have been found. That familial AD mutations of amyloid precursor protein, PS1 and PS2 promote neurodegeneration suggests the biological functions of these proteins play critical roles in neuronal survival. Evidence shows that the PS/gamma-secretase system promotes production of peptides involved in cell surface-to-nucleus signaling and gene expression, providing support for the hypothesis that familial AD mutations may contribute to neurodegeneration by inhibiting PS-dependent signaling pathways. Copyright 2010 S. Karger AG, Basel.

  14. Are Aβ and Its Derivatives Causative Agents or Innocent Bystanders in AD?

    Science.gov (United States)

    Robakis, Nikolaos K.

    2010-01-01

    Alzheimer's disease (AD) is characterized by neurodegeneration in neocortical regions of the brain. Currently, Aβ-based theories, including amyloid depositions and soluble Aβ, form the basis of most therapeutic approaches to AD. It remains unclear, however, whether Aβ and its derivatives are the primary causative agents of neuronal loss in AD. Reported studies show no significant correlations between brain amyloid depositions and either degree of dementia or loss of neurons, and brain amyloid loads similar to AD are often found in normal individuals. Furthermore, behavioral abnormalities in animal models overexpressing amyloid precursor protein seem independent of amyloid depositions. Soluble Aβ theories propose toxic Aβ42 or its oligomers as the agents that promote cell death in AD. Aβ peptides, however, are normal components of human serum and CSF, and it is unclear under what conditions these peptides become toxic. Presently, there is little evidence of disease-associated abnormalities in soluble Aβ and no toxic oligomers specific to AD have been found. That familial AD mutations of amyloid precursor protein, PS1 and PS2 promote neurodegeneration suggests the biological functions of these proteins play critical roles in neuronal survival. Evidence shows that the PS/γ-secretase system promotes production of peptides involved in cell surface-to-nucleus signaling and gene expression, providing support for the hypothesis that familial AD mutations may contribute to neurodegeneration by inhibiting PS-dependent signaling pathways. PMID:20160455

  15. Ethyl Pyruvate Emerges as a Safe and Fast Acting Agent against Trypanosoma brucei by Targeting Pyruvate Kinase Activity.

    Directory of Open Access Journals (Sweden)

    Netsanet Worku

    Full Text Available Human African Trypanosomiasis (HAT also called sleeping sickness is an infectious disease in humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100% mortality. Currently available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to similarities in cell metabolism between cancerous tumors and trypanosoma cells, some of the current registered drugs against HAT have also been tested in cancer chemotherapy. Here we demonstrate for the first time that the simple ester, ethyl pyruvate, comprises such properties.The current study covers the efficacy and corresponding target evaluation of ethyl pyruvate on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, phasecontrast microscopic video imaging and ex vivo toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki = 3.0±0.29 mM. The potential of ethyl pyruvate as a trypanocidal compound is also strengthened by its fast acting property, killing cells within three hours post exposure. This has been demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, ethyl pyruvate produces minimal side effects in human red cells and is known to easily cross the blood-brain-barrier. This makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug-resistance tests indicate irreversible cell death and a low incidence of resistance development under experimental conditions.Our results present ethyl pyruvate as a safe and fast acting trypanocidal compound and show that it inhibits the enzyme pyruvate kinase. Competitive inhibition of this enzyme was found to cause ATP depletion and cell death. Due to its ability to easily cross

  16. Evidence for a close phylogenetic relationship between Melissococcus pluton, the causative agent of European foulbrood disease, and the genus Enterococcus.

    Science.gov (United States)

    Cai, J; Collins, M D

    1994-04-01

    The 16S rRNA gene sequence of Melissococcus pluton, the causative agent of European foulbrood disease, was determined in order to investigate the phylogenetic relationships between this organism and other low-G + C-content gram-positive bacteria. A comparative sequence analysis revealed that M. pluton is a close phylogenetic relative of the genus Enterococcus.

  17. The genomic sequence of ectromelia virus, the causative agent of mousepox

    International Nuclear Information System (INIS)

    Chen Nanhai; Danila, Maria I.; Feng Zehua; Buller, R. Mark L.; Wang Chunlin; Han Xiaosi; Lefkowitz, Elliot J.; Upton, Chris

    2003-01-01

    Ectromelia virus is the causative agent of mousepox, an acute exanthematous disease of mouse colonies in Europe, Japan, China, and the U.S. The Moscow, Hampstead, and NIH79 strains are the most thoroughly studied with the Moscow strain being the most infectious and virulent for the mouse. In the late 1940s mousepox was proposed as a model for the study of the pathogenesis of smallpox and generalized vaccinia in humans. Studies in the last five decades from a succession of investigators have resulted in a detailed description of the virologic and pathologic disease course in genetically susceptible and resistant inbred and out-bred mice. We report the DNA sequence of the left-hand end, the predicted right-hand terminal repeat, and central regions of the genome of the Moscow strain of ectromelia virus (approximately 177,500 bp), which together with the previously sequenced right-hand end, yields a genome of 209,771 bp. We identified 175 potential genes specifying proteins of between 53 and 1924 amino acids, and 29 regions containing sequences related to genes predicted in other poxviruses, but unlikely to encode for functional proteins in ectromelia virus. The translated protein sequences were compared with the protein database for structure/function relationships, and these analyses were used to investigate poxvirus evolution and to attempt to explain at the cellular and molecular level the well-characterized features of the ectromelia virus natural life cycle

  18. Detection and impact on cancer causation of persons exhibiting abnormal susceptibility to carcinogenic agents

    International Nuclear Information System (INIS)

    Gentner, N.E.; Morrison, D.P.

    1988-01-01

    The so-called 'late biological effects', like cancer and genetic consequences and cytotoxic effects (cell killing, at higher doses), were once thought to be an inevitable consequence of a given level of exposure, whether to background radiation, to chemicals in our biosphere, or form spontaneous damage, the 'wear and tear' of living. The measurement of exposure, which results in living organisms in the formation of a related amount of DNA damage, became a surrogate for the end-effects that constitute risk. This may not be entirely appropriate. The concept of 'equal exposure -- equal risk' assumes a homogeneous response of individuals. However, there are subgroups within the human population of persons whose cultured cells exhibit abnormal sensitivity to specific carcinogenic agents and who may be at increased risk of cancer induced by these of similar agents. Modern molecular biology has shown that the majority of the damage in DNA is repaired by enzymatic DNA repair processes that restitute or ameliorate the lesions and restore normal DNA structure and function. In this view, it is not the initial damage that is of consequence but rather the residual damage left after the repair processes have acted. Since the vast majority of the initial DNA damage undergoes repair normally, variation in the efficiency of these processes in different persons may affect the actual risk of exposure. The human side of the cancer causation formula, that is, considerable importance. To understand how human DNA repair processes function, our laboratories at Chalk River have studied 'mutant' human cell strains in tissue culture. Generally, these DNA repair-defective cell strains are derived from individual donors with heritable disorders that are associated with carcinogen-hypersensitivity and cancer-proneness. Such studies, together with related epidemiological research, have highlighted the importance of this new 'human' factor in carcinogenesis

  19. Role of chicken astrovirus as a causative agent of gout in commercial broilers in India.

    Science.gov (United States)

    Bulbule, N R; Mandakhalikar, K D; Kapgate, S S; Deshmukh, V V; Schat, K A; Chawak, M M

    2013-01-01

    Several outbreaks of gout were reported in commercial broilers in India during 2011 and 2012, causing up to 40% mortality in the birds. Gross and histopathological observations confirmed gout. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis from kidney samples of gout-affected birds indicated the presence of chicken astrovirus (CAstV) in 41.7% of cases and a mixed infection of CAstV and avian nephritis virus (ANV) in 36.4% of cases. CAstV isolated from gout-affected kidneys by inoculating embryonated specific pathogen free (SPF) eggs showed dwarfing in embryos and a cytopathic effect in chicken embryo kidney cells. Inoculation of 1-day-old SPF and broiler chicks with CAstVs caused gout and mortality between 4 and 10 days post inoculation. Virus isolation and qRT-PCR analysis showed the presence of only CAstV in inoculated chicks. Sequence analysis of capsid genes indicated a major group of Indian CAstVs that displayed 92.0 to 99.2% intergroup amino acid identity and 83.9 to 90.4% identity with subgroup Bi CAstVs of UK origin. We designated this group Indian Bi. Analysis of the partial polymerase amino acid sequences of our isolates indicated two groups of CAstVs (Indian 1 and 2) that displayed 90.2 to 95.5% amino acid identity between them. We thus report for the first time that, in addition to infectious bronchitis virus and ANV, CAstVs are a causative agent of gout.

  20. Destructin-1 is a collagen-degrading endopeptidase secreted by Pseudogymnoascus destructans, the causative agent of white-nose syndrome

    OpenAIRE

    O'Donoghue, AJ; Knudsen, GM; Beekman, C; Perry, JA; Johnson, AD; DeRisi, JL; Craik, CS; Bennett, RJ

    2015-01-01

    © 2015, National Academy of Sciences. All rights reserved. Pseudogymnoascus destructans is the causative agent of white-nose syndrome, a disease that has caused the deaths of millions of bats in North America. This psychrophilic fungus proliferates at low temperatures and targets hibernating bats, resulting in their premature arousal from stupor with catastrophic consequences. Despite the impact of white-nose syndrome, little is known about the fungus itself or how it infects its mammalian ho...

  1. Probing the genome-scale metabolic landscape of Bordetella pertussis, the causative agent of whooping cough.

    Science.gov (United States)

    Branco Dos Santos, Filipe; Olivier, Brett G; Boele, Joost; Smessaert, Vincent; De Rop, Philippe; Krumpochova, Petra; Klau, Gunnar W; Giera, Martin; Dehottay, Philippe; Teusink, Bas; Goffin, Philippe

    2017-08-25

    Whooping cough is a highly-contagious respiratory disease caused by Bordetella pertussi s. Despite vaccination, its incidence has been rising alarmingly, and yet, the physiology of B. pertussis remains poorly understood. We combined genome-scale metabolic reconstruction, a novel optimization algorithm and experimental data to probe the full metabolic potential of this pathogen, using strain Tohama I as a reference. Experimental validation showed that B. pertussis secretes a significant proportion of nitrogen as arginine and purine nucleosides, which may contribute to modulation of the host response. We also found that B. pertussis can be unexpectedly versatile, being able to metabolize many compounds while displaying minimal nutrient requirements. It can grow without cysteine - using inorganic sulfur sources such as thiosulfate - and it can grow on organic acids such as citrate or lactate as sole carbon sources, providing in vivo demonstration that its TCA cycle is functional. Although the metabolic reconstruction of eight additional strains indicates that the structural genes underlying this metabolic flexibility are widespread, experimental validation suggests a role of strain-specific regulatory mechanisms in shaping metabolic capabilities. Among five alternative strains tested, three were shown to grow on substrate combinations requiring a functional TCA cycle, but only one could use thiosulfate. Finally, the metabolic model was used to rationally design growth media with over two-fold improvements in pertussis toxin production. This study thus provides novel insights into B. pertussis physiology, and highlights the potential, but also limitations of models solely based on metabolic gene content. IMPORTANCE The metabolic capabilities of Bordetella pertussis - the causative agent of whooping cough - were investigated from a systems-level perspective. We constructed a comprehensive genome-scale metabolic model for B. pertussis , and challenged its predictions

  2. Metabolic reprogramming during the Trypanosoma brucei life cycle [version 2; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Terry K. Smith

    2017-05-01

    Full Text Available Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

  3. Metabolic reprogramming during the Trypanosoma brucei life cycle [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Terry K. Smith

    2017-05-01

    Full Text Available Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

  4. Genetic and structural study of DNA-directed RNA polymerase II of Trypanosoma brucei, towards the designing of novel antiparasitic agents

    Directory of Open Access Journals (Sweden)

    Louis Papageorgiou

    2017-03-01

    Full Text Available Trypanosoma brucei brucei (TBB belongs to the unicellular parasitic protozoa organisms, specifically to the Trypanosoma genus of the Trypanosomatidae class. A variety of different vertebrate species can be infected by TBB, including humans and animals. Under particular conditions, the TBB can be hosted by wild and domestic animals; therefore, an important reservoir of infection always remains available to transmit through tsetse flies. Although the TBB parasite is one of the leading causes of death in the most underdeveloped countries, to date there is neither vaccination available nor any drug against TBB infection. The subunit RPB1 of the TBB DNA-directed RNA polymerase II (DdRpII constitutes an ideal target for the design of novel inhibitors, since it is instrumental role is vital for the parasite’s survival, proliferation, and transmission. A major goal of the described study is to provide insights for novel anti-TBB agents via a state-of-the-art drug discovery approach of the TBB DdRpII RPB1. In an attempt to understand the function and action mechanisms of this parasite enzyme related to its molecular structure, an in-depth evolutionary study has been conducted in parallel to the in silico molecular designing of the 3D enzyme model, based on state-of-the-art comparative modelling and molecular dynamics techniques. Based on the evolutionary studies results nine new invariant, first-time reported, highly conserved regions have been identified within the DdRpII family enzymes. Consequently, those patches have been examined both at the sequence and structural level and have been evaluated in regard to their pharmacological targeting appropriateness. Finally, the pharmacophore elucidation study enabled us to virtually in silico screen hundreds of compounds and evaluate their interaction capabilities with the enzyme. It was found that a series of chlorine-rich set of compounds were the optimal inhibitors for the TBB DdRpII RPB1 enzyme. All

  5. Etiology of Infectious Complications and Antibiotic-Resistance of Major Causative Agents in Victims with Severe Injury

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    T. A. Vasina

    2007-01-01

    Full Text Available Objective: to analyze the spectrum of major pathogens of infectious complications in patients with concomitant injury.Materials and methods. 560 biological samples taken from 331 patients were bacteriologically studied. A significant reduction in the isolation frequency of Pseudomonas aeruginosa and an increase in etiological role of Staphylococcus aureus were ascertained in victims with severe injury and concomitant infectious complications during long-term 1982—1984 and 2002—2004 follow-ups.Results. The significant pathogens of infectious complications in concomitant injuries are Staphylococcus aureus, Klebsiella and Escherichia coli. Vancomycin, imipenem/cilastatin, and amikacin are shown to be the most effective drugs for early antibiotic therapy. Thus, the findings reflect structural changes in the leading causative agents of infectious complications in victims with severe injury. If their principal pathogen was Pseudomonas aeruginosa in the 1990s, Staphylococcus aureus and representatives in the colibacillus group prevail today. This supports and generates a need for continuous microbiological monitoring of the causative agents of pyoin-flammatory complications in intensive care units wherein patients with immunosuppression are also present. Pathogen monitoring makes it possible to apply of a well-grounded and rational package of preventive and therapeutic measures and to perform early target antibiotic therapy. 

  6. Syphilis may be a confounding factor, not a causative agent, in syphilitic ALS.

    Science.gov (United States)

    Tuk, Bert

    2016-01-01

    Based upon a review of published clinical observations regarding syphilitic amyotrophic lateral sclerosis (ALS), I hypothesize that syphilis is actually a confounding factor, not a causative factor, in syphilitic ALS. Moreover, I propose that the successful treatment of ALS symptoms in patients with syphilitic ALS using penicillin G and hydrocortisone is an indirect consequence of the treatment regimen and is not due to the treatment of syphilis. Specifically, I propose that the observed effect is due to the various pharmacological activities of penicillin G ( e.g ., a GABA receptor antagonist) and/or the multifaceted pharmacological activity of hydrocortisone. The notion that syphilis may be a confounding factor in syphilitic ALS is highly relevant, as it suggests that treating ALS patients with penicillin G and hydrocortisone-regardless of whether they present with syphilitic ALS or non-syphilitic ALS-may be effective at treating this rapidly progressive, highly devastating disease.

  7. Is Ureaplasma spp. the leading causative agent of acute chorioamnionitis in women with preterm birth?

    Science.gov (United States)

    Kikhney, J; von Schöning, D; Steding, I; Schulze, J; Petrich, A; Hiergeist, A; Reischl, U; Moter, A; Thomas, A

    2017-02-01

    Aim of this study was to detect microorganisms in fetal membranes and placental tissue in preterm chorioamnionitis by combining fluorescence in situ hybridization (FISH) with broad range PCR. The combination of the two molecular techniques enables identification and localization of the microorganisms within the tissue, confirming their clinical relevance. In a prospective cohort study, we compared 31 women with preterm premature rupture of membranes or preterm labour and preterm delivery by caesarean section with a control group of 26 women undergoing elective caesarean section at term. Fetal membranes and placental tissue were analysed by FISH and broad range 16S rRNA-gene PCR and sequencing. For 20 women in the preterm group, caesarean section was performed because of a clinical diagnosis of chorioamnionitis. Microorganisms were detected in the tissues by both molecular techniques in 11 out of 20 women. Among those, Ureaplasma spp. was most abundant, with five cases that remained culture-negative and would have been missed by routine diagnostic procedures. Other infections were caused by Staphylococcus aureus, Streptococcus mitis or Escherichia coli. FISH and PCR were negative for all women without suspected chorioamnionitis and for the control group. Combination of FISH with broad-range PCR and sequencing permitted unambiguous identification of the causative microorganisms in chorioamnionitis. The high prevalence of Ureaplasma spp. should lead to a re-evaluation of its clinical significance and possible therapeutic consequences. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  8. Genetic diversity of the causative agent of ice-ice disease of the seaweed Kappaphycus alvarezii from Karimunjawa island, Indonesia

    Science.gov (United States)

    Syafitri, E.; Prayitno, S. B.; Ma'ruf, W. F.; Radjasa, O. K.

    2017-02-01

    An essential step in investigating the bacterial role in the occurrence of diseases in Kappaphycus alvarezii is the characterization of bacteria associated with this seaweed. A molecular characterization was conducted on the genetic diversity of the causative agents of ice-ice disease associated with K. alvarezii widely known as the main source of kappa carrageenan. K. alvrezii infected with ice-ice were collected from the Karimunjawa island, North Java Sea, Indonesia. Using Zobell 2216E marine agar medium, nine bacterial species were isolated from the infected seaweed. The molecular characterizations revealed that the isolated bacteria causing ice-ice disease were closely related to the genera of Alteromonas, Bacillus, Pseudomonas, Pseudoalteromonas, Glaciecola, Aurantimonas, and Rhodococcus. In order to identify the symptoms causative organisms, the isolated bacterial species were cultured and were evaluated for their pathogenity. Out of 9 species, only 3 isolates were able to cause the ice-ice symptoms and consisted of Alteromonas macleodii, Pseudoalteromonas issachenkonii and Aurantimonas coralicida. A. macleodii showed the highest pathogenity.

  9. Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design.

    Directory of Open Access Journals (Sweden)

    Juan Carlos Pizarro

    Full Text Available Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp, while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF. Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite.

  10. Infection of Parainfluenza type 3 (PI-3 as one of the causative agent of pneumonia in sheep and goats

    Directory of Open Access Journals (Sweden)

    Indrawati Sendow

    2002-03-01

    Full Text Available Serological survey was conducted to obtain the prevalence of Parainfluenza type 3 (PI-3 reactor as one of the causative agent of pneumonia in sheep and goats in abatoir at Jakarta and some small holder farms in Indonesia. Serological test using serum neutralization from 724 goat sera and 109 sheep sera indicated that only 1% of goats were serologically reactors and none of sheep sera had antibodies against PI-3 virus. Isolation of the virus from 56 bronchus and trachea swab and 345 lungs indicated that only one sampel from lung showed cythopathic effect (CPE in Madin Darby Bovine Kidney (MDBK cell lines identification of the virus using serum neutralization test indicated that the virus neutralized reference PI-3 antisera. The isolate came from one lung (7% of 24 that showed histopathologically pneumonia intertitialis that usually caused by viral infection.

  11. Helminth parasites of cats from the Vientiane Province, Laos, as indicators of the occurrence of causative agents of human parasitoses

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    Scholz T.

    2003-12-01

    Full Text Available A total of 55 domestic cats (Felis calus f. domestico and one wild (Bengal cat (Prionailurus bengalensis from the Vientiane Province, central Laos, were examined for helminth parasites with emphasis given to potential human parasites. The following species were found (parasites infective to man marked with an asterisk: Opisthorchis viverrini*, Haplorchis pumilio*,H. laichui*,H. yokogawai*, Stellantchasmus falcatus* (Digenea; Spirometra sp.*, Dipylidium caninum*, Taenia taeniaeformis (Cestoda; Capillariidae gen. sp., Toxocara canis*, T. cati*, Ancylostoma ceylanicum*, A. tubaeforme, Gnathostoma spinigerum*, Physaloptera preputials (Nematoda; and Oncicola sp. (Acanthocephala. This study demonstrated that examination of cats may provide useful data on the occurrence of helminths which are potential causative agents of human diseases.

  12. In vitro evaluation of the effects of some plant essential oils on Ascosphaera apis, the causative agent of Chalkbrood disease

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    Mohammad Javed Ansari

    2017-07-01

    Full Text Available Ascosphaera apis is one of the major fungal pathogens of honey bee broods and the causative agent of Chalkbrood disease. The factors responsible for the pathogenesis of Chalkbrood disease are still not fully understood, and the increasing resistance of A. apis to commonly used antifungal agents necessitates a search for new agents to control this disease. The in vitro antifungal activities of 27 plant essential oils against two isolates of A. apis (Aksu-4 and Aksu-9 were evaluated. Out of the 27 plant essential oils tested, 21 were found to be effective in killing both isolates of A. apis. Based on their minimum fungicidal concentration (MFC values, the effective oils were grouped into three categories: highly effective, moderately effective and minimally effective. Mountain pepper oil, Kala Bhangra oil, spearmint oil, babuna oil, betel leaf oil, carrot seed oil, cumin seed oil and clove bud oil were highly effective, with MBC values between 50.0 μg/mL and 600.0 μg/mL. Mountain pepper was the most effective essential oil, with an MBC value of 50.0 μg/mL. Citral and caryophyllene containing oils were the most effective with MIC 50 ppm. The essential oils tested exhibited significant antimicrobial activities against both strains of A. apis, and they may contain compounds that could play an important role in the treatment or prevention of Chalkbrood disease of honeybee.

  13. Inhibition of Xanthomonas fragariae, Causative Agent of Angular Leaf Spot of Strawberry, through Iron Deprivation

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    Peter Henry

    2016-10-01

    Full Text Available In commercial production settings, few options exist to prevent or treat angular leaf spot of strawberry, a disease of economic importance and caused by the bacterial pathogen Xanthomonas fragariae (Xfr. In the process of isolating and identifying Xfr bacteria from symptomatic plants, we observed growth inhibition of Xfr by bacterial isolates from the same leaf macerates. Identified as species of Pseudomonas and Rhizobium, these isolates were confirmed to suppress growth of Xfr in agar overlay plates and in microtiter plate cultures, as did our reference strain Pseudomonas putida KT2440. Screening of a transposon mutant library of KT2440 revealed that disruption of the biosynthetic pathway for the siderophore pyoverdine resulted in complete loss of Xfr antagonism, suggesting iron competition as a mode of action. Antagonism could be replicated on plate and in culture by addition of purified pyoverdine or by addition of the chelating agents tannic acid and dipyridyl, while supplementing the medium with iron negated the inhibitory effects of pyoverdine, tannic acid and dipyridyl. When co-inoculated with tannic acid onto strawberry plants, Xfr’s ability to cause foliar symptoms was greatly reduced, suggesting a possible opportunity for iron-based management of angular leaf spot. We discuss our findings in the context of ‘nutritional immunity’, the idea that plant hosts restrict pathogens access to iron, either directly, or indirectly through their associated microbiota.

  14. Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis

    Science.gov (United States)

    2014-01-01

    Background Sporotrichosis is a chronic subcutaneous mycosis of humans and animals, which is typically acquired by traumatic inoculation of plant material contaminated with Sporothrix propagules, or via animals, mainly felines. Sporothrix infections notably occur in outbreaks, with large epidemics currently taking place in southeastern Brazil and northeastern China. Pathogenic species include Sporothrix brasiliensis, Sporothrix schenckii s. str., Sporothrix globosa, and Sporothrix luriei, which exhibit differing geographical distribution, virulence, and resistance to antifungals. The phylogenetically remote species Sporothrix mexicana also shows a mild pathogenic potential. Methods We assessed a genetically diverse panel of 68 strains. Susceptibility profiles of medically important Sporothrix species were evaluated by measuring the MICs and MFCs for amphotericin B (AMB), fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), posaconazole (PCZ), flucytosine (5FC), and caspofungin (CAS). Haplotype networks were constructed to reveal interspecific divergences within clinical Sporothrix species to evaluate genetically deviant isolates. Results ITC and PCZ were moderately effective against S. brasiliensis (MIC90 = 2 and 2 μg/mL, respectively) and S. schenckii (MIC90 = 4 and 2 μg/mL, respectively). PCZ also showed low MICs against the rare species S. mexicana. 5FC, CAS, and FLC showed no antifungal activity against any Sporothrix species. The minimum fungicidal concentration ranged from 2 to >16 μg/mL for AMB against S. brasiliensis and S. schenckii, while the MFC90 was >16 μg/mL for ITC, VRC, and PCZ. Conclusion Sporothrix species in general showed high degrees of resistance against antifungals. Evaluating a genetically diverse panel of strains revealed evidence of multidrug resistant phenotypes, underlining the need for molecular identification of etiologic agents to predict therapeutic outcome. PMID:24755107

  15. Vibrio harveyi as a causative agent of the White Syndrome in tropical stony corals.

    Science.gov (United States)

    Luna, Gian Marco; Bongiorni, Lucia; Gili, Claudia; Biavasco, Francesca; Danovaro, Roberto

    2010-02-01

    We investigated bacterial assemblages associated with corals displaying symptoms of the 'White Syndrome' (WS), a general term used for indicating the appearance of bands, spots or patches of tissue loss, which is devastating wide areas of tropical ecosystems worldwide. We collected WS-diseased (n = 15) and healthy (n = 15) corals from the natural reef (Indonesia, Indian Ocean) and from four large public aquaria. By using culture-dependent and culture-independent techniques, we found that a large fraction (73%) of the investigated WS events was associated with the presence of a high bacterial abundance and, specifically, of Vibrio spp. Vibrio harveyi, a pathogen of many marine organisms and recently involved in coral Yellow Band disease, was the most represented species, being recovered from five out of 15 diseased corals. In experimental infection assays, two V. harveyi strains, isolated from diseased corals, were inoculated on a total of 62 healthy colonies of Pocillopora damicornis. WS signs appeared in 57 corals, confirming the ability of V. harveyi strains to induce the disease. We conclude that V. harveyi is one of the coral pathogens involved in the appearance of WS. However, not all of the investigated WSs were associated to V. harveyi detection, nor to other Vibrio species (such as V. coralliilyticus), which supports the hypothesis that WS is not caused exclusively by Vibrio spp., but rather can have a multifactorial aetiology, or can represent a group of diseases caused by a variety of agents. Further investigations to identify specific virulence traits will contribute to the understanding of the role of V. harveyi in WS pathogenesis. © 2009 Society for Applied Microbiology and Blackwell Publishing Ltd.

  16. A comparison of DNA extraction procedures for the detection of Mycobacterium ulcerans, the causative agent of Buruli ulcer, in clinical and environmental specimens

    DEFF Research Database (Denmark)

    Durnez, Lies; Stragier, Pieter; Roebben, Karen

    2008-01-01

    Mycobacterium ulcerans is the causative agent of Buruli ulcer, the third most common mycobacterial disease in humans after tuberculosis and leprosy. Although the disease is associated with aquatic ecosystems, cultivation of the bacillus from the environment is difficult to achieve. Therefore...

  17. Taxonomy Icon Data: Trypanosoma brucei [Taxonomy Icon

    Lifescience Database Archive (English)

    Full Text Available Trypanosoma brucei Trypanosoma brucei Trypanosoma_brucei_L.png Trypanosoma_brucei_NL.png Trypanoso...ma_brucei_S.png Trypanosoma_brucei_NS.png http://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Trypanoso...ma+brucei&t=L http://biosciencedbc.jp/taxonomy_icon/icon.cgi?i=Trypanosoma+brucei&t=NL http://bioscie...ncedbc.jp/taxonomy_icon/icon.cgi?i=Trypanosoma+brucei&t=S http://biosciencedbc.jp.../taxonomy_icon/icon.cgi?i=Trypanosoma+brucei&t=NS http://togodb.biosciencedbc.jp/togodb/view/taxonomy_icon_comment_en?species_id=121 ...

  18. Mycobacterium avium subspecies paratuberculosis: A possible causative agent in human morbidity and risk to public health safety

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    Mary Garvey

    2018-05-01

    Full Text Available Mycobacterium avium subspecies paratuberculosis is a bacterial parasite and the causative agent of paratuberculosis, a disease predominately found in cattle and sheep. Infection with this microorganism results in substantial farming economic losses and animal morbidity. The link between infection with this pathogen and human disease has been theorised for many years with Crohn’s disease being one of many suspected resultant conditions. Mycobacterium avium may be spread from animal to human hosts by water and foodborne transmission routes, where the foodborne route of exposure represents a significant risk for susceptible populations, namely children and the immune-compromised. Following colonisation of the host, the parasitic organism evades the host immune system by use of molecular mimicry, displaying peptide sequences similar to that of the host cells causing a disruption of self-verses non self-recognition. Theoretically, this failure to recognise the invading organism as distinct from host cells may result in numerous autoimmune conditions. Here, the author presents current information assessing the link between numerous diseases states in humans such inflammatory bowel disease, Type 1 diabetes, rheumatoid arthritis, Hashimoto\\'s thyroiditis, multiple sclerosis and autism following infection with Mycobacterium avium paratuberculosis. The possibility of zoonotic transmission of the organism and its significant risk to public health safety as a consequence is also discussed.

  19. [Epidemiologic diagnostic of nosocomial suppurative-septic infections of Pseudomonas etiology based on intraspecies typing of causative agent].

    Science.gov (United States)

    Fel'dblium, I V; Zakharova, Iu A; Nikolaeva, A M; Fedotova, O S

    2013-01-01

    Scientific justification of optimization of epidemiologic diagnostic of suppurative-septic infection (SSI) caused by Pseudomonas aeruginosa based on comparability of antibiotic sensitivity and beta-lactamase production. Intraspecies typing of 37 P. aeruginosa strains isolated during microbiological monitoring of 106 patients and 131 objects of clinical environment of surgical and obstetrician hospitals by using a complex ofphenotypic and molecular-biological methods including determination of sensitivity to antibiotics by serial dilutions method and PCR-diagnostics with determination of TEM, SHV, CTX, OXA, MBL, VIM genes was performed. P. aeruginosa strains combined into groups by isolation location during studies turned out to be heterogeneous by sensitivity to antibiotics and beta-lactamase production that allowed to form subgroups of strains by focality attribute. Isolates recovered from different SSI foci had significant differences in minimal inhibitory concentration (MIC) reaching 1024 times. MIC parameter within subgroups did not exceed 8 - 16 consequent dilutions. Use of a complex of phenotypic and molecular-biologic methods of causative agent typing including determination of sensitivity to antibiotics by serial dilutions method and evaluation of beta-lactamase production allowed to establish a mechanism of development of SSI epidemic process caused by P. aeruginosa, detect origins and reservoirs of infection in hospital, modes and factors of transmission and reach maximum justification of epidemiologic control and prophylaxis measures of localization of foci of nosocomial infections of pseudomonas etiology.

  20. Destructin-1 is a collagen-degrading endopeptidase secreted by Pseudogymnoascus destructans, the causative agent of white-nose syndrome.

    Science.gov (United States)

    O'Donoghue, Anthony J; Knudsen, Giselle M; Beekman, Chapman; Perry, Jenna A; Johnson, Alexander D; DeRisi, Joseph L; Craik, Charles S; Bennett, Richard J

    2015-06-16

    Pseudogymnoascus destructans is the causative agent of white-nose syndrome, a disease that has caused the deaths of millions of bats in North America. This psychrophilic fungus proliferates at low temperatures and targets hibernating bats, resulting in their premature arousal from stupor with catastrophic consequences. Despite the impact of white-nose syndrome, little is known about the fungus itself or how it infects its mammalian host. P. destructans is not amenable to genetic manipulation, and therefore understanding the proteins involved in infection requires alternative approaches. Here, we identify hydrolytic enzymes secreted by P. destructans, and use a novel and unbiased substrate profiling technique to define active peptidases. These experiments revealed that endopeptidases are the major proteolytic activities secreted by P. destructans, and that collagen, the major structural protein in mammals, is actively degraded by the secretome. A serine endopeptidase, hereby-named Destructin-1, was subsequently identified, and a recombinant form overexpressed and purified. Biochemical analysis of Destructin-1 showed that it mediated collagen degradation, and a potent inhibitor of peptidase activity was identified. Treatment of P. destructans-conditioned media with this antagonist blocked collagen degradation and facilitated the detection of additional secreted proteolytic activities, including aminopeptidases and carboxypeptidases. These results provide molecular insights into the secretome of P. destructans, and identify serine endopeptidases that have the clear potential to facilitate tissue invasion and pathogenesis in the mammalian host.

  1. Clinicoepidemiologic pattern of cutaneous leishmaniasis and molecular characterization of its causative agent in Hajjah governorate, northwest of Yemen.

    Science.gov (United States)

    Mogalli, Nabil M; El Hossary, Shabaan S; Khatri, Mishri Lal; Mukred, Abdualdaim M; Kassem, Hala A; El Sawaf, Bahira M; Ramadan, Nadia F

    2016-11-01

    The clinicoepidemiologic profile of 143 cases (93 males and 50 females) with cutaneous leishmaniasis from 18 villages of Hajjah governorate, Yemen was studied. Dry-type lesions were seen in 98.6% and wet-type lesions in 1.4% of patients. Lesions were localized in all cases with different morphological patterns. Microscopic examination of Giemsa-stained slit smears revealed amastigotes in 74.1% of patients with dry-type lesions and 0% in patients with wet-type lesions. The burden of the parasites in the lesions was high indicating active transmission of the disease. Most cases were from villages with moderate altitude range (8001-1600m). All age groups were affected, but most cases were seen in ages from 5 to 15 years. Leishmania species identification was done for all cases by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The biopsic material was scraped from both Giemsa-stained and methanol-fixed smears. The molecular characterization of Leishmania species revealed Leishmania tropica as the causative agent of cutaneous leishmaniasis in Hajjah, Yemen. The risk factors associated with the transmission of the disease and recommendations for improving case detection were discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Survey and molecular detection of Melissococcus plutonius, the causative agent of European Foulbrood in honeybees in Saudi Arabia

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    Mohammad Javed Ansari

    2017-09-01

    Full Text Available A large-scale field survey was conducted to screen major Saudi Arabian beekeeping locations for infection by Melissococcus plutonius. M. plutonius is one of the major bacterial pathogens of honeybee broods and is the causative agent of European Foulbrood disease (EFB. Larvae from samples suspected of infection were collected from different apiaries and homogenized in phosphate buffered saline (PBS. Bacteria were isolated on MYPGP agar medium. Two bacterial isolates, ksuMP7 and ksuMP9 (16S rRNA GenBank accession numbers, KX417565 and KX417566, respectively, were subjected to molecular identification using M. plutonius -specific primers, a BLAST sequence analysis revealed that the two isolates were M. plutonius with more than 98% sequence identity. The molecular detection of M. plutonius from honeybee is the first recorded incidence of this pathogen in Saudi Arabia. This study emphasizes the need for official authorities to take immediate steps toward treating and limiting the spread of this disease throughout the country.

  3. Historical distribution and host-vector diversity of Francisella tularensis, the causative agent of tularemia, in Ukraine.

    Science.gov (United States)

    Hightower, Jake; Kracalik, Ian T; Vydayko, Nataliya; Goodin, Douglas; Glass, Gregory; Blackburn, Jason K

    2014-10-16

    Francisella tularensis, the causative agent of tularemia, is a zoonotic agent that remains across much of the northern hemisphere, where it exists in enzootic cycles. In Ukraine, tularemia has a long history that suggests a need for sustained surveillance in natural foci. To better characterize the host-vector diversity and spatial distribution of tularemia, we analyzed historical data from field collections carried out from 1941 to 2008. We analyzed the spatial-temporal distribution of bacterial isolates collected from field samples. Isolates were characterized by source and dominant land cover type. To identify environmental persistence and spatial variation in the source of isolation, we used the space-time permutation and multinomial models in SaTScan. A total of 3,086 positive isolates were taken from 1,084 geographic locations. Isolation of F. tularensis was more frequent among arthropods [n = 2,045 (66.3%)] followed by mammals [n = 619 (20.1%)], water [n = 393 (12.7%)], and farm produce [n = 29 (0.94%)], respectively. Four areas of persistent bacterial isolation were identified. Water and farm produce as sources of bacterial isolation were clustered. Our findings confirm the presence of long-standing natural foci of F. tularensis in Ukraine. Given the history of tularemia as well as its environmental persistence there exists a possibility of (re)emergence in human populations. Heterogeneity in the distribution of tularemia isolate recovery related to land cover type supports the theory of natural nidality and clusters identify areas to target potential sources of the pathogen and improve surveillance.

  4. Proteome remodelling during development from blood to insect-form Trypanosoma brucei quantified by SILAC and mass spectrometry

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    Gunasekera Kapila

    2012-10-01

    Full Text Available Abstract Background Trypanosoma brucei is the causative agent of human African sleeping sickness and Nagana in cattle. In addition to being an important pathogen T. brucei has developed into a model system in cell biology. Results Using Stable Isotope Labelling of Amino acids in Cell culture (SILAC in combination with mass spectrometry we determined the abundance of >1600 proteins in the long slender (LS, short stumpy (SS mammalian bloodstream form stages relative to the procyclic (PC insect-form stage. In total we identified 2645 proteins, corresponding to ~30% of the total proteome and for the first time present a comprehensive overview of relative protein levels in three life stages of the parasite. Conclusions We can show the extent of pre-adaptation in the SS cells, especially at the level of the mitochondrial proteome. The comparison to a previously published report on monomorphic in vitro grown bloodstream and procyclic T. brucei indicates a loss of stringent regulation particularly of mitochondrial proteins in these cells when compared to the pleomorphic in vivo situation. In order to better understand the different levels of gene expression regulation in this organism we compared mRNA steady state abundance with the relative protein abundance-changes and detected moderate but significant correlation indicating that trypanosomes possess a significant repertoire of translational and posttranslational mechanisms to regulate protein abundance.

  5. Neonatal nosocomial sepsis in a level-III NICU: evaluation of the causative agents and antimicrobial susceptibilities.

    Science.gov (United States)

    Yalaz, Mehmet; Cetin, Hasan; Akisu, Mete; Aydemir, Söhret; Tunger, Alper; Kültürsay, Nilgün

    2006-01-01

    Despite advances in supportive care and use of antibiotics, sepsis preserves its importance due to its high mortality and morbidity for neonates. Identifying the causative agents and antibiotic resistance yearly in a neonatal intensive care unit (NICU) helps the physician to choose the most appropriate empirical therapy. In this study we aimed to evaluate positive blood cultures and antibiotic susceptibilities of newborns with proven sepsis during the years 2000-2002 in our NICU. The charts of babies with sepsis were evaluated for clinical characteristics, positive cultures and antimicrobial susceptibilities, retrospectively. Although most of the admitted patients were premature (76.5%), the frequency of proven sepsis was quite low, at 9.1% among 909 newborns. Mortality rate in sepsis was 16%. The most commonly isolated micro-organisms were coagulase-negative staphylococci (CoNS) (31.3%), fungi (19.2%), Staphylococcus aureus (13%) and Klebsiella pneumoniae (10.5%). Methicillin resistance for CoNS was 92.3% and for S. aureus was 72.7%. In the last year, a significant increase in the frequency of Klebsiella pneumoniae (8.3 vs 14.2%), CoNS (27.1 vs 37.1%), Pseudomonas aeruginosa (2.1 vs 8.6%) and fungal infections (18.8 vs 20%) was observed compared to the previous years. An initial empirical antibiotic therapy for late-onset sepsis was designed with teicoplanin + piperacillin-tazobactam/meropenem + antifungal (fluconazole or amphotericin B) as the best combination to cover this spectrum until the culture results arrive. However, this combination is only compatible with our results and may not be applied in all units. Every unit must follow the bacterial spectrum and antibacterial resistance patterns to choose their specific empirical treatment strategy for nosocomial infections.

  6. Identification of actinomycetes from plant rhizospheric soils with inhibitory activity against Colletotrichum spp., the causative agent of anthracnose disease.

    Science.gov (United States)

    Intra, Bungonsiri; Mungsuntisuk, Isada; Nihira, Takuya; Igarashi, Yasuhiro; Panbangred, Watanalai

    2011-04-01

    Colletotrichum is one of the most widespread and important genus of plant pathogenic fungi worldwide. Various species of Colletotrichum are the causative agents of anthracnose disease in plants, which is a severe problem to agricultural crops particularly in Thailand. These phytopathogens are usually controlled using chemicals; however, the use of these agents can lead to environmental pollution. Potential non-chemical control strategies for anthracnose disease include the use of bacteria capable of producing anti-fungal compounds such as actinomycetes spp., that comprise a large group of filamentous, Gram positive bacteria from soil. The aim of this study was to isolate actinomycetes capable of inhibiting the growth of Colletotrichum spp, and to analyze the diversity of actinomycetes from plant rhizospheric soil. A total of 304 actinomycetes were isolated and tested for their inhibitory activity against Colletotrichum gloeosporioides strains DoA d0762 and DoA c1060 and Colletotrichum capsici strain DoA c1511 which cause anthracnose disease as well as the non-pathogenic Saccharomyces cerevisiae strain IFO 10217. Most isolates (222 out of 304, 73.0%) were active against at least one indicator fungus or yeast. Fifty four (17.8%) were active against three anthracnose fungi and 17 (5.6%) could inhibit the growth of all three fungi and S. cerevisiae used in the test. Detailed analysis on 30 selected isolates from an orchard at Chanthaburi using the comparison of 16S rRNA gene sequences revealed that most of the isolates (87%) belong to the genus Streptomyces sp., while one each belongs to Saccharopolyspora (strain SB-2) and Nocardiopsis (strain CM-2) and two to Nocardia (strains BP-3 and LK-1). Strains LC-1, LC-4, JF-1, SC-1 and MG-1 exerted high inhibitory activity against all three anthracnose fungi and yeast. In addition, the organic solvent extracts prepared from these five strains inhibited conidial growth of the three indicator fungi. Preliminary analysis of crude

  7. The complete genome sequence of Yersinia pseudotuberculosis IP31758, the causative agent of Far East scarlet-like fever.

    Directory of Open Access Journals (Sweden)

    Mark Eppinger

    2007-08-01

    Full Text Available The first reported Far East scarlet-like fever (FESLF epidemic swept the Pacific coastal region of Russia in the late 1950s. Symptoms of the severe infection included erythematous skin rash and desquamation, exanthema, hyperhemic tongue, and a toxic shock syndrome. The term FESLF was coined for the infection because it shares clinical presentations with scarlet fever caused by group A streptococci. The causative agent was later identified as Yersinia pseudotuberculosis, although the range of morbidities was vastly different from classical pseudotuberculosis symptoms. To understand the origin and emergence of the peculiar clinical features of FESLF, we have sequenced the genome of the FESLF-causing strain Y. pseudotuberculosis IP31758 and compared it with that of another Y. pseudotuberculosis strain, IP32953, which causes classical gastrointestinal symptoms. The unique gene pool of Y pseudotuberculosis IP31758 accounts for more than 260 strain-specific genes and introduces individual physiological capabilities and virulence determinants, with a significant proportion horizontally acquired that likely originated from Enterobacteriaceae and other soil-dwelling bacteria that persist in the same ecological niche. The mobile genome pool includes two novel plasmids phylogenetically unrelated to all currently reported Yersinia plasmids. An icm/dot type IVB secretion system, shared only with the intracellular persisting pathogens of the order Legionellales, was found on the larger plasmid and could contribute to scarlatinoid fever symptoms in patients due to the introduction of immunomodulatory and immunosuppressive capabilities. We determined the common and unique traits resulting from genome evolution and speciation within the genus Yersinia and drew a more accurate species border between Y. pseudotuberculosis and Y. pestis. In contrast to the lack of genetic diversity observed in the evolutionary young descending Y. pestis lineage, the population

  8. The In Vitro Antifungal Activity of Sudanese Medicinal Plants against Madurella mycetomatis, the Eumycetoma Major Causative Agent

    NARCIS (Netherlands)

    H. Elfadil (Hassabelrasoul); A.H. Fahal (Ahmed); W. Kloezen (Wendy); E.M. Ahmed (Elhadi M.); W.W.J. van de Sande (Wendy)

    2015-01-01

    textabstractEumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it is endemic in many tropical and subtropical regions. The major causative organism is the fungus Madurella mycetomatis. The current treatment of eumycetoma is suboptimal and characterized by

  9. Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei.

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    Eduard J Kerkhoven

    Full Text Available Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i including additional enzymatic reactions in the glycosome, or (ii adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.

  10. The activity of aminoglycoside antibiotics against Trypanosoma brucei.

    Science.gov (United States)

    Maina, N W; Kinyanjui, B; Onyango, J D; Auma, J E; Croj, S

    1998-01-01

    The trypanocidal activity of four aminoglycosides was determined against Trypanosoma brucei in vitro. The drug activity in descending order, was as follows; paromomycin kanamycin>gentamycin > neomycin. Paromomycin bad the highest activity and the concentration that inhibited 50% of trypanosome growth (IC50) was 11.4microM. The effect of paromomycin on the causative agents of the East African form of sleeping sickness - T.b. rhodesiense KETRI 265, 2285, 2545, 2562 and EATRO 110,112, 1152 was subsequently assessed. Variations sensitivities between the trypanosome populations were observed and IC50 values ranging from 13.01 to 43.06 microM recorded. However, when paromomycin was administered intraperitoneally (i.p) at 500 mg/kg, it was not effective in curing mice infected with T. b. rhodesienseKETRI 2545 the most drug-sensitive isolate in vitro. Lack of in vivo activity may be because the trypanosome is an extracellular parasite. The pharmacokinetics of paromomycin in the mouse model need to be determined.

  11. Divergent Small Tim Homologues Are Associated with TbTim17 and Critical for the Biogenesis of TbTim17 Protein Complexes in Trypanosoma brucei

    Science.gov (United States)

    Smith, Joseph T.; Singha, Ujjal K.; Misra, Smita

    2018-01-01

    ABSTRACT The small Tim proteins belong to a group of mitochondrial intermembrane space chaperones that aid in the import of mitochondrial inner membrane proteins with internal targeting signals. Trypanosoma brucei, the protozoan parasite that causes African trypanosomiasis, possesses multiple small Tim proteins that include homologues of T. brucei Tim9 (TbTim9) and Tim10 (TbTim10) and a unique small Tim that shares homology with both Tim8 and Tim13 (TbTim8/13). Here, we found that these three small TbTims are expressed as soluble mitochondrial intermembrane space proteins. Coimmunoprecipitation and mass spectrometry analysis showed that the small TbTims stably associated with each other and with TbTim17, the major component of the mitochondrial inner membrane translocase in T. brucei. Yeast two-hybrid analysis indicated direct interactions among the small TbTims; however, their interaction patterns appeared to be different from those of their counterparts in yeast and humans. Knockdown of the small TbTims reduced cell growth and decreased the steady-state level of TbTim17 and T. brucei ADP/ATP carrier (TbAAC), two polytopic mitochondrial inner membrane proteins. Knockdown of small TbTims also reduced the matured complexes of TbTim17 in mitochondria. Depletion of any of the small TbTims reduced TbTim17 import moderately but greatly hampered the stability of the TbTim17 complexes in T. brucei. Altogether, our results revealed that TbTim9, TbTim10, and TbTim8/13 interact with each other, associate with TbTim17, and play a crucial role in the integrity and maintenance of the levels of TbTim17 complexes. IMPORTANCE Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite’s mitochondrion represents a useful source for potential chemotherapeutic targets. Similarly to yeast and humans, mitochondrial functions depend on the import of proteins that are encoded in the nucleus and made in the cytosol. Even though the machinery involved in this

  12. Loop-mediated isothermal amplification as an emerging technology for detection of Yersinia ruckeri the causative agent of enteric red mouth disease in fish

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    Soliman Hatem

    2008-08-01

    Full Text Available Abstract Background Enteric Redmouth (ERM disease also known as Yersiniosis is a contagious disease affecting salmonids, mainly rainbow trout. The causative agent is the gram-negative bacterium Yersinia ruckeri. The disease can be diagnosed by isolation and identification of the causative agent, or detection of the Pathogen using fluorescent antibody tests, ELISA and PCR assays. These diagnostic methods are laborious, time consuming and need well trained personnel. Results A loop-mediated isothermal amplification (LAMP assay was developed and evaluated for detection of Y. ruckeri the etiological agent of enteric red mouth (ERM disease in salmonids. The assay was optimised to amplify the yruI/yruR gene, which encodes Y. ruckeri quorum sensing system, in the presence of a specific primer set and Bst DNA polymerase at an isothermal temperature of 63°C for one hour. Amplification products were detected by visual inspection, agarose gel electrophoresis and by real-time monitoring of turbidity resulted by formation of LAMP amplicons. Digestion with HphI restriction enzyme demonstrated that the amplified product was unique. The specificity of the assay was verified by the absence of amplification products when tested against related bacteria. The assay had 10-fold higher sensitivity compared with conventional PCR and successfully detected Y. ruckeri not only in pure bacterial culture but also in tissue homogenates of infected fish. Conclusion The ERM-LAMP assay represents a practical alternative to the microbiological approach for rapid, sensitive and specific detection of Y. ruckeri in fish farms. The assay is carried out in one hour and needs only a heating block or water bath as laboratory furniture. The advantages of the ERM-LAMP assay make it a promising tool for molecular detection of enteric red mouth disease in fish farms.

  13. Cutaneous adverse drug reactions: clinical pattern and causative agents--a 6 year series from Chandigarh, India.

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    Sharma V

    2001-04-01

    Full Text Available AIM: To study the different clinical spectrum of cutaneous adverse drug reactions (ADR and to determine the causative drugs. MATERIALS & METHODS: A prospective, hospital based study was carried out over a period of 6 years recording various cutaneous ADR. RESULTS: A total of 500 patients with cutaneous ADR were enrolled in the study. The most common types of cutaneous ADR patterns were maculopapular rash (34.6%, fixed drug eruption (FDE (30% and urticaria (14%. The drugs most often incriminated for the various cutaneous ADR were antimicrobials (42.6%, anticonvulsants (22.2% and NSAIDs (18%. Anticonvulsants were implicated in 41.6% of maculopapular rashes. Sulfonamides accounted for 43.3% and NSAIDs for 30.7% of FDE. Urticaria was caused mainly by NSAIDs(24.3% and penicillins(20%. Anticonvulsants were responsible for 43.8% of life-threatening toxic epidermal necrolysis and Stevens Johnson syndrome. CONCLUSIONS: The clinical pattern and drugs causing cutaneous ADR are similar to those observed in other countries except for minor variations. Cutaneous ADR patterns and the drugs causing various reactions are changing every year, which may be due to the emergence of newer molecules and changing trends in the use of drugs.

  14. [Public health pests. Arthropods and rodents as causative disease agents as well as reservoirs and vectors of pathogens].

    Science.gov (United States)

    Faulde, M; Freise, J

    2014-05-01

    Globally, infectious diseases pose the most important cause of death. Among known human pathogenic diseases, approximately 50 % are zoonoses. When considering emerging infectious diseases separately 73 % currently belong to the group of zoonoses. In Central Europe, hard ticks show by far the biggest potential as vectors of agents of human disease. Lyme borreliosis, showing an estimated annual incidence between 60,000 and 214,000 cases is by far the most frequent tick-borne disease in Germany. Continually, formerly unknown disease agents could be discovered in endemic vector species. Additionally, introduction of new arthropod vectors and/or agents of disease occur constantly. Recently, five mosquito species of the genus Aedes have been newly introduced to Europe where they are currently spreading in different regions. Uncommon autochthonous transmission of dengue and chikungunya fever viruses in Southern Europe could be directly linked to these vector species and of these Ae. albopictus and Ae. japonicus are currently reported to occur in Germany. The German Protection against Infection Act only covers the control of public health pests which are either active hematophagous vectors or mechanical transmitters of agents of diseases. Use of officially recommended biocidal products aiming to interrupt transmission cycles of vector-borne diseases, is confined to infested buildings only, including sewage systems in the case of Norway rat control. Outdoor vectors, such as hard ticks and mosquitoes, are currently not taken into consideration. Additionally, adjustments of national public health regulations, detailed arthropod vector and rodent reservoir mapping, including surveillance of vector-borne disease agents, are necessary in order to mitigate future disease risks.

  15. The in vitro antifungal activity of sudanese medicinal plants against Madurella mycetomatis, the eumycetoma major causative agent.

    Science.gov (United States)

    Elfadil, Hassabelrasoul; Fahal, Ahmed; Kloezen, Wendy; Ahmed, Elhadi M; van de Sande, Wendy

    2015-03-01

    Eumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it is endemic in many tropical and subtropical regions. The major causative organism is the fungus Madurella mycetomatis. The current treatment of eumycetoma is suboptimal and characterized by low cure rate and high recurrence rates. Hence, an alternative therapy is needed to address this. Here we determined the antifungal activity of seven Sudanese medicinal plant species against Madurella mycetomatis. Of these, only three species; Boswellia papyrifera, Acacia nubica and Nigella sativa, showed some antifungal activity against M. mycetomatis and were further studied. Crude methanol, hexane and defatted methanol extracts of these species were tested for their antifungal activity. B. papyrifera had the highest antifungal activity (MIC50 of 1 ug/ml) and it was further fractionated. The crude methanol and the soluble ethyl acetate fractions of B. papyrifera showed some antifungal activity. The Gas-Liquid-Chromatography hybrid Mass-Spectrophotometer analysis of these two fractions showed the existence of beta-amyrin, beta-amyrone, beta-Sitosterol and stigmatriene. Stigmatriene had the best antifungal activity, compared to other three phytoconstituents, with an MIC-50 of 32 μg/ml. Although the antifungal activity of the identified phytoconstituents was only limited, the antifungal activity of the complete extracts is more promising, indicating synergism. Furthermore these plant extracts are also known to have anti-inflammatory activity and can stimulate wound-healing; characteristics which might also be of great value in the development of novel therapeutic drugs for this chronic inflammatory disease. Therefore further exploration of these plant species in the treatment of mycetoma is encouraging.

  16. The in vitro antifungal activity of sudanese medicinal plants against Madurella mycetomatis, the eumycetoma major causative agent.

    Directory of Open Access Journals (Sweden)

    Hassabelrasoul Elfadil

    2015-03-01

    Full Text Available Eumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it is endemic in many tropical and subtropical regions. The major causative organism is the fungus Madurella mycetomatis. The current treatment of eumycetoma is suboptimal and characterized by low cure rate and high recurrence rates. Hence, an alternative therapy is needed to address this. Here we determined the antifungal activity of seven Sudanese medicinal plant species against Madurella mycetomatis. Of these, only three species; Boswellia papyrifera, Acacia nubica and Nigella sativa, showed some antifungal activity against M. mycetomatis and were further studied. Crude methanol, hexane and defatted methanol extracts of these species were tested for their antifungal activity. B. papyrifera had the highest antifungal activity (MIC50 of 1 ug/ml and it was further fractionated. The crude methanol and the soluble ethyl acetate fractions of B. papyrifera showed some antifungal activity. The Gas-Liquid-Chromatography hybrid Mass-Spectrophotometer analysis of these two fractions showed the existence of beta-amyrin, beta-amyrone, beta-Sitosterol and stigmatriene. Stigmatriene had the best antifungal activity, compared to other three phytoconstituents, with an MIC-50 of 32 μg/ml. Although the antifungal activity of the identified phytoconstituents was only limited, the antifungal activity of the complete extracts is more promising, indicating synergism. Furthermore these plant extracts are also known to have anti-inflammatory activity and can stimulate wound-healing; characteristics which might also be of great value in the development of novel therapeutic drugs for this chronic inflammatory disease. Therefore further exploration of these plant species in the treatment of mycetoma is encouraging.

  17. Assays for Detection and Identification of the Causative Agent of Mange in Free-Ranging Black Bears ( Ursus americanus).

    Science.gov (United States)

    Peltier, Sarah K; Brown, Justin D; Ternent, Mark A; Fenton, Heather; Niedringhaus, Kevin D; Yabsley, Michael J

    2018-03-02

    Three mite species ( Demodex ursi, Ursicoptes americanus, and Sarcoptes scabiei) have been associated with mange in black bears ( Ursus americanus). Since the early 1990s, the number and geographic distribution of mange cases in black bears in Pennsylvania has increased; however, the causative mites have yet to be completely defined. We evaluated several diagnostic approaches for detection and identification of mites in 72 black bears with severe lesions consistent with mange. Sarcoptes scabiei was morphologically identified in skin scrapes from 66 of the bears; no mites were identified in the remaining six. Histopathologic lesions consistent with sarcoptic mange were observed in 39 of 40 bear skin samples examined, and intralesional mites were observed in samples from 38 of these bears. Samples were collected from a subset of the 72 bears for PCR testing targeting both the internal transcribed spacer (ITS)-2 region and cytochrome c oxidase I ( cox1) gene including 69 skin scrapes ( ITS-2 only), 56 skin biopsies ( ITS-2 and cox1), and 36 fecal samples ( ITS-2 and cox1). Skin scrapes were a more sensitive sample for PCR detection than either skin biopsies or fecal samples, and the ITS-2 primers proved more sensitive than cox1. Using a commercial indirect enzyme-linked immunosorbent assay, antibodies to S. scabiei were detected in 45/49 (92%) black bears with confirmed mange and 0/62 (0%) cubs with no gross lesions suggestive of mange and which were born to seronegative sows. Sarcoptes scabiei was the predominant mite associated with mange in black bears in Pennsylvania. Diagnostically, cytologic examination of skin scrapes was the most effective approach for diagnosing active mite infestations in black bears. The evaluated serologic assay accurately detected antibodies to S. scabiei in most bears with confirmed S. scabiei infestations. Additional research is needed to determine the usefulness of this approach for larger scale surveys and for asymptomatic bears.

  18. In Vitro Antibiotic Susceptibilities of Burkholderia mallei (Causative Agent of Glanders) Determined by Broth Microdilution and E-Test

    Science.gov (United States)

    Heine, Henry S.; England, Marilyn J.; Waag, David M.; Byrne, W. Russell

    2001-01-01

    In vitro susceptibilities to 28 antibiotics were determined for 11 strains of Burkholderia mallei by the broth microdilution method. The B. mallei strains demonstrated susceptibility to aminoglycosides, macrolides, quinolones, doxycycline, piperacillin, ceftazidime, and imipenem. For comparison and evaluation, 17 antibiotic susceptibilities were also determined by the E-test. E-test values were always lower than the broth dilution values. Establishing and comparing antibiotic susceptibilities of specific B. mallei strains will provide reference information for assessing new antibiotic agents. PMID:11408233

  19. Endogenous sterol biosynthesis is important for mitochondrial function and cell morphology in procyclic forms of Trypanosoma brucei.

    Science.gov (United States)

    Pérez-Moreno, Guiomar; Sealey-Cardona, Marco; Rodrigues-Poveda, Carlos; Gelb, Michael H; Ruiz-Pérez, Luis Miguel; Castillo-Acosta, Víctor; Urbina, Julio A; González-Pacanowska, Dolores

    2012-10-01

    Sterol biosynthesis inhibitors are promising entities for the treatment of trypanosomal diseases. Insect forms of Trypanosoma brucei, the causative agent of sleeping sickness, synthesize ergosterol and other 24-alkylated sterols, yet also incorporate cholesterol from the medium. While sterol function has been investigated by pharmacological manipulation of sterol biosynthesis, molecular mechanisms by which endogenous sterols influence cellular processes remain largely unknown in trypanosomes. Here we analyse by RNA interference, the effects of a perturbation of three specific steps of endogenous sterol biosynthesis in order to dissect the role of specific intermediates in proliferation, mitochondrial function and cellular morphology in procyclic cells. A decrease in the levels of squalene synthase and squalene epoxidase resulted in a depletion of cellular sterol intermediates and end products, impaired cell growth and led to aberrant morphologies, DNA fragmentation and a profound modification of mitochondrial structure and function. In contrast, cells deficient in sterol methyl transferase, the enzyme involved in 24-alkylation, exhibited a normal growth phenotype in spite of a complete abolition of the synthesis and content of 24-alkyl sterols. Thus, the data provided indicates that while the depletion of squalene and post-squalene endogenous sterol metabolites results in profound cellular defects, bulk 24-alkyl sterols are not strictly required to support growth in insect forms of T. brucei in vitro. Copyright © 2012 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  20. A review of the Mycrocylus ulei Ascomycetes fungus, causative agent of South American rubber-leaf blight

    Directory of Open Access Journals (Sweden)

    Ibonne Aydee García-Romero

    2006-07-01

    Full Text Available The Microcyclus ulei Ascomycetes fungus is the causal agent of south-American leaf blight (SALB, this being one of the most important diseases affecting the natural rubber tree (Hevea brasiliensis in Latina-America and has been responsible for numerous economic losses. This fungus has presented high physiological variability, suggesting its great adaptability. HCN tolerance has been described as being one of the mechanisms associated with its virulence. Resistant Hevea clones have been obtained by genetic improvement; however, the mechanisms associated with this are still not well known. Greater knowledge of this pathogen will lead to developing new control strategies and better understanding of the mechanisms associated with host resistance. Key words: Microcyclus ulei, SALB, Hevea brasiliensis.

  1. Identification of compounds with anti-proliferative activity against Trypanosoma brucei brucei strain 427 by a whole cell viability based HTS campaign.

    Directory of Open Access Journals (Sweden)

    Melissa L Sykes

    Full Text Available Human African Trypanosomiasis (HAT is caused by two trypanosome sub-species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Drugs available for the treatment of HAT have significant issues related to difficult administration regimes and limited efficacy across species and disease stages. Hence, there is considerable need to find new alternative and less toxic drugs. An approach to identify starting points for new drug candidates is high throughput screening (HTS of large compound library collections. We describe the application of an Alamar Blue based, 384-well HTS assay to screen a library of 87,296 compounds against the related trypanosome subspecies, Trypanosoma brucei brucei bloodstream form lister 427. Primary hits identified against T.b. brucei were retested and the IC(50 value compounds were estimated for T.b. brucei and a mammalian cell line HEK293, to determine a selectivity index for each compound. The screening campaign identified 205 compounds with greater than 10 times selectivity against T.b. brucei. Cluster analysis of these compounds, taking into account chemical and structural properties required for drug-like compounds, afforded a panel of eight compounds for further biological analysis. These compounds had IC(50 values ranging from 0.22 µM to 4 µM with associated selectivity indices ranging from 19 to greater than 345. Further testing against T.b. rhodesiense led to the selection of 6 compounds from 5 new chemical classes with activity against the causative species of HAT, which can be considered potential candidates for HAT early drug discovery. Structure activity relationship (SAR mining revealed components of those hit compound structures that may be important for biological activity. Four of these compounds have undergone further testing to 1 determine whether they are cidal or static in vitro at the minimum inhibitory concentration (MIC, and 2 estimate the time to kill.

  2. Cynaropicrin targets the trypanothione redox system in Trypanosoma brucei.

    Science.gov (United States)

    Zimmermann, Stefanie; Oufir, Mouhssin; Leroux, Alejandro; Krauth-Siegel, R Luise; Becker, Katja; Kaiser, Marcel; Brun, Reto; Hamburger, Matthias; Adams, Michael

    2013-11-15

    In mice cynaropicrin (CYN) potently inhibits the proliferation of Trypanosoma brucei-the causative agent of Human African Trypanosomiasis-by a so far unknown mechanism. We hypothesized that CYNs α,β-unsaturated methylene moieties act as Michael acceptors for glutathione (GSH) and trypanothione (T(SH)2), the main low molecular mass thiols essential for unique redox metabolism of these parasites. The analysis of this putative mechanism and the effects of CYN on enzymes of the T(SH)2 redox metabolism including trypanothione reductase, trypanothione synthetase, glutathione-S-transferase, and ornithine decarboxylase are shown. A two step extraction protocol with subsequent UPLC-MS/MS analysis was established to quantify intra-cellular CYN, T(SH)2, GSH, as well as GS-CYN and T(S-CYN)2 adducts in intact T. b. rhodesiense cells. Within minutes of exposure to CYN, the cellular GSH and T(SH)2 pools were entirely depleted, and the parasites entered an apoptotic stage and died. CYN also showed inhibition of the ornithine decarboxylase similar to the positive control eflornithine. Significant interactions with the other enzymes involved in the T(SH)2 redox metabolism were not observed. Alongside many other biological activities sesquiterpene lactones including CYN have shown antitrypanosomal effects, which have been postulated to be linked to formation of Michael adducts with cellular nucleophiles. Here the interaction of CYN with biological thiols in a cellular system in general, and with trypanosomal T(SH)2 redox metabolism in particular, thus offering a molecular explanation for the antitrypanosomal activity is demonstrated. At the same time, the study provides a novel extraction and analysis protocol for components of the trypanosomal thiol metabolism. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. The life cycle of Ascocotyle (Phagicola) longa (Digenea: Heterophyidae), a causative agent of fish-borne trematodosis.

    Science.gov (United States)

    Simões, Susana Balmant Emerique; Barbosa, Helene Santos; Santos, Cláudia Portes

    2010-03-01

    The complete life cycle of the trematode Ascocotyle (Phagicola) longa (Digenea: Heterophyidae) is elucidated by natural observation validated by experimental infections. The natural first intermediate host of A. (P.) longa, an agent of human heterophyiasis in Brazil, is the cochliopid snail Heleobia australis (new first intermediate host). Metacercariae were found encysted in the body musculature, heart, stomach, liver, kidney, spleen, gonads and mesentery of mullets Mugil liza. Hamsters Mesocricetus auratus were experimentally infected with metacercariae of A. (P.) longa obtained from the mullets, and the adults recovered were used to infect the snails H. australis. Rediae and cercariae of A. (P.) longa are described for the first time. The ultrastructure of the tegument of A. (P.) longa shows a change in spination pattern from the cercaria with single-pointed spines to the metacercaria and adult with multipointed, brush-shaped spines. The life cycle of A. (P.) longa is related to estuaries and coastal lagoons where the recruitment of mugilid juveniles occurs. The high prevalence (100%) of A. (P.) longa encysted in the mullets examined within the urban area of Rio de Janeiro indicates the potentially great public health impact of the consumption of raw mullets. Copyright 2009 Elsevier B.V. All rights reserved.

  4. Minimum Information Loss Based Multi-kernel Learning for Flagellar Protein Recognition in Trypanosoma Brucei

    KAUST Repository

    Wang, Jim Jing-Yan

    2014-12-01

    Trypanosma brucei (T. Brucei) is an important pathogen agent of African trypanosomiasis. The flagellum is an essential and multifunctional organelle of T. Brucei, thus it is very important to recognize the flagellar proteins from T. Brucei proteins for the purposes of both biological research and drug design. In this paper, we investigate computationally recognizing flagellar proteins in T. Brucei by pattern recognition methods. It is argued that an optimal decision function can be obtained as the difference of probability functions of flagella protein and the non-flagellar protein for the purpose of flagella protein recognition. We propose to learn a multi-kernel classification function to approximate this optimal decision function, by minimizing the information loss of such approximation which is measured by the Kull back-Leibler (KL) divergence. An iterative multi-kernel classifier learning algorithm is developed to minimize the KL divergence for the problem of T. Brucei flagella protein recognition, experiments show its advantage over other T. Brucei flagellar protein recognition and multi-kernel learning methods. © 2014 IEEE.

  5. Transcriptome Profiling of Trypanosoma brucei Development in the Tsetse Fly Vector Glossina morsitans.

    Directory of Open Access Journals (Sweden)

    Amy F Savage

    Full Text Available African trypanosomes, the causative agents of sleeping sickness in humans and nagana in animals, have a complex digenetic life cycle between a mammalian host and an insect vector, the blood-feeding tsetse fly. Although the importance of the insect vector to transmit the disease was first realized over a century ago, many aspects of trypanosome development in tsetse have not progressed beyond a morphological analysis, mainly due to considerable challenges to obtain sufficient material for molecular studies. Here, we used high-throughput RNA-Sequencing (RNA-Seq to profile Trypanosoma brucei transcript levels in three distinct tissues of the tsetse fly, namely the midgut, proventriculus and salivary glands. Consistent with current knowledge and providing a proof of principle, transcripts coding for procyclin isoforms and several components of the cytochrome oxidase complex were highly up-regulated in the midgut transcriptome, whereas transcripts encoding metacyclic VSGs (mVSGs and the surface coat protein brucei alanine rich protein or BARP were extremely up-regulated in the salivary gland transcriptome. Gene ontology analysis also supported the up-regulation of biological processes such as DNA metabolism and DNA replication in the proventriculus transcriptome and major changes in signal transduction and cyclic nucleotide metabolism in the salivary gland transcriptome. Our data highlight a small repertoire of expressed mVSGs and potential signaling pathways involving receptor-type adenylate cyclases and members of a surface carboxylate transporter family, called PADs (Proteins Associated with Differentiation, to cope with the changing environment, as well as RNA-binding proteins as a possible global regulators of gene expression.

  6. Protein functional links in Trypanosoma brucei, identified by gene fusion analysis

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    Trimpalis Philip

    2011-07-01

    Full Text Available Abstract Background Domain or gene fusion analysis is a bioinformatics method for detecting gene fusions in one organism by comparing its genome to that of other organisms. The occurrence of gene fusions suggests that the two original genes that participated in the fusion are functionally linked, i.e. their gene products interact either as part of a multi-subunit protein complex, or in a metabolic pathway. Gene fusion analysis has been used to identify protein functional links in prokaryotes as well as in eukaryotic model organisms, such as yeast and Drosophila. Results In this study we have extended this approach to include a number of recently sequenced protists, four of which are pathogenic, to identify fusion linked proteins in Trypanosoma brucei, the causative agent of African sleeping sickness. We have also examined the evolution of the gene fusion events identified, to determine whether they can be attributed to fusion or fission, by looking at the conservation of the fused genes and of the individual component genes across the major eukaryotic and prokaryotic lineages. We find relatively limited occurrence of gene fusions/fissions within the protist lineages examined. Our results point to two trypanosome-specific gene fissions, which have recently been experimentally confirmed, one fusion involving proteins involved in the same metabolic pathway, as well as two novel putative functional links between fusion-linked protein pairs. Conclusions This is the first study of protein functional links in T. brucei identified by gene fusion analysis. We have used strict thresholds and only discuss results which are highly likely to be genuine and which either have already been or can be experimentally verified. We discuss the possible impact of the identification of these novel putative protein-protein interactions, to the development of new trypanosome therapeutic drugs.

  7. Potential of Microbispora sp. V2 as biocontrol agent against Sclerotium rolfsii, the causative agent of southern blight of Zea mays L (Baby corn)--in vitro studies.

    Science.gov (United States)

    Patil, N N; Waghmode, M S; Gaikwad, P S; Gajbhiye, M H; Gunjal, A B; Nawani, N N; Kapadnis, B P

    2014-11-01

    The study was undertaken with the aim of exploring novel and beneficial agro activities of rare actinomycetes like Microbispora sp. V2. The antagonistic activity of Microbispora sp. V2 was evaluated as a biocontrol agents against Sclerotium rolfsii, a soil-borne fungal plant pathogen. The methodology performed for evaluation of biocontrol agent was in vitro evaluation assay which comprised of three tests viz., cellophane overlay technique, seed germination test and Thiram (fungicide) tolerance of Microbispora sp. V2. The isolate was found to inhibit the fungal pathogen Sclerotium rolfsii to 91.43% in cellophane assay. In seed germination assay, Microbispora sp. V2 treated seeds resulted in 25.75% increased germination efficiency, as compared to seeds infected by Sclerotium rolfsii. The isolate Microbispora sp. V2 could tolerate 1000 microg mL(-1) of Thiram (fungicide). The in vitro assay studies proved that Microbispora sp. V2 can be used as antifungal antagonist and thus posses' great potential as biocontrol agent against southern blight caused by Sclerotium rolfsii in Zea mays L (Baby corn) which causes large economical losses.

  8. Bioaccumulation of Stentorin, the Probable Causative Agent for Discolored ("Purple") Eggs and Ovaries in Blue Catfish (Ictalurus furcatus) from Eufaula Lake, Oklahoma, USA.

    Science.gov (United States)

    Gale, Robert W; Papoulias, Diana M; Schmitt, Christopher J

    2015-08-18

    Observations of reddish to "purple" discolored eggs in the ovaries of adult female blue catfish (Ictalurus furcatus) from the northern arm of Eufaula Lake, a eutrophic multiuse impoundment in east-central Oklahoma, were first reported in 2006. Blue catfish eggs are normally cream to light yellow. Reports peaked in 2007-2008 and declined through 2009-2010; purple eggs have not been reported between 2010 and 2014. In the laboratory, all tissues and fluids of affected fish were strongly orange-red fluorescent under UV illumination, with the fluorescence most apparent in the lipid-rich ovaries and eggs. The causative agent was isolated chromatographically and confirmed by mass spectrometry as stentorin (1,3,4,6,8,10,11,13-octahydroxy-2,5-diisopropyl-phenanthro[1,10,9,8,o,p,q,r,a]perylene-7,14-dione), the fluorescent, lipophilic pigment associated with the photoreceptor protein of the ciliated protozoan Stentor coeruleus (Heterotrichea; Stentoridae). Larval medaka (Orizias latipes) readily consumed S. coeruleus in the laboratory and were observed to fluoresce in the same manner as the affected blue catfish. Potential deleterious effects of stentorin bioaccumulation remain to be determined, as do the geographic extent and the identities of other fluorescent compounds isolated from catfish eggs and ovaries.

  9. Bioaccumulation of stentorin, the probable causative agent for discolored (“purple”) eggs and ovaries in blue catfish (Ictalurus furcatus) from Eufaula Lake, Oklahoma, USA

    Science.gov (United States)

    Gale, Robert W.; Papoulias, Diana M.; Schmitt, Christopher J.

    2015-01-01

    Observations of reddish to “purple” discolored eggs in the ovaries of adult female blue catfish (Ictalurus furcatus) from the northern arm of Eufaula Lake, a eutrophic multiuse impoundment in east-central Oklahoma, were first reported in 2006. Blue catfish eggs are normally cream to light yellow. Reports peaked in 2007–2008 and declined through 2009–2010; purple eggs have not been reported between 2010 and 2014. In the laboratory, all tissues and fluids of affected fish were strongly orange-red fluorescent under UV illumination, with the fluorescence most apparent in the lipid-rich ovaries and eggs. The causative agent was isolated chromatographically and confirmed by mass spectrometry as stentorin (1,3,4,6,8,10,11,13-octahydroxy-2,5-diisopropyl-phenanthro[1,10,9,8,o,p,q,r,a]perylene-7,14-dione), the fluorescent, lipophilic pigment associated with the photoreceptor protein of the ciliated protozoan Stentor coeruleus (Heterotrichea; Stentoridae). Larval medaka (Orizias latipes) readily consumed S. coeruleus in the laboratory and were observed to fluoresce in the same manner as the affected blue catfish. Potential deleterious effects of stentorin bioaccumulation remain to be determined, as do the geographic extent and the identities of other fluorescent compounds isolated from catfish eggs and ovaries.

  10. Revisiting Francisella tularensis subsp. holarctica, Causative Agent of Tularemia in Germany With Bioinformatics: New Insights in Genome Structure, DNA Methylation and Comparative Phylogenetic Analysis

    Directory of Open Access Journals (Sweden)

    Anne Busch

    2018-03-01

    Full Text Available Francisella (F. tularensis is a highly virulent, Gram-negative bacterial pathogen and the causative agent of the zoonotic disease tularemia. Here, we generated, analyzed and characterized a high quality circular genome sequence of the F. tularensis subsp. holarctica strain 12T0050 that caused fatal tularemia in a hare. Besides the genomic structure, we focused on the analysis of oriC, unique to the Francisella genus and regulating replication in and outside hosts and the first report on genomic DNA methylation of a Francisella strain. The high quality genome was used to establish and evaluate a diagnostic whole genome sequencing pipeline. A genotyping strategy for F. tularensis was developed using various bioinformatics tools for genotyping. Additionally, whole genome sequences of F. tularensis subsp. holarctica isolates isolated in the years 2008–2015 in Germany were generated. A phylogenetic analysis allowed to determine the genetic relatedness of these isolates and confirmed the highly conserved nature of F. tularensis subsp. holarctica.

  11. Response of Tripanosoma brucei brucei –induced anaemia to a ...

    African Journals Online (AJOL)

    A study was therefore carried out to determine the effect of the preparation on packed cell volume (PCV) and haemoglobin (Hb) concentrations in anaemic rabbits. The PCV and Hb concentrations of healthy rabbits infected with Trypanosoma brucei brucei were monitored for 49 days. T. b. brucei produced a significant ...

  12. Development and Evaluation of a Molecular Diagnostic Method for Rapid Detection of Histoplasma capsulatum var. farciminosum, the Causative Agent of Epizootic Lymphangitis, in Equine Clinical Samples.

    Science.gov (United States)

    Scantlebury, C E; Pinchbeck, G L; Loughnane, P; Aklilu, N; Ashine, T; Stringer, A P; Gordon, L; Marshall, M; Christley, R M; McCarthy, A J

    2016-12-01

    Histoplasma capsulatum var. farciminosum, the causative agent of epizootic lymphangitis (EZL), is endemic in parts of Africa. Diagnosis based on clinical signs and microscopy lacks specificity and is a barrier to further understanding this neglected disease. Here, a nested PCR method targeting the internal transcribed spacer (ITS) region of the rRNA operon was validated for application to equine clinical samples. Twenty-nine horses with signs of EZL from different climatic regions of Ethiopia were clinically examined. Blood samples and aspirates of pus from cutaneous nodules were taken, along with blood from a further 20 horses with no cutaneous EZL lesions. Among the 29 horses with suspected cases of EZL, H. capsulatum var. farciminosum was confirmed by extraction of DNA from pus and blood samples from 25 and 17 horses, respectively. Positive PCR results were also obtained with heat-inactivated pus (24 horses) and blood (23 horses) spotted onto Whatman FTA cards. Two positive results were obtained among blood samples from 20 horses that did not exhibit clinical signs of EZL. These are the first reports of the direct detection of H. capsulatum var. farciminosum in equine blood and at high frequency among horses exhibiting cutaneous lesions. The nested PCR outperformed conventional microscopic diagnosis, as characteristic yeast cells could be observed only in 14 pus samples. The presence of H. capsulatum var. farciminosum DNA was confirmed by sequencing the cloned PCR products, and while alignment of the ITS amplicons showed very little sequence variation, there was preliminary single nucleotide polymorphism-based evidence for the existence of two subgroups of H. capsulatum var. farciminosum This molecular diagnostic method now permits investigation of the epidemiology of EZL. Copyright © 2016 Scantlebury et al.

  13. Potent Inhibition of Pseudogymnoascus destructans, the Causative Agent of White-Nose Syndrome in Bats, by Cold-Pressed, Terpeneless, Valencia Orange Oil.

    Science.gov (United States)

    Boire, Nicholas; Zhang, Sean; Khuvis, Joshua; Lee, Rick; Rivers, Jennifer; Crandall, Philip; Keel, M Kevin; Parrish, Nicole

    2016-01-01

    The causative agent of White-nose Syndrome (WNS), Pseudogymnoascus destructans, has been shown to be fatal to several species of bats in North America. To date, no compounds or chemical control measures have been developed which eliminates the growth of the fungus in the environment or in affected animals. In the current study, we evaluated the activity of cold-pressed, terpeneless orange oil (CPT) against multiple isolates of P. destructans in vitro. For all assays, a modified Kirby-Bauer disk diffusion assay was used. Standardized spore suspensions were prepared, adjusted to a specific optical density, and used to plate fungal lawns. Plates were incubated at either 15°C or 4°C for up to 6 months and checked at regular intervals for growth. Once controls had grown, zones of inhibition were measured (mm) on test plates and compared to those obtained using current antifungal drugs. All P. destructans isolates were completely inhibited by 100% CPT (10 μL) at 1 month of incubation regardless of temperature (4°C and 15°C). Complete inhibition persisted up to 6 months following a single exposure at this concentration. Of the standard antifungals, only amphotericin B demonstrated any activity, resulting in zone diameters ranging from 58 mm to 74 mm. CPT, at the highest concentration tested (100%), had no significant effect against a variety of other environmental organisms including various filamentous fungi, bacteria and aerobic actinomycetes. Given that CPT is relatively non-toxic, the possibility exists that the all-natural, mixture could be used as an environmental pre-treatment to eradicate P. destructans from bat habitats. Additional studies are needed to assess any undesirable effects of CPT on bat behavior and health and overall impacts on other members of the interconnected ecosystem(s).

  14. Potent Inhibition of Pseudogymnoascus destructans, the Causative Agent of White-Nose Syndrome in Bats, by Cold-Pressed, Terpeneless, Valencia Orange Oil.

    Directory of Open Access Journals (Sweden)

    Nicholas Boire

    Full Text Available The causative agent of White-nose Syndrome (WNS, Pseudogymnoascus destructans, has been shown to be fatal to several species of bats in North America. To date, no compounds or chemical control measures have been developed which eliminates the growth of the fungus in the environment or in affected animals. In the current study, we evaluated the activity of cold-pressed, terpeneless orange oil (CPT against multiple isolates of P. destructans in vitro. For all assays, a modified Kirby-Bauer disk diffusion assay was used. Standardized spore suspensions were prepared, adjusted to a specific optical density, and used to plate fungal lawns. Plates were incubated at either 15°C or 4°C for up to 6 months and checked at regular intervals for growth. Once controls had grown, zones of inhibition were measured (mm on test plates and compared to those obtained using current antifungal drugs. All P. destructans isolates were completely inhibited by 100% CPT (10 μL at 1 month of incubation regardless of temperature (4°C and 15°C. Complete inhibition persisted up to 6 months following a single exposure at this concentration. Of the standard antifungals, only amphotericin B demonstrated any activity, resulting in zone diameters ranging from 58 mm to 74 mm. CPT, at the highest concentration tested (100%, had no significant effect against a variety of other environmental organisms including various filamentous fungi, bacteria and aerobic actinomycetes. Given that CPT is relatively non-toxic, the possibility exists that the all-natural, mixture could be used as an environmental pre-treatment to eradicate P. destructans from bat habitats. Additional studies are needed to assess any undesirable effects of CPT on bat behavior and health and overall impacts on other members of the interconnected ecosystem(s.

  15. Urinary Tract Infections Among Hospitalized Adults in the Early Post-Liver Transplant Period: Prevalence, Risk Factors, Causative Agents, and Microbial Susceptibility.

    Science.gov (United States)

    Pouladfar, Gholamreza; Jafarpour, Zahra; Firoozifar, Mohammad; Malek Hosseini, Seyed Ali; Rasekh, Razieh; Khosravifard, Leila; Janghorban, Parisa

    2017-02-01

    Urinary tract infections are among the most common infections after liver transplant, especially soon after surgery. This study analyzed urinary tract infections or bacteriuria, their causative agents, and related risk factors in the early period after liver transplant in hospitalized adult transplant recipients in the main liver transplant referral center in Iran. In this prospective study, 389 consecutive adult patients who underwent liver transplant at the Nemazee Teaching Hospital were enrolled between October 2014 and October 2015. Risk factors were compared for patients who developed urinary tract infections or bacteriuria ("infection group "; n = 63 [16.2% ]) and patients without evidence of infection ("control group "; n = 211 [54.2% ]). Patients with sites of infection other than the urinary tract were excluded. Antimicrobial sus ceptibility testing was performed using the Kirby-Bauer disk-diffusion method. Univariate and multivariate analyses compared variables between the 2 groups. Seventy-nine episodes of urinary tract infections or bacteriuria occurred in the infection group. Multiple logistic regression analysis showed that female sex, hospitalization 2 to 7 days before transplant, and frequency of abdominal exploration were 11.0, 5.9, and 3.0 times more common in the infection group than in the control group. The chance of infection rises 1.1 times with each one unit increase of body mass index. The most common infection causes were gram-negative bacteria (n = 50; 63.3%), predominantly Escherichia coli (n = 24; 30.4%); followed by gram-positive bacteria (n = 20; 25.3%), predominantly Enterococcus species (n = 14; 17.8%) that had a high incidence of vancomycin resistance (n = 10; 71.4%); and non-Candida albicans species isolates (n = 9; 11.4%). Urinary tract infections are a common infection in hospitalized adult patients soon after liver transplant. Female sex, hospitalization shortly before transplant, more frequent abdominal exploration, and higher

  16. Development and Evaluation of a Molecular Diagnostic Method for Rapid Detection of Histoplasma capsulatum var. farciminosum, the Causative Agent of Epizootic Lymphangitis, in Equine Clinical Samples

    Science.gov (United States)

    Pinchbeck, G. L.; Loughnane, P.; Aklilu, N.; Ashine, T.; Stringer, A. P.; Gordon, L.; Marshall, M.; Christley, R. M.

    2016-01-01

    Histoplasma capsulatum var. farciminosum, the causative agent of epizootic lymphangitis (EZL), is endemic in parts of Africa. Diagnosis based on clinical signs and microscopy lacks specificity and is a barrier to further understanding this neglected disease. Here, a nested PCR method targeting the internal transcribed spacer (ITS) region of the rRNA operon was validated for application to equine clinical samples. Twenty-nine horses with signs of EZL from different climatic regions of Ethiopia were clinically examined. Blood samples and aspirates of pus from cutaneous nodules were taken, along with blood from a further 20 horses with no cutaneous EZL lesions. Among the 29 horses with suspected cases of EZL, H. capsulatum var. farciminosum was confirmed by extraction of DNA from pus and blood samples from 25 and 17 horses, respectively. Positive PCR results were also obtained with heat-inactivated pus (24 horses) and blood (23 horses) spotted onto Whatman FTA cards. Two positive results were obtained among blood samples from 20 horses that did not exhibit clinical signs of EZL. These are the first reports of the direct detection of H. capsulatum var. farciminosum in equine blood and at high frequency among horses exhibiting cutaneous lesions. The nested PCR outperformed conventional microscopic diagnosis, as characteristic yeast cells could be observed only in 14 pus samples. The presence of H. capsulatum var. farciminosum DNA was confirmed by sequencing the cloned PCR products, and while alignment of the ITS amplicons showed very little sequence variation, there was preliminary single nucleotide polymorphism-based evidence for the existence of two subgroups of H. capsulatum var. farciminosum. This molecular diagnostic method now permits investigation of the epidemiology of EZL. PMID:27707938

  17. Essential Oils of Myrtaceae Species Growing Wild in Tunisia: Chemical Variability and Antifungal Activity Against Biscogniauxia mediterranea, the Causative Agent of Charcoal Canker.

    Science.gov (United States)

    Yangui, Islem; Zouaoui Boutiti, Meriem; Boussaid, Mohamed; Messaoud, Chokri

    2017-07-01

    The chemical composition of five Eucalyptus species and five Myrtus communis L. populations was investigated using GC/MS and GC-FID. For Eucalyptus essential oils, 32 compounds, representing 88.56 - 96.83% of the total oil according to species, were identified. The main compounds were 1,8-cineole, α-pinene, p-cymene, γ-gurjunene, α-aromadendrene, and β-phellandrene. For Myrtle essential oils, 26 compounds, representing 93.13 - 98.91% of the total oil were identified. α-Pinene, 1,8-cineole, linalool, and myrtenyl acetate were found to be the major compounds. Principal component analysis (PCA) showed chemical differentiation between Eucalyptus species and between Myrtle populations. Biscogniauxia mediterranea, the causative agent of charcoal canker, was identified according to its morphological and molecular characteristics. Essential oils of the investigated Eucalyptus species and Myrtle populations were tested for their antifungal capacity against this fungus. The antifungal activity varied according to the essential oil composition. Biscogniauxia mediterranea exhibited powerful resistance to some essential oils including them of Eucalyptus lehmannii and Eucalyptus sideroxylon but it was very sensitive to Eucalyptus camaldulensis oil (IC 50  = 3.83 mg/ml) and M. communis oil from Zaghouan (IC 50  = 1 mg/ml). This sensitivity was found to be correlated to some essential oil compounds such as p-cymene, carvacrol, cuminaldehyde, and linalool. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  18. Field and laboratory evidence that Bungowannah virus, a recently recognised pestivirus, is the causative agent of the porcine myocarditis syndrome (PMC).

    Science.gov (United States)

    Finlaison, Deborah S; King, Katherine R; Frost, Melinda J; Kirkland, Peter D

    2009-05-12

    In 2003 an outbreak of sudden deaths occurred in 2-3-week-old piglets on a piggery in New South Wales, Australia. There was a marked increase in the birth of stillborn piglets and preweaning losses associated with a multifocal non-suppurative myocarditis with myonecrosis. The aim of this study was to review existing data and to undertake further investigations of specimens from naturally infected pigs to provide evidence to support the hypothesis that Bungowannah virus, a recently recognised pestivirus, causes the porcine myocarditis syndrome (PMC). Sera collected from gilts and sows from affected and unaffected units were tested for Bungowannah virus antibody by a peroxidase-linked assay and Bungowannah virus RNA by qRT-PCR in selected cases. Stillborn piglets from affected and an unaffected unit were also tested for Bungowannah virus antibody and RNA. Body fluid IgG levels and the incidence of myocardial lesions in these stillborn piglets are summarised. Tissue sections from stillborn piglets with myocarditis/myonecrosis were examined for Bungowannah virus RNA by in situ hybridisation. A clear temporal association between the occurrence of PMC on a unit or module and exposure to Bungowannah virus was identified by serological tests in both breeding aged animals and stillborn pigs. In addition, at the individual animal level on affected units, Bungowannah virus RNA was detected in stillborn piglets in large amounts by qRT-PCR and in association with myocardial lesions by in situ hybridisation. The examination of field material from cases of PMC by serology, qRT-PCR and in situ hybridisation provides strong indirect evidence that Bungowannah virus is the causative agent for PMC.

  19. Study of the Prevalence of Causative Bacterial&Protozoal Agents of in Stool Samples of 470 Gastroenteritis Patients Referring to the Nikoopour Clinic in Yazd,Iran

    Directory of Open Access Journals (Sweden)

    MR Sharifi

    2004-04-01

    Full Text Available Interoduction: Gasteroenteritis is one of the problems worth consideration all over the world. It is one of the important causes of mortality, especially in children < 5 years of age, in developing countries including Iran. The aim of this descriptive study was to determine the demographic conditions influencing the presence of causative bacteria and protozoa, followed by antibiograms of isolated bacteria from stool samples of patients with gasteroenteritis referring to Nikoopour Clinic in the city of Yazd, Iran from 1998 – 2001. Materials and method: A total of 470 samples were microbiologically examined by direct method, culture and then antibiogramed. In order to isolate the possible bacteria, differential and selected media were used. Also, wet – mount technique was applied for detection of protozoa. Results: Results revealed that 272 samples (57.9% were infected by pathogenic bacteria or protozoa. 138 (50.8% pathogenic specimens were from male patients and the remaining 134(49.3% were from female patients. Isolated species were: Enteropathogenic E.coli 117(43%, Shigella 51(18.8%, Salmonella.interetidis 25(9.2%, C.jejuni 16(5.9%, Giardia lambdia 51(18.8% and Amoebae spp 12(4.4%. The most commonly detected shigella species was dysenteriae, (74.5% while boydii with 2% was the least common type observed in the specimens. Except shigella, all the other bacteria were more common in males than female, but insignificant statistically. In order to determine the sensitivity and/or resistance of pathogenic bacteria, antibiogram test was performed using selected antibiotic disks such as Ampicillin, Nalidixic Acid, Ciprofloxacin, Gentamycin and Sulfamethaxazole. Conclusion: Results revealed that some patients were probably infected by pathogenic factors other than bacteria or protozoa. Since all viruses and parasites are almost resistant to antibiotics and on the other hand, administration of antibiotics may lead to resistance of bacterial agents

  20. Trypanosoma brucei gambiense group 1 is distinguished by a unique amino acid substitution in the HpHb receptor implicated in human serum resistance.

    Directory of Open Access Journals (Sweden)

    Rebecca E Symula

    Full Text Available Trypanosoma brucei rhodesiense (Tbr and T. b. gambiense (Tbg, causative agents of Human African Trypanosomiasis (sleeping sickness in Africa, have evolved alternative mechanisms of resisting the activity of trypanosome lytic factors (TLFs, components of innate immunity in human serum that protect against infection by other African trypanosomes. In Tbr, lytic activity is suppressed by the Tbr-specific serum-resistance associated (SRA protein. The mechanism in Tbg is less well understood but has been hypothesized to involve altered activity and expression of haptoglobin haemoglobin receptor (HpHbR. HpHbR has been shown to facilitate internalization of TLF-1 in T.b. brucei (Tbb, a member of the T. brucei species complex that is susceptible to human serum. By evaluating the genetic variability of HpHbR in a comprehensive geographical and taxonomic context, we show that a single substitution that replaces leucine with serine at position 210 is conserved in the most widespread form of Tbg (Tbg group 1 and not found in related taxa, which are either human serum susceptible (Tbb or known to resist lysis via an alternative mechanism (Tbr and Tbg group 2. We hypothesize that this single substitution contributes to reduced uptake of TLF and thus may play a key role in conferring serum resistance to Tbg group 1. In contrast, similarity in HpHbR sequence among isolates of Tbg group 2 and Tbb/Tbr provides further evidence that human serum resistance in Tbg group 2 is likely independent of HpHbR function.

  1. Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography.

    Science.gov (United States)

    Patterson, Stephen; Alphey, Magnus S; Jones, Deuan C; Shanks, Emma J; Street, Ian P; Frearson, Julie A; Wyatt, Paul G; Gilbert, Ian H; Fairlamb, Alan H

    2011-10-13

    Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.

  2. Seroprevalence and risk factors for Coxiella burnetii, the causative agent of Q fever in the dromedary camel (Camelus dromedarius population in Algeria

    Directory of Open Access Journals (Sweden)

    Mohammed H. Benaissa

    2017-08-01

    Full Text Available Query (Q fever is a globally distributed zoonotic disease caused by Coxiella burnetii, a bacterial agent for which ruminants are the most prevalent natural reservoir. Data regarding Q fever infection in camels in Algeria are limited. Therefore, a survey to detect seroprevalence of C. burnetii antibodies was conducted among healthy camel populations in a vast area in southeastern Algeria to determine distribution of the Q fever causative organism and to identify risk factors associated with infection. Between January and March 2016, blood samples were collected from 184 camels and serum samples were subsequently analysed using a commercial Enzyme-Linked Immunosorbent Assay (ELISA kit. At the time of blood collection, a questionnaire investigating 13 potential predisposing factors associated with C. burnetii seropositivity was completed for every dromedary camel and herd. Results were analysed by a chi-square (χ2 test and multivariate logistic regression. The seroprevalence of C. burnetii at the animal level was 71.2% (95% CI: 65.2–78.3 and 85.3% (95% CI: 72.8–97.8 at the herd level. At the animal level, differences in seroprevalence were observed because of herd size, animal age, animal sex, presence of ticks and contact with other herds. A multivariable logistic regression model identified three main risk factors associated with individual seropositivity: (1 age class > 11 years (OR = 8.81, 95% CI: 2.55–30.41, (2 herd size > 50 head (OR = 4.46, 95% CI: 1.01–19.59 and (3 infestation with ticks (OR 2.2; 95% CI: 1.1–4.5. This study of seroprevalence of C. burnetii infection in camels in Algeria revealed a high seroprevalence of Q fever in camel populations in southeastern Algeria and provided strong evidence that Q fever represents an economic, public health and veterinary concern. Appropriate measures should be taken to prevent the spread of C. burnetii and to reduce the risk of Q fever in farm animals and humans in this agro

  3. Spliced leader RNA silencing (SLS - a programmed cell death pathway in Trypanosoma brucei that is induced upon ER stress

    Directory of Open Access Journals (Sweden)

    Michaeli Shulamit

    2012-05-01

    Full Text Available Abstract Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite cycles between its insect (procyclic form and mammalian hosts (bloodstream form. Trypanosomes lack conventional transcription regulation, and their genes are transcribed in polycistronic units that are processed by trans-splicing and polyadenylation. In trans-splicing, which is essential for processing of each mRNA, an exon, the spliced leader (SL is added to all mRNAs from a small RNA, the SL RNA. Trypanosomes lack the machinery for the unfolded protein response (UPR, which in other eukaryotes is induced under endoplasmic reticulum (ER stress. Trypanosomes respond to such stress by changing the stability of mRNAs, which are essential for coping with the stress. However, under severe ER stress that is induced by blocking translocation of proteins to the ER, treatment of cells with chemicals that induce misfolding in the ER, or extreme pH, trypanosomes elicit the spliced leader silencing (SLS pathway. In SLS, the transcription of the SL RNA gene is extinguished, and tSNAP42, a specific SL RNA transcription factor, fails to bind to its cognate promoter. SLS leads to complete shut-off of trans-splicing. In this review, I discuss the UPR in mammals and compare it to the ER stress response in T. brucei leading to SLS. I summarize the evidence supporting the notion that SLS is a programmed cell death (PCD pathway that is utilized by the parasites to substitute for the apoptosis observed in higher eukaryotes under prolonged ER stress. I present the hypothesis that SLS evolved to expedite the death process, and rapidly remove from the population unfit parasites that, by elimination via SLS, cause minimal damage to the parasite population.

  4. Malleable Mitochondrion of Trypanosoma brucei

    Czech Academy of Sciences Publication Activity Database

    Verner, Zdeněk; Basu, Somsuvro; Benz, C.; Dixit, S.; Dobáková, Eva; Faktorová, Drahomíra; Hashimi, Hassan; Horáková, Eva; Huang, Zhenqiu; Paris, Zdeněk; Peña-Diaz, Priscila; Ridlon, L.; Týč, Jiří; Wildridge, David; Zíková, Alena; Lukeš, Julius

    2015-01-01

    Roč. 315, 2015 Feb 07 (2015), s. 73-151 ISSN 1937-6448 R&D Projects: GA ČR GAP302/12/2513; GA MŠk LL1205; GA MŠk(CZ) EE2.3.30.0032; GA MŠk LH12104; GA ČR GAP305/12/2261 EU Projects: European Commission(XE) 316304 Institutional support: RVO:60077344 Keywords : Kinetoplast * Metabolism * Mitochondrial transport * Mitochondrion * RNA import * T. brucei * Trypanosome * kDNA Subject RIV: EE - Microbiology, Virology Impact factor: 3.752, year: 2015

  5. Coxsackievirus B4 as a Causative Agent of Diabetes Mellitus Type 1: Is There a Role of Inefficiently Treated Drinking Water and Sewage in Virus Spreading?

    Science.gov (United States)

    El-Senousy, Waled M; Abdel-Moneim, Adel; Abdel-Latif, Mahmoud; El-Hefnawy, Mohamed H; Khalil, Rehab G

    2018-03-01

    for isolation of separate EV isolates from treated and untreated water and sewage samples. Characterization of the EV amplicons by RT-PCR followed by sequencing of these isolates revealed high homology (97%) with human coxsackievirus B4 (CV B4) in 60% of the isolates, while the rest of the isolates belonged to poliovirus type 1 and type 2 vaccine strains. On the other hand, characterization of the EV amplicons by RT-PCR followed by sequencing for T1D-EV + children specimens indicated that all samples contained CV B4 with the same sequence characterized in the environmental samples. CV B4-contaminated drinking water or treated sewage may play a role as a causative agent of T1D in children.

  6. In vitro susceptibility of Trypanosoma brucei brucei to selected essential oils and their major components.

    Science.gov (United States)

    Costa, Sonya; Cavadas, Cláudia; Cavaleiro, Carlos; Salgueiro, Lígia; do Céu Sousa, Maria

    2018-07-01

    Aiming for discovering effective and harmless antitrypanosomal agents, 17 essential oils and nine major components were screened for their effects on T. b. brucei. The essential oils were obtained by hydrodistillation from fresh plant material and analyzed by GC and GC-MS. The trypanocidal activity was assessed using blood stream trypomastigotes cultures of T. b. brucei and the colorimetric resazurin method. The MTT test was used to assess the cytotoxicity of essential oils on macrophage cells and Selectivity Indexes were calculated. Of the 17 essential oils screened three showed high trypanocidal activity (IC 50  oils had no cytotoxic effects on macrophage cells showing the highest values of Selectivity Index (63.4, 9.0 and 11.8, respectively). The oils of Distichoselinum tenuifolium, Lavandula viridis, Origanum virens, Seseli tortuosom, Syzygium aromaticum, and Thymbra capitata also exhibited activity (IC 50 of 10-25 μg/mL) but showed cytotoxicity on macrophages. Of the nine compounds tested, α-pinene (IC 50 of 2.9 μg/mL) and citral (IC 50 of 18.9 μg/mL) exhibited the highest anti-trypanosomal activities. Citral is likely the active component of C. citratus and α-pinene is responsible for the antitrypanosomal effects of J. oxycedrus. The present work leads us to propose the J. oxycedrus, C. citratus and L. luisieri oils as valuable sources of new molecules for African Sleeping Sickness treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Non-cytochrome mediated mitochondrial ATP production in bloodstream form Trypanosoma brucei brucei

    NARCIS (Netherlands)

    Bienen, E. J.; Maturi, R. K.; Pollakis, G.; Clarkson, A. B.

    1993-01-01

    The life cycle of Trypanosoma brucei brucei involves a series of differentiation steps characterized by marked changes in mitochondrial development and function. The bloodstream forms of this parasite completely lack cytochromes and have not been considered to have any Krebs cycle function. It has

  8. Stearoyl-CoA desaturase is an essential enzyme for the parasitic protist Trypanosoma brucei

    Energy Technology Data Exchange (ETDEWEB)

    Alloatti, Andres [Instituto de Biologia Molecular y Celular de Rosario (IBR), CONICET, Facultad de Ciencias Bioquimicas y Farmaceuticas, Universidad Nacional de Rosario, Santa Fe (Argentina); Gupta, Shreedhara; Gualdron-Lopez, Melisa; Nguewa, Paul A. [Research Unit for Tropical Diseases, de Duve Institute and Laboratory of Biochemistry, Universite Catholique de Louvain, Brussels (Belgium); Altabe, Silvia G. [Instituto de Biologia Molecular y Celular de Rosario (IBR), CONICET, Facultad de Ciencias Bioquimicas y Farmaceuticas, Universidad Nacional de Rosario, Santa Fe (Argentina); Deumer, Gladys; Wallemacq, Pierre [Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, LTAP, Universite Catholique de Louvain, Brussels (Belgium); Michels, Paul A.M. [Research Unit for Tropical Diseases, de Duve Institute and Laboratory of Biochemistry, Universite Catholique de Louvain, Brussels (Belgium); Uttaro, Antonio D., E-mail: toniuttaro@yahoo.com.ar [Instituto de Biologia Molecular y Celular de Rosario (IBR), CONICET, Facultad de Ciencias Bioquimicas y Farmaceuticas, Universidad Nacional de Rosario, Santa Fe (Argentina)

    2011-08-26

    Highlights: {yields} Inhibiting {Delta}9 desaturase drastically changes T. brucei's fatty-acid composition. {yields} Isoxyl specifically inhibits the {Delta}9 desaturase causing a growth arrest. {yields} RNA interference of desaturase expression causes a similar effect. {yields} Feeding T. brucei-infected mice with Isoxyl decreases the parasitemia. {yields} 70% of Isoxyl-treated mice survived the trypanosome infection. -- Abstract: Trypanosoma brucei, the etiologic agent of sleeping sickness, is exposed to important changes in nutrients and temperature during its life cycle. To adapt to these changes, the fluidity of its membranes plays a crucial role. This fluidity, mediated by the fatty-acid composition, is regulated by enzymes named desaturases. We have previously shown that the oleoyl desaturase is essential for Trypanosoma cruzi and T. brucei. In this work, we present experimental support for the relevance of stearoyl-CoA desaturase (SCD) for T. brucei's survival, in both its insect or procyclic-form (PCF) and bloodstream-form (BSF) stages. We evaluated this essentiality in two different ways: by generating a SCD knocked-down parasite line using RNA interference, and by chemical inhibition of the enzyme with two compounds, Isoxyl and a thiastearate with the sulfur atom at position 10 (10-TS). The effective concentration for 50% growth inhibition (EC{sub 50}) of PCF was 1.0 {+-} 0.2 {mu}M for Isoxyl and 5 {+-} 2 {mu}M for 10-TS, whereas BSF appeared more susceptible with EC{sub 50} values 0.10 {+-} 0.03 {mu}M (Isoxyl) and 1.0 {+-} 0.6 {mu}M (10-TS). RNA interference showed to be deleterious for both stages of the parasite. In addition, T. brucei-infected mice were fed with Isoxyl, causing a reduction of the parasitemia and an increase of the rodents' survival.

  9. Stearoyl-CoA desaturase is an essential enzyme for the parasitic protist Trypanosoma brucei

    International Nuclear Information System (INIS)

    Alloatti, Andres; Gupta, Shreedhara; Gualdron-Lopez, Melisa; Nguewa, Paul A.; Altabe, Silvia G.; Deumer, Gladys; Wallemacq, Pierre; Michels, Paul A.M.; Uttaro, Antonio D.

    2011-01-01

    Highlights: → Inhibiting Δ9 desaturase drastically changes T. brucei's fatty-acid composition. → Isoxyl specifically inhibits the Δ9 desaturase causing a growth arrest. → RNA interference of desaturase expression causes a similar effect. → Feeding T. brucei-infected mice with Isoxyl decreases the parasitemia. → 70% of Isoxyl-treated mice survived the trypanosome infection. -- Abstract: Trypanosoma brucei, the etiologic agent of sleeping sickness, is exposed to important changes in nutrients and temperature during its life cycle. To adapt to these changes, the fluidity of its membranes plays a crucial role. This fluidity, mediated by the fatty-acid composition, is regulated by enzymes named desaturases. We have previously shown that the oleoyl desaturase is essential for Trypanosoma cruzi and T. brucei. In this work, we present experimental support for the relevance of stearoyl-CoA desaturase (SCD) for T. brucei's survival, in both its insect or procyclic-form (PCF) and bloodstream-form (BSF) stages. We evaluated this essentiality in two different ways: by generating a SCD knocked-down parasite line using RNA interference, and by chemical inhibition of the enzyme with two compounds, Isoxyl and a thiastearate with the sulfur atom at position 10 (10-TS). The effective concentration for 50% growth inhibition (EC 50 ) of PCF was 1.0 ± 0.2 μM for Isoxyl and 5 ± 2 μM for 10-TS, whereas BSF appeared more susceptible with EC 50 values 0.10 ± 0.03 μM (Isoxyl) and 1.0 ± 0.6 μM (10-TS). RNA interference showed to be deleterious for both stages of the parasite. In addition, T. brucei-infected mice were fed with Isoxyl, causing a reduction of the parasitemia and an increase of the rodents' survival.

  10. Structural Equations and Causation

    OpenAIRE

    Hall, Ned

    2007-01-01

    Structural equations have become increasingly popular in recent years as tools for understanding causation. But standard structural equations approaches to causation face deep problems. The most philosophically interesting of these consists in their failure to incorporate a distinction between default states of an object or system, and deviations therefrom. Exploring this problem, and how to fix it, helps to illuminate the central role this distinction plays in our causal thinking.

  11. Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: a review of agents and causative mechanisms.

    Science.gov (United States)

    Nair, Urmila; Bartsch, Helmut; Nair, Jagadeesan

    2004-07-01

    In south-east Asia, Taiwan and Papua New Guinea, smoking, alcohol consumption and chewing of betel quid with or without tobacco or areca nut with or without tobacco are the predominant causes of oral cancer. In most areas, betel quid consists of a mixture of areca nut, slaked lime, catechu and several condiments according to taste, wrapped in a betel leaf. Almost all habitual chewers use tobacco with or without the betel quid. In the last few decades, small, attractive and inexpensive sachets of betel quid substitutes have become widely available. Aggressively advertised and marketed, often claimed to be safer products, they are consumed by the very young and old alike, particularly in India, but also among migrant populations from these areas world wide. The product is basically a flavoured and sweetened dry mixture of areca nut, catechu and slaked lime with tobacco (gutkha) or without tobacco (pan masala). These products have been strongly implicated in the recent increase in the incidence of oral submucous fibrosis, especially in the very young, even after a short period of use. This precancerous lesion, which has a high rate of malignant transformation, is extremely debilitating and has no known cure. The use of tobacco with lime, betel quid with tobacco, betel quid without tobacco and areca nut have been classified as carcinogenic to humans. As gutkha and pan masala are mixtures of several of these ingredients, their carcinogenic affect can be surmised. We review evidence that strongly supports causative mechanisms for genotoxicity and carcinogenicity of these substitute products. Although some recent curbs have been put on the manufacture and sale of these products, urgent action is needed to permanently ban gutkha and pan masala, together with the other established oral cancer-causing tobacco products. Further, education to reduce or eliminate home-made preparations needs to be accelerated.

  12. Fixed drug eruption induced by an iodinated non-ionic X-ray contrast medium: a practical approach to identify the causative agent and to prevent its recurrence

    Energy Technology Data Exchange (ETDEWEB)

    Boehm, Ingrid; Block, Wolfgang; Schild, Hans H. [University of Bonn, Department of Radiology, Bonn (Germany); Medina, Jesus; Prieto, Pilar [JUSTESA IMAGEN SA, Biological R and D Department, Madrid (Spain)

    2007-02-15

    We describe the case of a 61-year-old physician who developed a fixed drug eruption (FDE) after i.v. administration of a non-ionic monomeric iodinated X-ray contrast medium (CM) (iopromide). During CM injection, a sensation of heat occurred, which was most intense in the right inguinal region. Four hours later, the FDE arose with a red macule of approximately 2 cm in diameter covering a dermal infiltration in the right inguinal region, and enlarged up to a final size of 15 x 8 cm, accompanied by a burning sensation. The patient's history revealed a similar reaction in the same localization and of the same clinical appearance after CM injection 1 year before. Patch testing 4 months later revealed positive reactions to iomeprol and iohexol. Iopamidol injection for another CT examination 23 months later was well tolerated. Based on these results, we suggest patch testing after CM-induced FDE, which could help to select a CM for future CT examinations. Late onset of adverse CM reactions may manifest as FDE. Patch testing within the previous skin reaction area is the diagnostic tool that should be used to confirm the suspected agent, possible cross-reacting agents and well-tolerated agents. (orig.)

  13. Fixed drug eruption induced by an iodinated non-ionic X-ray contrast medium: a practical approach to identify the causative agent and to prevent its recurrence

    International Nuclear Information System (INIS)

    Boehm, Ingrid; Block, Wolfgang; Schild, Hans H.; Medina, Jesus; Prieto, Pilar

    2007-01-01

    We describe the case of a 61-year-old physician who developed a fixed drug eruption (FDE) after i.v. administration of a non-ionic monomeric iodinated X-ray contrast medium (CM) (iopromide). During CM injection, a sensation of heat occurred, which was most intense in the right inguinal region. Four hours later, the FDE arose with a red macule of approximately 2 cm in diameter covering a dermal infiltration in the right inguinal region, and enlarged up to a final size of 15 x 8 cm, accompanied by a burning sensation. The patient's history revealed a similar reaction in the same localization and of the same clinical appearance after CM injection 1 year before. Patch testing 4 months later revealed positive reactions to iomeprol and iohexol. Iopamidol injection for another CT examination 23 months later was well tolerated. Based on these results, we suggest patch testing after CM-induced FDE, which could help to select a CM for future CT examinations. Late onset of adverse CM reactions may manifest as FDE. Patch testing within the previous skin reaction area is the diagnostic tool that should be used to confirm the suspected agent, possible cross-reacting agents and well-tolerated agents. (orig.)

  14. Genetic control of resistance to Trypanosoma brucei brucei infection in mice

    Czech Academy of Sciences Publication Activity Database

    Šíma, Matyáš; Havelková, Helena; Quan, L.; Svobodová, M.; Jarošíková, T.; Vojtíšková, Jarmila; Stassen, A. P. M.; Demant, P.; Lipoldová, Marie

    2011-01-01

    Roč. 5, č. 6 (2011), e1173 ISSN 1935-2735 R&D Projects: GA AV ČR IAA500520606; GA MŠk(CZ) LC06009 Grant - others:NIH-NCI(US) 1R01CA127162-01 Institutional research plan: CEZ:AV0Z50520514 Keywords : Trypanosoma brucei brucei * mouse recombinant congenic strains * Tbbr Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.716, year: 2011

  15. An Investigation of the Spanish Causatives: "Hacer Ver, Hacer Creer, Hacer Pensar, Hacer Saber."

    Science.gov (United States)

    Dowling, Lee H.

    1981-01-01

    Presents study which shows that although these causatives have same surface structure as productive causative constructions they differ in several ways, e.g., unlike other productive causatives their meaning changes when "que" subjunctive is substituted for the infinitive, and they function like lexical causatives which involve agent-patient, not…

  16. Wild chimpanzees are infected by Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Milan Jirků

    2015-12-01

    Finally, we demonstrated that the mandrill serum was able to efficiently lyse T. b. brucei and T. b. rhodesiense, and to some extent T. b. gambiense, while the chimpanzee serum failed to lyse any of these subspecies.

  17. Characterization of Trypanosoma brucei gambiense stocks isolated ...

    African Journals Online (AJOL)

    Trypanosoma brucei gambiense was isolated twice from each of 23 patients in Côte d'Ivoire. Genetic characterization using RAPD (Random Primed Amplified Polymorphic DNA) showed additional variability within a given isoenzyme profile (zymodeme), confirming that this fingerprinting method has a higher discriminative ...

  18. Interaction between Trypanosoma brucei and Haemonchus ...

    African Journals Online (AJOL)

    In order to investigate the immunomodulatory influence of concurrent T. brucei and H. contortus infection in West African Dwarf (WAD) goats, 28 infected and 7 uninfected (control) of 8-9 months old male WAD goats were studied. The infected goats were separated into resistant (Class 1) and susceptible (Class 2) Faecal ...

  19. Identification and functional analysis of the S-layer protein SplA of Paenibacillus larvae, the causative agent of American Foulbrood of honey bees.

    Directory of Open Access Journals (Sweden)

    Lena Poppinga

    Full Text Available The gram-positive, spore-forming bacterium Paenibacillus larvae is the etiological agent of American Foulbrood (AFB, a globally occurring, deathly epizootic of honey bee brood. AFB outbreaks are predominantly caused by two genotypes of P. larvae, ERIC I and ERIC II, with P. larvae ERIC II being the more virulent genotype on larval level. Recently, comparative proteome analyses have revealed that P. larvae ERIC II but not ERIC I might harbour a functional S-layer protein, named SplA. We here determine the genomic sequence of splA in both genotypes and demonstrate by in vitro self-assembly studies of recombinant and purified SplA protein in combination with electron-microscopy that SplA is a true S-layer protein self-assembling into a square 2D lattice. The existence of a functional S-layer protein is novel for this bacterial species. For elucidating the biological function of P. larvae SplA, a genetic system for disruption of gene expression in this important honey bee pathogen was developed. Subsequent analyses of in vivo biological functions of SplA were based on comparing a wild-type strain of P. larvae ERIC II with the newly constructed splA-knockout mutant of this strain. Differences in cell and colony morphology suggest that SplA is a shape-determining factor. Marked differences between P. larvae ERIC II wild-type and mutant cells with regard to (i adhesion to primary pupal midgut cells and (ii larval mortality as measured in exposure bioassays corroborate the assumption that the S-layer of P. larvae ERIC II is an important virulence factor. Since SplA is the first functionally proven virulence factor for this species, our data extend the knowledge of the molecular differences between these two genotypes of P. larvae and contribute to explaining the observed differences in virulence. These results present an immense advancement in our understanding of P. larvae pathogenesis.

  20. Detection of Trypanosoma brucei gambiense and T. b. rhodesiense ...

    African Journals Online (AJOL)

    Detection of Trypanosoma brucei gambiense and T. b. rhodesiense in Glossina fuscipes fuscipes ( Diptera: Glossinidae ) and Stomoxys flies using the polymerase chain reaction (PCR) technique in southern Sudan.

  1. Identification and characterization of a phospholipase A1 activity type three secreted protein, PP_ExoU from Pseudomonas plecoglossicida NB2011, the causative agent of visceral granulomas disease in large yellow croaker (Larimichthys crocea).

    Science.gov (United States)

    Zhang, J; Wang, Y; Guo, H; Mao, Z; Ge, C

    2017-06-01

    Pseudomonas plecoglossicida NB2011, the causative agent of visceral granulomas disease in farmed Larimichthys crocea in China, encodes a predicted type three effector PP_ExoU, a homolog of the cytotoxin ExoU of Pseudomonas aeruginosa. In this study, secretion of PP_ExoU was tested in various broth, the protein was expressed with the pET30a prokaryotic system, the phospholipase A (PLA) activity of the recombinant protein was determined with fluorogenic phospholipid substrates, fusion expression with green fluorescent protein in transfected HeLa cells was investigated, and the lactate dehydrogenase (LDH) level was measured. The results showed the protein was type three secreted in several media; the recombinant protein displayed significant PLA1 activity with ubiquitin. Fluorescence was observed on the cell membrane and scattered in the cytoplasm of HeLa cells expressing catalytic wild-type PP_ExoU, blebbing and stretching developed in the cell membranes indicating of membrane damage. Fluorescence scattered in the cytoplasm of cells expressing the catalytic inactive protein. A significant LDH level was detected in HeLa cells expressing wild-type PP_exoU, but not in the Ser/Asp-mutated protein, suggestion mutation of predicted catalytic residues abolished the PLA activity. This is the first report on the function of a secreted type three protein from P. plecoglossicida. © 2016 John Wiley & Sons Ltd.

  2. A comparison of disease susceptibility and innate immune response between diploid and triploid Atlantic salmon (Salmo salar) siblings following experimental infection with Neoparamoeba perurans, causative agent of amoebic gill disease.

    Science.gov (United States)

    Chalmers, Lynn; Taylor, John F; Roy, William; Preston, Andrew C; Migaud, Herve; Adams, Alexandra

    2017-08-01

    Few studies have focussed on the health and immunity of triploid Atlantic salmon and therefore much is still unknown about their response to commercially significant pathogens. This is important if triploid stocks are to be considered for full-scale commercial production. This study aimed to investigate and compare the response of triploid and diploid Atlantic salmon to an experimental challenge with Neoparamoeba perurans, causative agent of amoebic gill disease (AGD). This disease is economically significant for the aquaculture industry. The results indicated that ploidy had no significant effect on gross gill score or gill filaments affected, while infection and time had significant effects. Ploidy, infection and time did not affect complement or anti-protease activities. Ploidy had a significant effect on lysozyme activity at 21 days post-infection (while infection and time did not), although activity was within the ranges previously recorded for salmonids. Stock did not significantly affect any of the parameters measured. Based on the study results, it can be suggested that ploidy does not affect the manifestation or severity of AGD pathology or the serum innate immune response. Additionally, the serum immune response of diploid and triploid Atlantic salmon may not be significantly affected by amoebic gill disease.

  3. Causation and International State Responsibility

    NARCIS (Netherlands)

    Castellanos-Jankiewicz, L.

    2012-01-01

    This work studies causation in the law of international State responsibility. It is submitted that the absence of causation as an element of the internationally wrongful act owes more to the structure of international law, than to the inadequateness of causation as a conceptual and legal construct

  4. Studies on the glycosome of Trypanosoma brucei

    International Nuclear Information System (INIS)

    Aman, R.A.

    1985-01-01

    Glycosomes (microbodies) have been purified from bloodstream form Trypanosoma brucei by an improved procedure involving freezing and thawing live organisms in 15% glycerol prior to cell disruption. Highly purified organelles of bloodstream form T. brucei contain 11 major proteins of which 8 tentatively identified glycolytic enzymes make up about 90% of the total glycosomal protein. Treatment of these intact isolated organelles with the bisimidoester dimethylsuberimidate (DMSI) resulted in crosslinking of all glycosomal proteins into a large complex suggestive of juxtapositioning of the glycosomal proteins. The crosslinked complex was capable of catalyzing the multienzyme conversion of glucose to glycerol-3-phosphate but did not possess any special kinetic features different from those of the unaggregated enzymes represented by solubilized glycosomes. The multienzyme reaction had a lab phase associated with it and [ 14 C]-glucose label incorporation into sugar phosphate intermediates was effectively competed by unlabeled intermediates. Glycosomes were also purified from culture form T. brucei by several different procedures. Comparison of highly purified organelles from the two different life stages of the organism showed reduced specific activities and contents of the early glycolytic enzymes in organelles from the culture form with a decrease from 87% to 35% of the contribution of glycolytic enzymes to the total glycosomal protein

  5. Mating compatibility in the parasitic protist Trypanosoma brucei.

    Science.gov (United States)

    Peacock, Lori; Ferris, Vanessa; Bailey, Mick; Gibson, Wendy

    2014-02-21

    Genetic exchange has been described in several kinetoplastid parasites, but the most well-studied mating system is that of Trypanosoma brucei, the causative organism of African sleeping sickness. Sexual reproduction takes place in the salivary glands (SG) of the tsetse vector and involves meiosis and production of haploid gametes. Few genetic crosses have been carried out to date and consequently there is little information about the mating compatibility of different trypanosomes. In other single-celled eukaryotes, mating compatibility is typically determined by a system of two or more mating types (MT). Here we investigated the MT system in T. brucei. We analysed a large series of F1, F2 and back crosses by pairwise co-transmission of red and green fluorescent cloned cell lines through experimental tsetse flies. To analyse each cross, trypanosomes were cloned from fly SG containing a mixture of both parents, and genotyped by microsatellites and molecular karyotype. To investigate mating compatibility at the level of individual cells, we directly observed the behaviour of SG-derived gametes in intra- or interclonal mixtures of red and green fluorescent trypanosomes ex vivo. Hybrid progeny were found in all F1 and F2 crosses and most of the back crosses. The success of individual crosses was highly variable as judged by the number of hybrid clones produced, suggesting a range of mating compatibilities among F1 progeny. As well as hybrids, large numbers of recombinant genotypes resulting from intraclonal mating (selfers) were found in some crosses. In ex vivo mixtures, red and green fluorescent trypanosome gametes were observed to pair up and interact via their flagella in both inter- and intraclonal combinations. While yellow hybrid trypanosomes were frequently observed in interclonal mixtures, such evidence of cytoplasmic exchange was rare in the intraclonal mixtures. The outcomes of individual crosses, particularly back crosses, were variable in numbers of both

  6. Probability of causation approach

    International Nuclear Information System (INIS)

    Jose, D.E.

    1988-01-01

    Probability of causation (PC) is sometimes viewed as a great improvement by those persons who are not happy with the present rulings of courts in radiation cases. The author does not share that hope and expects that PC will not play a significant role in these issues for at least the next decade. If it is ever adopted in a legislative compensation scheme, it will be used in a way that is unlikely to please most scientists. Consequently, PC is a false hope for radiation scientists, and its best contribution may well lie in some of the spin-off effects, such as an influence on medical practice

  7. HELICOBACTER PYLORI: THE CAUSATIVE AGENT OF PEPTIC ...

    African Journals Online (AJOL)

    DR. AMINU

    Helicobacter pylori by treatment with antibiotics in peptic ulcer patients resulted in the healing of the ulcer. ... and gastric cancers. .... H. pyloris cause chronic active gastritis in humans and ... of the night when the stomach is empty and is.

  8. Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response.

    Science.gov (United States)

    Salmon, Didier

    2018-04-25

    Trypanosoma brucei , etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva ( Salivaria ). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor-type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA). T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense.

  9. Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response

    Directory of Open Access Journals (Sweden)

    Didier Salmon

    2018-04-01

    Full Text Available Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria. In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC that are topologically similar to receptor-type guanylate cyclase (GC of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs, rather than the classical protein kinase A cAMP effector (PKA. T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense.

  10. Epidemiological and genetic analysis concerning the non-enterovirus 71 and non-coxsackievirus A16 causative agents related to hand, foot and mouth disease in Anyang city, Henan Province, China, from 2011 to 2015.

    Science.gov (United States)

    Li, Yang; Bao, Honghong; Zhang, Xiangping; Zhai, Mingqiang; Bao, Xiaobing; Wang, Demin; Zhang, Shuanhu

    2017-10-01

    Enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) are major pathogens of hand, foot, and mouth disease (HFMD) and have been associated with consecutive outbreaks of HFMD in China over the past years. Although several other human enteroviruses (HEVs) have also acted as causative agents of HFMD, published information on their roles in the prevalence of HFMD is limited. This study was conducted to reveal the characteristics of the pathogenic spectrum and molecular epidemiology of the non-EV-71 and -CV-A16 HEVs in Anyang City, which is located in north-central China and has a population of five million. From 2011 to 2015, 2270 samples were collected from HFMD patients (3.89 ± 1.06 years of age), and 1863 HEV-positive samples, including 524 samples with 23 non-EV-71 and non-CV-A16 serotypes, were identified. Based on the nucleotide sequence of the VP1 gene, 6 common non-EV-71 and non-CV-A16 HEVs, including coxsackievirus A2, A6, A10, A14, B2, and B5, were studied to determine their phylogenies and selective pressures. Phylogenetic analyses revealed a high level of genetic divergence and a pattern of lineage replacement over time in Mainland China. Selective pressure analyses showed that purifying selection was predominant in the evolution of the VP1 gene, whereas positive selection acted on individual codons. Overall, non-EV-71 and non-CV-A16 HEVs were important constituents of the pathogenic spectrum of HFMD in Anyang City during 2011-2015. Some of these HEVs with complex and active phylogenies represent a potential threat to public health, suggesting that long-term monitoring of these pathogens should be implemented to prevent HFMD outbreaks. © 2017 Wiley Periodicals, Inc.

  11. Onicomicosis: epidemiología, agentes causales y evaluación de los métodos diagnósticos de laboratorio Onychomycoses: epidemiology, causative agents and assessment of diagnostic laboratory methods

    OpenAIRE

    Javier R Nazar; Paula E Gerosa; Osvaldo A Díaz

    2012-01-01

    Desde marzo de 2007 hasta marzo de 2011 se estudiaron prospectivamente 414 pacientes con onicodistrofias en un laboratorio privado de Esquel. La prevalencia de onicomicosis de pie fue del 78 %; la de mano, del 58 %. Los principales agentes etiológicos fueron Trichophyton rubrum, Candida spp. y Trichophyton mentagrophytes. El desarrollo de dermatofitos prevaleció en las onicopatías de pie y el de Candida spp. en las de uñas de mano (ambos, p < 0,05). En las onicomicosis candidiásicas predomina...

  12. Neural Damage in Experimental Trypanosoma brucei gambiense Infection: Hypothalamic Peptidergic Sleep and Wake-Regulatory Neurons

    Directory of Open Access Journals (Sweden)

    Claudia Laperchia

    2018-02-01

    Full Text Available Neuron populations of the lateral hypothalamus which synthesize the orexin (OX/hypocretin or melanin-concentrating hormone (MCH peptides play crucial, reciprocal roles in regulating wake stability and sleep. The disease human African trypanosomiasis (HAT, also called sleeping sickness, caused by extracellular Trypanosoma brucei (T. b. parasites, leads to characteristic sleep-wake cycle disruption and narcoleptic-like alterations of the sleep structure. Previous studies have revealed damage of OX and MCH neurons during systemic infection of laboratory rodents with the non-human pathogenic T. b. brucei subspecies. No information is available, however, on these peptidergic neurons after systemic infection with T. b. gambiense, the etiological agent of 97% of HAT cases. The present study was aimed at the investigation of immunohistochemically characterized OX and MCH neurons after T. b. gambiense or T. b. brucei infection of a susceptible rodent, the multimammate mouse, Mastomysnatalensis. Cell counts and evaluation of OX fiber density were performed at 4 and 8 weeks post-infection, when parasites had entered the brain parenchyma from the periphery. A significant decrease of OX neurons (about 44% reduction and MCH neurons (about 54% reduction was found in the lateral hypothalamus and perifornical area at 8 weeks in T. b. gambiense-infected M. natalensis. A moderate decrease (21% and 24% reduction, respectively, which did not reach statistical significance, was found after T. b. brucei infection. In two key targets of diencephalic orexinergic innervation, the peri-suprachiasmatic nucleus (SCN region and the thalamic paraventricular nucleus (PVT, densitometric analyses showed a significant progressive decrease in the density of orexinergic fibers in both infection paradigms, and especially during T. b. gambiense infection. Altogether the findings provide novel information showing that OX and MCH neurons are highly vulnerable to chronic

  13. Onicomicosis: epidemiología, agentes causales y evaluación de los métodos diagnósticos de laboratorio Onychomycoses: epidemiology, causative agents and assessment of diagnostic laboratory methods

    Directory of Open Access Journals (Sweden)

    Javier R Nazar

    2012-03-01

    Full Text Available Desde marzo de 2007 hasta marzo de 2011 se estudiaron prospectivamente 414 pacientes con onicodistrofias en un laboratorio privado de Esquel. La prevalencia de onicomicosis de pie fue del 78 %; la de mano, del 58 %. Los principales agentes etiológicos fueron Trichophyton rubrum, Candida spp. y Trichophyton mentagrophytes. El desarrollo de dermatofitos prevaleció en las onicopatías de pie y el de Candida spp. en las de uñas de mano (ambos, p Since March 2007 to March 2011, 414 patients with onychopathies were prospectively analyzed. Prevalence of the toenail and fingernail mycoses was 78 % and 58 %, respectively. The major etiological agents were Trichophyton rubrum, Candida spp. and Trichophyton mentagrophytes. Dermatophytes were more frequently cultured from toenails, whereas Candida spp. from fingernails (both, p < 0.05. In candidal onychomycosis, species different from C. albicans were prevalent. A higher prevalence of toenail and fingernail mycoses, a predominance of T. rubrum in toenails (p < 0.05, and greater positivity in the direct examination (DE and in culture (both, p < 0.05 were more frequently observed in men than in women. The correlation between DE and culture was 68 %. DE and culture yields were associated with a greater size lesion. DE was more effective in onycodystrophies with duration of more than 5 years. Culture positivity was independent of nail affection chronicity.

  14. Calcium-dependent disorder-to-order transitions are central to the secretion and folding of the CyaA toxin of Bordetella pertussis, the causative agent of whooping cough.

    Science.gov (United States)

    O'Brien, Darragh P; Perez, Ana Cristina Sotomayor; Karst, Johanna; Cannella, Sara E; Enguéné, Véronique Yvette Ntsogo; Hessel, Audrey; Raoux-Barbot, Dorothée; Voegele, Alexis; Subrini, Orso; Davi, Marilyne; Guijarro, J Inaki; Raynal, Bertrand; Baron, Bruno; England, Patrick; Hernandez, Belen; Ghomi, Mahmoud; Hourdel, Véronique; Malosse, Christian; Chamot-Rooke, Julia; Vachette, Patrice; Durand, Dominique; Brier, Sébastien; Ladant, Daniel; Chenal, Alexandre

    2018-01-12

    The adenylate cyclase toxin (CyaA) plays an essential role in the early stages of respiratory tract colonization by Bordetella pertussis, the causative agent of whooping cough. Once secreted, CyaA invades eukaryotic cells, leading to cell death. The cell intoxication process involves a unique mechanism of translocation of the CyaA catalytic domain directly across the plasma membrane of the target cell. Herein, we review our recent results describing how calcium is involved in several steps of this intoxication process. In conditions mimicking the low calcium environment of the crowded bacterial cytosol, we show that the C-terminal, calcium-binding Repeat-in-ToXin (RTX) domain of CyaA, RD, is an extended, intrinsically disordered polypeptide chain with a significant level of local, secondary structure elements, appropriately sized for transport through the narrow channel of the secretion system. Upon secretion, the high calcium concentration in the extracellular milieu induces the refolding of RD, which likely acts as a scaffold to favor the refolding of the upstream domains of the full-length protein. Due to the presence of hydrophobic regions, CyaA is prone to aggregate into multimeric forms in vitro, in the absence of a chaotropic agent. We have recently defined the experimental conditions required for CyaA folding, comprising both calcium binding and molecular confinement. These parameters are critical for CyaA folding into a stable, monomeric and functional form. The monomeric, calcium-loaded (holo) toxin exhibits efficient liposome permeabilization and hemolytic activities in vitro, even in a fully calcium-free environment. By contrast, the toxin requires sub-millimolar calcium concentrations in solution to translocate its catalytic domain across the plasma membrane, indicating that free calcium in solution is actively involved in the CyaA toxin translocation process. Overall, this data demonstrates the remarkable adaptation of bacterial RTX toxins to the

  15. A review of the Mycrocylus ulei Ascomycetes fungus, causative agent of South American rubber-leaf blight Revisión sobre el hongo Microcyclus ulei, agente causal del mal suramericano de la hoja del caucho

    Directory of Open Access Journals (Sweden)

    Ancízar Aristizábar Fabio

    2006-12-01

    Full Text Available The Microcyclus ulei Ascomycetes fungus is the causal agent of south-American leaf blight (SALB, this being one of the most important diseases affecting the natural rubber tree (Hevea brasiliensis in Latina-America and has been responsible for numerous economic losses. This fungus has presented high physiological variability, suggesting its great adaptability. HCN tolerance has been described as being one of the mechanisms associated with its virulence. Resistant Hevea clones have been obtained by genetic improvement; however, the mechanisms associated with this are still not well known. Greater knowledge of this pathogen will lead to developing new control strategies and better understanding of the mechanisms associated with host resistance. Key words: Microcyclus ulei, SALB, Hevea brasiliensis.El hongo ascomycete Microcyclus ulei es el agente causal del SALB que es una de las enfermedades más importan­tes del árbol de caucho natural (Hevea brasiliensis en América Latina y ha sido responsable de numerosas pérdidas económicas. Este hongo ha presentado alta variabilidad fisiológica y se sugiere su alta adaptabilidad, dentro de los mecanismos asociados a su virulencia se ha descrito la tolerancia al HCN. Se han obtenido clones de Hevea resistentes mediante mejoramiento genético, sin embargo, aun no son bien conocidos los mecanismos asociados a ésta. Un mayor conocimiento de este patógeno permitirá el desarrollo de nuevas estrategias de control así como el mayor entendimiento de los mecanismos asociados a resistencia del hospedero. Palabras clave: Microcyclus ulei, SALB, Hevea brasiliensis.

  16. Factual causation in medical negligence.

    Science.gov (United States)

    Manning, Joanna

    2007-12-01

    The conventional approach to causation in negligence is the "but for" test, decided on the balance of probabilities. Even when supplemented by the "material contribution" principle, satisfying the onus of proof of causation can be an insuperable obstacle for plaintiffs, particularly in medical cases. Yet, having found a breach of duty, a court's sympathies may gravitate toward the plaintiff at this point in the case. Accordingly, courts have sometimes accepted a relaxation of strict causation principles. The judicial devices are described: a special principle of causation in particular duties of care; a shifting burden of proof; "bridging the evidentiary gap" by drawing a robust inference of causation; treating a material increase in risk as sufficient proof of causation; and permitting causation to be established on the basis of the loss of a material chance of achieving a better outcome and discounting damages. In Accident Compensation Corp v Ambros [2007] NZCA 304 the New Zealand Court of Appeal recognised the need for a legal device to ameliorate the injustice sometimes caused by the strict rules of causation, and preferred the "inferential reasoning" approach favoured by the Canadian common law for use in the context of the accident compensation scheme. It is hoped that the New Zealand Supreme Court approves Ambros if the opportunity arises.

  17. CHARACTERIZATION AND ANTIPARASITIC ACTIVITY OF BENZOPHENONE THIOSEMICARBAZONES ON Trypanosoma brucei brucei

    Directory of Open Access Journals (Sweden)

    Georges C. Accrombessi

    2011-02-01

    Full Text Available The structure of four synthesized thiosemicarbazones, substituted or not, of benzophenone has been confirmed by spectrometrical analysis IR, NMR 1H and 13C. Their anti-trypanosomal activities were evaluated on Trypanosoma brucei brucei. Among these compounds, benzophenone 4 phenyl-3-thiosemicarbazone 4 has the highest activity with the half-inhibitory concentration (IC50 = 8.48 micromolar (µM. Benzophenone 4-methyl-3-thiosemicarbazone 3 and benzophenone thiosemicarbazone 1 showed moderate anti-trypanosomal activity with IC50 values equal to 23.27 µM and 67.17 µM respectively. Benzophenone 2 methyl-3-thiosemicarbazone 2 showed no activity up to IC50 = 371.74 µM.

  18. In vivo trypanocidal activity of Nymphaea lotus Linn. methanol extract against Trypanosoma brucei brucei

    Directory of Open Access Journals (Sweden)

    Muhammad Haruna Garba

    2015-10-01

    Full Text Available Objective: To evaluate the antitrypanosomal potentials of methanol extract of Nymphaea lotus Linn. (N. lotus with the aim of obtaining a new lead for formulating safe, inexpensive, nontoxic and readily available trypanocidal drugs. Methods: Seventy percent (v/v (methanol/water crude extract of N. lotus was evaluated for antitrypanosomal activity in experimental trypanosomiasis using Trypanosoma brucei bruceiinfected mice. Infected mice in different groups were administered intraperitoneally 100, 200, 300 and 400 mg/kg body weight/day of the crude for two weeks, while a positive control group was treated with standard drug, berenil. Results: The crude extract at a dose of 100 mg/kg body weight/day was more effective than the higher doses in completely clearing parasites from the blood of mice infected with Trypanosoma brucei brucei. Pre-treatment of healthy mice with the crude extract for 5 days before infection did not prevent the establishment of the infection, indicating that the extract had no prophylactic activity. Subinoculation of the blood and cerebrospinal fluid drawn from the cured mice into healthy mice failed to produce any infection within 50 days post inoculation. Administration of 1 000 mg/kg body weight of the crude extract led to the death of 50% of the experimental animals indicating a high level of toxicity of the extract at higher doses. Conclusions: This study has demonstrated the potency of the crude extract of N. lotus in treating experimental trypanosomiasis at lower doses.

  19. Classical clinical signs in rats experimemtally infected with Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Nwoha Rosemary Ijeoma Ogechi

    2015-02-01

    Full Text Available Objective: To investigate clinical signs in Trypanosoma brucei infection in albino rats. Methods: Fourteen rats grouped into 2 with 7 rats in each group were used to determine classical clinical manifestation of Trypanosoma brucei infection in rats. Group A rats were uninfected control and Group B rats were infected with Trypanosoma brucei. Results: Parasitaemia was recorded in Group B by (3.86±0.34 d and the peak of parasitaemia was observed at Day 5 post infection. Classical signs observed included squint eyes, raised whiskers, lethargy, no weight loss, pyrexia, isolation from the other rats, and starry hair coat. Conclusions: These signs could be diagnostic or aid in diagnosis of Trypanosoma brucei infection in rats.

  20. Role of cytokines in Trypanosoma brucei-induced anaemia: A ...

    African Journals Online (AJOL)

    species Trypanosoma brucei that are transmitted by a tsetse fly (Glossina spp.) ... of autologous immunoglobulin antibodies on the red cell surfaces and also to ... development for the detection and management of anaemia in trypanosomiasis.

  1. Some liver function indices and blood parameters in T. brucei ...

    African Journals Online (AJOL)

    JTEkanem

    symptoms of African sleeping sickness9. Despite the prolific research ... is a disease for which both man and other animals whether ... on some symptoms caused by T. brucei infection. .... immune response is insufficient to clear infection21-23.

  2. View of Causation for CSCW

    DEFF Research Database (Denmark)

    Christensen, Lars R.; Bertelsen, Olav W.

    2015-01-01

    In this chapter, we attempt to achieve a better understanding of how cooperative work is partly accomplished by virtue of the actors’ manipulation and control of causal relationships central to their material field of work. Previous CSCW studies have not focused extensively on causation in cooper...... in cooperative work (e.g. see Schmidt and Bannon 2013). Consequently, it is a challenge to find a conception of causation appropriate for the study of cooperative work. This chapter addresses this challenge....

  3. Fluid convection, constraint and causation

    Science.gov (United States)

    Bishop, Robert C.

    2012-01-01

    Complexity—nonlinear dynamics for my purposes in this essay—is rich with metaphysical and epistemological implications but is receiving sustained philosophical analysis only recently. I will explore some of the subtleties of causation and constraint in Rayleigh–Bénard convection as an example of a complex phenomenon, and extract some lessons for further philosophical reflection on top-down constraint and causation particularly with respect to causal foundationalism. PMID:23386955

  4. Regulation and spatial organization of PCNA in Trypanosoma brucei

    International Nuclear Information System (INIS)

    Kaufmann, Doris; Gassen, Alwine; Maiser, Andreas; Leonhardt, Heinrich; Janzen, Christian J.

    2012-01-01

    Highlights: ► Characterization of the proliferating cell nuclear antigen in Trypanosoma brucei (TbPCNA). ► TbPCNA is a suitable marker to detect replication in T. brucei. ► TbPCNA distribution and regulation is different compared to closely related parasites T. cruzi and Leishmania donovani. -- Abstract: As in most eukaryotic cells, replication is regulated by a conserved group of proteins in the early-diverged parasite Trypanosoma brucei. Only a few components of the replication machinery have been described in this parasite and regulation, sub-nuclear localization and timing of replication are not well understood. We characterized the proliferating cell nuclear antigen in T. brucei (TbPCNA) to establish a spatial and temporal marker for replication. Interestingly, PCNA distribution and regulation is different compared to the closely related parasites Trypanosoma cruzi and Leishmania donovani. TbPCNA foci are clearly detectable during S phase of the cell cycle but in contrast to T. cruzi they are not preferentially located at the nuclear periphery. Furthermore, PCNA seems to be degraded when cells enter G2 phase in T. brucei suggesting different modes of replication regulation or functions of PCNA in these closely related eukaryotes.

  5. Regulation and spatial organization of PCNA in Trypanosoma brucei

    Energy Technology Data Exchange (ETDEWEB)

    Kaufmann, Doris; Gassen, Alwine [University of Munich (LMU), Department Biology I, Genetics, Grosshaderner Str. 2-4, 82152 Martinsried (Germany); Maiser, Andreas; Leonhardt, Heinrich [University of Munich (LMU), Department Biology II, Grosshaderner Str. 2-4, 82152 Martinsried (Germany); Janzen, Christian J., E-mail: christian.janzen@uni-wuerzburg.de [University of Munich (LMU), Department Biology I, Genetics, Grosshaderner Str. 2-4, 82152 Martinsried (Germany)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer Characterization of the proliferating cell nuclear antigen in Trypanosoma brucei (TbPCNA). Black-Right-Pointing-Pointer TbPCNA is a suitable marker to detect replication in T. brucei. Black-Right-Pointing-Pointer TbPCNA distribution and regulation is different compared to closely related parasites T. cruzi and Leishmania donovani. -- Abstract: As in most eukaryotic cells, replication is regulated by a conserved group of proteins in the early-diverged parasite Trypanosoma brucei. Only a few components of the replication machinery have been described in this parasite and regulation, sub-nuclear localization and timing of replication are not well understood. We characterized the proliferating cell nuclear antigen in T. brucei (TbPCNA) to establish a spatial and temporal marker for replication. Interestingly, PCNA distribution and regulation is different compared to the closely related parasites Trypanosoma cruzi and Leishmania donovani. TbPCNA foci are clearly detectable during S phase of the cell cycle but in contrast to T. cruzi they are not preferentially located at the nuclear periphery. Furthermore, PCNA seems to be degraded when cells enter G2 phase in T. brucei suggesting different modes of replication regulation or functions of PCNA in these closely related eukaryotes.

  6. Phenolic Constituents of Medicinal Plants with Activity against Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Ya Nan Sun

    2016-04-01

    Full Text Available Neglected tropical diseases (NTDs affect over one billion people all over the world. These diseases are classified as neglected because they impact populations in areas with poor financial conditions and hence do not attract sufficient research investment. Human African Trypanosomiasis (HAT or sleeping sickness, caused by the parasite Trypanosoma brucei, is one of the NTDs. The current therapeutic interventions for T. brucei infections often have toxic side effects or require hospitalization so that they are not available in the rural environments where HAT occurs. Furthermore, parasite resistance is increasing, so that there is an urgent need to identify novel lead compounds against this infection. Recognizing the wide structural diversity of natural products, we desired to explore and identify novel antitrypanosomal chemotypes from a collection of natural products obtained from plants. In this study, 440 pure compounds from various medicinal plants were tested against T. brucei by in a screening using whole cell in vitro assays. As the result, twenty-two phenolic compounds exhibited potent activity against cultures of T. brucei. Among them, eight compounds—4, 7, 11, 14, 15, 18, 20, and 21—showed inhibitory activity against T. brucei, with IC50 values below 5 µM, ranging from 0.52 to 4.70 μM. Based on these results, we attempt to establish some general trends with respect to structure-activity relationships, which indicate that further investigation and optimization of these derivatives might enable the preparation of potentially useful compounds for treating HAT.

  7. Evaluation of In Vitro Activity of Essential Oils against Trypanosoma brucei brucei and Trypanosoma evansi

    Directory of Open Access Journals (Sweden)

    Nathan Habila

    2010-01-01

    Full Text Available Essential oils (EOs from Cymbopogon citratus (CC, Eucalyptus citriodora (EC, Eucalyptus camaldulensis (ED, and Citrus sinensis (CS were obtained by hydrodistillation process. The EOs were evaluated in vitro for activity against Trypanosoma brucei brucei (Tbb and Trypanosoma evansi (T. evansi. The EOs were found to possess antitrypanosomal activity in vitro in a dose-dependent pattern in a short period of time. The drop in number of parasite over time was achieved doses of 0.4 g/ml, 0.2 g/mL, and 0.1 g/mL for all the EOs. The concentration of 0.4 g/mL CC was more potent at 3 minutes and 2 minutes for Tbb and T. evansi, respectively. The GC-MS analysis of the EOs revealed presence of Cyclobutane (96.09% in CS, 6-octenal (77.11% in EC, Eucalyptol (75% in ED, and Citral (38.32% in CC among several other organic compounds. The results are discussed in relation to trypanosome chemotherapy.

  8. Troglitazone induces differentiation in Trypanosoma brucei

    International Nuclear Information System (INIS)

    Denninger, Viola; Figarella, Katherine; Schoenfeld, Caroline; Brems, Stefanie; Busold, Christian; Lang, Florian; Hoheisel, Joerg; Duszenko, Michael

    2007-01-01

    Trypanosoma brucei, a protozoan parasite causing sleeping sickness, is transmitted by the tsetse fly and undergoes a complex lifecycle including several defined stages within the insect vector and its mammalian host. In the latter, differentiation from the long slender to the short stumpy form is induced by a yet unknown factor of trypanosomal origin. Here we describe that some thiazolidinediones are also able to induce differentiation. In higher eukaryotes, thiazolidinediones are involved in metabolism and differentiation processes mainly by binding to the intracellular receptor peroxisome proliferator activated receptor γ. Our studies focus on the effects of troglitazone on bloodstream form trypanosomes. Differentiation was monitored using mitochondrial markers (membrane potential, succinate dehydrogenase activity, inhibition of oxygen uptake by KCN, amount of cytochrome transcripts), morphological changes (Transmission EM and light microscopy), and transformation experiments (loss of the Variant Surface Glycoprotein coat and increase of dihydroliponamide dehydrogenase activity). To further investigate the mechanisms responsible for these changes, microarray analyses were performed, showing an upregulation of expression site associated gene 8 (ESAG8), a potential differentiation regulator

  9. Analytical purification of a 60-kDa target protein of artemisinin detected in Trypanosoma brucei brucei

    Directory of Open Access Journals (Sweden)

    Benetode Konziase

    2015-12-01

    Full Text Available Here we describe the isolation and purity determination of Trypanosoma brucei (T. b. brucei candidate target proteins of artemisinin. The candidate target proteins were detected and purified from their biological source (T. b. brucei lysate using the diazirine-free biotinylated probe 5 for an affinity binding to a streptavidin-tagged resin and, subsequently, the labeled target proteins were purified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE. We herein showed the electrophoresis gel and the immunoblotting film containing the 60-kDa trypanosomal candidate target protein of artemisinin as a single band, which was visualized on-gel by the reverse-staining method and on a Western blotting film by enhanced chemiluminescence. The data provided in this article are related to the original research article “Biotinylated probes of artemisinin with labeling affinity toward Trypanosoma brucei brucei target proteins”, by Konziase (Anal. Biochem., vol. 482, 2015, pp. 25–31. http://dx.doi.org/10.1016/j.ab.2015.04.020.

  10. Triacylglycerol Storage in Lipid Droplets in Procyclic Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Stefan Allmann

    Full Text Available Carbon storage is likely to enable adaptation of trypanosomes to nutritional challenges or bottlenecks during their stage development and migration in the tsetse. Lipid droplets are candidates for this function. This report shows that feeding of T. brucei with oleate results in a 4-5 fold increase in the number of lipid droplets, as quantified by confocal fluorescence microscopy and by flow cytometry of BODIPY 493/503-stained cells. The triacylglycerol (TAG content also increased 4-5 fold, and labeled oleate is incorporated into TAG. Fatty acid carbon can thus be stored as TAG in lipid droplets under physiological growth conditions in procyclic T. brucei. β-oxidation has been suggested as a possible catabolic pathway for lipids in T. brucei. A single candidate gene, TFEα1 with coding capacity for a subunit of the trifunctional enzyme complex was identified. TFEα1 is expressed in procyclic T. brucei and present in glycosomal proteomes, Unexpectedly, a TFEα1 gene knock-out mutant still expressed wild-type levels of previously reported NADP-dependent 3-hydroxyacyl-CoA dehydrogenase activity, and therefore, another gene encodes this enzymatic activity. Homozygous Δtfeα1/Δtfeα1 null mutant cells show a normal growth rate and an unchanged glycosomal proteome in procyclic T. brucei. The decay kinetics of accumulated lipid droplets upon oleate withdrawal can be fully accounted for by the dilution effect of cell division in wild-type and Δtfeα1/Δtfeα1 cells. The absence of net catabolism of stored TAG in procyclic T. brucei, even under strictly glucose-free conditions, does not formally exclude a flux through TAG, in which biosynthesis equals catabolism. Also, the possibility remains that TAG catabolism is completely repressed by other carbon sources in culture media or developmentally activated in post-procyclic stages in the tsetse.

  11. Social mechanisms and social causation

    OpenAIRE

    Friedel Weinert

    2014-01-01

    The aim of this paper is to examine the notion of social mechanisms by comparison with the notions of evolutionary and physical mechanisms. It is argued that social mechanisms are based on trends, and not lawlike regularities, so that social mechanisms are different from mechanisms in the natural sciences. Taking as an example of social causation the abolition of the slave trade, this paper argues that social mechanisms should be incorporated in Weber’s wider ...

  12. A tropical tale: how Naja nigricollis venom beats Trypanosoma brucei

    DEFF Research Database (Denmark)

    Martos Esteban, Andrea; Laustsen, Andreas Hougaard; Carrington, Mark

    Trypanosoma brucei is a parasitic protozoan species capable to infecting insect vectors whose bite further produces African sleeping sickness inhuman beings [1]. During the parasite’s extracellular life in the mammalian host,its outer coat, mainly composed of Variable Surface Glycoproteins (VSGs)...

  13. What controls glycolysis in bloodstream form Trypanosoma brucei?

    NARCIS (Netherlands)

    Bakker, B.M.; Michels, P.A.M.; Opperdoes, F.R.; Westerhoff, H.V.

    1999-01-01

    On the basis of the experimentally determined kinetic properties of the trypanosomal enzymes, the question is addressed of which step limits the glycolytic flux in bloodstream form Trypanosoma brucei. There appeared to be no single answer; in the physiological range, control shifted between the

  14. Serum Iron and Nitric Oxide Production in Trypanosoma brucei ...

    African Journals Online (AJOL)

    JTEkanem

    reduction in the serum iron status and a modulation of nitric oxide synthase activity of T. brucei infected rats. ... inflammation and tissue damage15. ... The serum iron level was determined ... concentration or of total nitrate and nitrite ... 15. 16. 17. 18. Days. S e ru m iro n lev e l mg. /ml. Infected treated. Infected untreated. 0.

  15. Meiosis and Haploid Gametes in the Pathogen Trypanosoma brucei

    OpenAIRE

    Peacock, Lori; Bailey, Mick; Carrington, Mark; Gibson, Wendy

    2014-01-01

    Summary In eukaryote pathogens, sex is an important driving force in spreading genes for drug resistance, pathogenicity, and virulence [1]. For the parasitic trypanosomes that cause African sleeping sickness, mating occurs during transmission by the tsetse vector [2, 3] and involves meiosis [4], but haploid gametes have not yet been identified. Here, we show that meiosis is a normal part of development in the insect salivary glands for all subspecies of Trypanosoma brucei, including the human...

  16. Trypanosoma brucei Mitochondrial Respiratome: Composition and Organization in Procyclic Form

    Czech Academy of Sciences Publication Activity Database

    Acestor, N.; Zíková, Alena; Dalley, R. A.; Anupama, A.; Panigrahi, A. K.; Stuart, K. D.

    2011-01-01

    Roč. 10, č. 9 (2011), s. 1-14 ISSN 1535-9476 R&D Projects: GA ČR GP204/09/P563 Institutional research plan: CEZ:AV0Z60220518 Keywords : SUCCINATE DEHYDROGENASE * EDITED MESSENGER-RNA * COMPLEX-I * TRYPANOSOMA-BRUCEI * UBIQUINONE OXIDOREDUCTASE * TAP-TAG * PROTEIN INTERACTION * ALTERNATIVE OXIDASE * STATISTICAL-MODEL * MASS-SPECTROMETRY Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.398, year: 2011

  17. Trypanosoma brucei solanesyl-diphosphate synthase localizes to the mitochondrion

    Czech Academy of Sciences Publication Activity Database

    Lai, D.-H.; Bontempi, E. J.; Lukeš, Julius

    2012-01-01

    Roč. 183, č. 2 (2012), s. 189-192 ISSN 0166-6851 R&D Projects: GA ČR(CZ) GAP305/11/2179 Institutional support: RVO:60077344 Keywords : Trypanosoma brucei * Sleeping sickness * Ubiquinone * Solanesyl-diphosphate synthase * Digitonin permeabilization * In situ tagging Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.734, year: 2012 http://www.sciencedirect.com/science/article/pii/S0166685112000539

  18. Trypanosoma brucei mitochondrial respiratome: Composition and organization in procyclic form

    KAUST Repository

    Acestor, Nathalie

    2011-05-24

    The mitochondrial respiratory chain is comprised of four different protein complexes (I-IV), which are responsible for electron transport and generation of proton gradient in the mitochondrial intermembrane space. This proton gradient is then used by F oF 1-ATP synthase (complex V) to produce ATP by oxidative phosphorylation. In this study, the respiratory complexes I, II, and III were affinity purified from Trypanosoma brucei procyclic form cells and their composition was determined by mass spectrometry. The results along with those that we previously reported for complexes IV and V showed that the respiratome of Trypanosoma is divergent because many of its proteins are unique to this group of organisms. The studies also identified two mitochondrial subunit proteins of respiratory complex IV that are encoded by edited RNAs. Proteomics data from analyses of complexes purified using numerous tagged component proteins in each of the five complexes were used to generate the first predicted protein-protein interaction network of the Trypanosoma brucei respiratory chain. These results provide the first comprehensive insight into the unique composition of the respiratory complexes in Trypanosoma brucei, an early diverged eukaryotic pathogen. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Crystal structure of arginine methyltransferase 6 from Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Chongyuan Wang

    Full Text Available Arginine methylation plays vital roles in the cellular functions of the protozoan Trypanosoma brucei. The T. brucei arginine methyltransferase 6 (TbPRMT6 is a type I arginine methyltransferase homologous to human PRMT6. In this study, we report the crystal structures of apo-TbPRMT6 and its complex with the reaction product S-adenosyl-homocysteine (SAH. The structure of apo-TbPRMT6 displays several features that are different from those of type I PRMTs that were structurally characterized previously, including four stretches of insertion, the absence of strand β15, and a distinct dimerization arm. The comparison of the apo-TbPRMT6 and SAH-TbPRMT6 structures revealed the fine rearrangements in the active site upon SAH binding. The isothermal titration calorimetry results demonstrated that SAH binding greatly increases the affinity of TbPRMT6 to a substrate peptide derived from bovine histone H4. The western blotting and mass spectrometry results revealed that TbPRMT6 methylates bovine histone H4 tail at arginine 3 but cannot methylate several T. brucei histone tails. In summary, our results highlight the structural differences between TbPRMT6 and other type I PRMTs and reveal that the active site rearrangement upon SAH binding is important for the substrate binding of TbPRMT6.

  20. The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei.

    Science.gov (United States)

    Carvalho, Luis; Martínez-García, Marta; Pérez-Victoria, Ignacio; Manzano, José Ignacio; Yardley, Vanessa; Gamarro, Francisco; Pérez-Victoria, José M

    2015-10-01

    The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca(2+), and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. Molecular detection of the causative agent of white-nose syndrome on Rafinesque's big-eared bats (Corynorhinus rafinesquii) and two species of migratory bats in the southeastern USA.

    Science.gov (United States)

    Bernard, Riley F; Foster, Jeffrey T; Willcox, Emma V; Parise, Katy L; McCracken, Gary F

    2015-04-01

    Pseudogymnoascus destructans, the causal agent of white-nose syndrome (WNS), is responsible for widespread mortality of hibernating bats across eastern North America. To document P. destructans exposure and infections on bats active during winter in the southeastern US, we collected epidermal swabs from bats captured during winters 2012-13 and 2013-14 in mist nets set outside of hibernacula in Tennessee. Epidermal swab samples were collected from eight Rafinesque's big-eared bats (Corynorhinus rafinesquii), six eastern red bats (Lasiurus borealis), and three silver-hair bats (Lasionycteris noctivagans). Using real-time PCR methods, we identified DNA sequences of P. destructans from skin swabs of two Rafinesque's big-eared bats, two eastern red bats, and one silver-haired bat. This is the first detection of the WNS fungus on Rafinesque's big-eared bats and eastern red bats and the second record of the presence of the fungus on silver-haired bats.

  2. Intraclonal mating occurs during tsetse transmission of Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Ferris Vanessa

    2009-09-01

    Full Text Available Abstract Background Mating in Trypanosoma brucei is a non-obligatory event, triggered by the co-occurrence of different strains in the salivary glands of the vector. Recombinants that result from intra- rather than interclonal mating have been detected, but only in crosses of two different trypanosome strains. This has led to the hypothesis that when trypanosomes recognize a different strain, they release a diffusible factor or pheromone that triggers mating in any cell in the vicinity whether it is of the same or a different strain. This idea assumes that the trypanosome can recognize self and non-self, although there is as yet no evidence for the existence of mating types in T. brucei. Results We investigated intraclonal mating in T. b. brucei by crossing red and green fluorescent lines of a single strain, so that recombinant progeny can be detected in the fly by yellow fluorescence. For strain 1738, seven flies had both red and green trypanosomes in the salivary glands and, in three, yellow trypanosomes were also observed, although they could not be recovered for subsequent analysis. Nonetheless, both red and non-fluorescent clones from these flies had recombinant genotypes as judged by microsatellite and karyotype analyses, and some also had raised DNA contents, suggesting recombination or genome duplication. Strain J10 produced similar results indicative of intraclonal mating. In contrast, trypanosome clones recovered from other flies showed that genotypes can be transmitted with fidelity. When a yellow hybrid clone expressing both red and green fluorescent protein genes was transmitted, the salivary glands contained a mixture of fluorescent-coloured trypanosomes, but only yellow and red clones were recovered. While loss of the GFP gene in the red clones could have resulted from gene conversion, some of these clones showed loss of heterozygosity and raised DNA contents as in the other single strain transmissions. Our observations suggest

  3. The flagellum of Trypanosoma brucei: new tricks from an old dog

    Science.gov (United States)

    Ralston, Katherine S.; Hill, Kent L.

    2010-01-01

    African trypanosomes, i.e. Trypanosoma brucei and related sub-species, are devastating human and animal pathogens that cause significant human mortality and limit sustained economic development in sub-Saharan Africa. Trypanosoma brucei is a highly motile protozoan parasite and coordinated motility is central to both disease pathogenesis in the mammalian host and parasite development in the tsetse fly vector. Since motility is critical for parasite development and pathogenesis, understanding unique aspects of the T. brucei flagellum may uncover novel targets for therapeutic intervention in African sleeping sickness. Moreover, studies of conserved features of the T. brucei flagellum are directly relevant to understanding fundamental aspects of flagellum and cilium function in other eukaryotes, making T. brucei an important model system. The T. brucei flagellum contains a canonical 9 + 2 axoneme, together with additional features that are unique to kinetoplastids and a few closely-related organisms. Until recently, much of our knowledge of the structure and function of the trypanosome flagellum was based on analogy and inference from other organisms. There has been an explosion in functional studies in T. brucei in recent years, revealing conserved as well as novel and unexpected structural and functional features of the flagellum. Most notably, the flagellum has been found to be an essential organelle, with critical roles in parasite motility, morphogenesis, cell division and immune evasion. This review highlights recent discoveries on the T. brucei flagellum. PMID:18472102

  4. Rab23 is a flagellar protein in Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Field Mark C

    2011-06-01

    Full Text Available Abstract Background Rab small GTPases are important mediators of membrane transport, and orthologues frequently retain similar locations and functions, even between highly divergent taxa. In metazoan organisms Rab23 is an important negative regulator of Sonic hedgehog signaling and is crucial for correct development and differentiation of cellular lineages by virtue of an involvement in ciliary recycling. Previously, we reported that Trypanosoma brucei Rab23 localized to the nuclear envelope 1, which is clearly inconsistent with the mammalian location and function. As T. brucei is unicellular the potential that Rab23 has no role in cell signaling was possible. Here we sought to further investigate the role(s of Rab23 in T. brucei to determine if Rab23 was an example of a Rab protein with divergent function in distinct taxa. Methods/major findings The taxonomic distribution of Rab23 was examined and compared with the presence of flagella/cilia in representative taxa. Despite evidence for considerable secondary loss, we found a clear correlation between a conventional flagellar structure and the presence of a Rab23 orthologue in the genome. By epitope-tagging, Rab23 was localized and found to be present at the flagellum throughout the cell cycle. However, RNAi knockdown did not result in a flagellar defect, suggesting that Rab23 is not required for construction or maintenance of the flagellum. Conclusions The location of Rab23 at the flagellum is conserved between mammals and trypanosomes and the Rab23 gene is restricted to flagellated organisms. These data may suggest the presence of a Rab23-mediated signaling mechanism in trypanosomes.

  5. On Reciprocal Causation in the Evolutionary Process.

    Science.gov (United States)

    Svensson, Erik I

    2018-01-01

    Recent calls for a revision of standard evolutionary theory (SET) are based partly on arguments about the reciprocal causation. Reciprocal causation means that cause-effect relationships are bi-directional, as a cause could later become an effect and vice versa. Such dynamic cause-effect relationships raise questions about the distinction between proximate and ultimate causes, as originally formulated by Ernst Mayr. They have also motivated some biologists and philosophers to argue for an Extended Evolutionary Synthesis (EES). The EES will supposedly expand the scope of the Modern Synthesis (MS) and SET, which has been characterized as gene-centred, relying primarily on natural selection and largely neglecting reciprocal causation. Here, I critically examine these claims, with a special focus on the last conjecture. I conclude that reciprocal causation has long been recognized as important by naturalists, ecologists and evolutionary biologists working in the in the MS tradition, although it it could be explored even further. Numerous empirical examples of reciprocal causation in the form of positive and negative feedback are now well known from both natural and laboratory systems. Reciprocal causation have also been explicitly incorporated in mathematical models of coevolutionary arms races, frequency-dependent selection, eco-evolutionary dynamics and sexual selection. Such dynamic feedback were already recognized by Richard Levins and Richard Lewontin in their bok The Dialectical Biologist . Reciprocal causation and dynamic feedback might also be one of the few contributions of dialectical thinking and Marxist philosophy in evolutionary theory. I discuss some promising empirical and analytical tools to study reciprocal causation and the implications for the EES. Finally, I briefly discuss how quantitative genetics can be adapated to studies of reciprocal causation, constructive inheritance and phenotypic plasticity and suggest that the flexibility of this approach

  6. Detection and diagnosis of prions, the causative agent for the ...

    African Journals Online (AJOL)

    The technique is also a sensitive tool for studying and uncovering the mechanism of potential drugs that can inhibit or slow down the spread of TSE infection. It will advance the frontiers on the study of the mode of infection and conversion of prions and has significantly already contributed to the new paradigm that has ...

  7. Aspergillus species as emerging causative agents of onychomycosis.

    Science.gov (United States)

    Nouripour-Sisakht, S; Mirhendi, H; Shidfar, M R; Ahmadi, B; Rezaei-Matehkolaei, A; Geramishoar, M; Zarei, F; Jalalizand, N

    2015-06-01

    Onychomycosis is a common nail infection caused by dermatophytes, non-dermatophyte molds (NDM), and yeasts. Aspergillus species are emerging as increasing causes of toenail onychomycosis. The purpose of this study was species delineation of Aspergillus spp. isolated from patients with onychomycosis. During a period of one year (2012-2013), nail samples were collected from patients clinically suspected of onychomycosis and subjected to microscopic examination and culture. Species identification was performed based on macro- and micro-morphology of colonies. For precise species identification, PCR-amplification and sequencing of the beta-tubulin gene followed by BLAST queries were performed where required. A total of 463/2,292 (20.2%) tested nails were diagnosed with onychomycosis. Among the positive specimens, 154 cases (33.2%) were identified as saprophytic NDM onychomycosis, 135 (29.2%) of which were attributable to Aspergillus. Aspergillus species isolated from the infected nails included Aspergillus flavus (77.3%, n=119), Aspergillus niger (n=4), Aspergillus tubingensis (n=4), Aspergillus terreus (n=3), Aspergillus sydowii (n=2), Aspergillus spp. (n=2), and Aspergillus candidus (n=1). Among the patients diagnosed with onychomycosis due to Aspergillus (average patient age, 47.4 years), 40 had fingernail and 95 toenail involvement. The large toenails were most commonly affected. This study identified a markedly high occurrence of A. flavus, and this fungus appears to be an emerging cause of saprophytic onychomycosis in Iran. The study moreover highlights the necessity of differentiating between dermatophytic and non-dermatophytic nail infections for informed decisions on appropriate therapy. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  8. Large Truck Crash Causation Study (LTCCS)

    Data.gov (United States)

    Department of Transportation — The Large Truck* Crash Causation Study (LTCCS) is based on a three-year data collection project conducted by the Federal Motor Carrier Safety Administration (FMCSA)...

  9. Rationality, mental causation and social sciences

    Directory of Open Access Journals (Sweden)

    Mladenović Ivan

    2009-01-01

    Full Text Available The aim of this paper is to investigate the role of mental causation in the context of rational choice theory. The author defends psychological aspect of rational explanation against the challenge of contemporary reductive materialism.

  10. Pedestrian injury causation study (pedestrian accident typing)

    Science.gov (United States)

    1982-08-01

    A new computerized pedestrian accident typing procedure was tested on 1,997 cases from the Pedestrian Injury Causation Study (PICS). Two coding procedures were used to determine the effects of quantity and quality of information on accident typing ac...

  11. National Motor Vehicle Crash Causation Survey (NMVCCS)

    Data.gov (United States)

    Department of Transportation — The National Motor Vehicle Crash Causation Survey (NMVVCS) was a nationwide survey of crashes involving light passenger vehicles, with a focus on the factors related...

  12. Rationality, mental causation and social sciences

    OpenAIRE

    Mladenović Ivan

    2009-01-01

    The aim of this paper is to investigate the role of mental causation in the context of rational choice theory. The author defends psychological aspect of rational explanation against the challenge of contemporary reductive materialism.

  13. Telomeric expression sites are highly conserved in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Christiane Hertz-Fowler

    Full Text Available Subtelomeric regions are often under-represented in genome sequences of eukaryotes. One of the best known examples of the use of telomere proximity for adaptive purposes are the bloodstream expression sites (BESs of the African trypanosome Trypanosoma brucei. To enhance our understanding of BES structure and function in host adaptation and immune evasion, the BES repertoire from the Lister 427 strain of T. brucei were independently tagged and sequenced. BESs are polymorphic in size and structure but reveal a surprisingly conserved architecture in the context of extensive recombination. Very small BESs do exist and many functioning BESs do not contain the full complement of expression site associated genes (ESAGs. The consequences of duplicated or missing ESAGs, including ESAG9, a newly named ESAG12, and additional variant surface glycoprotein genes (VSGs were evaluated by functional assays after BESs were tagged with a drug-resistance gene. Phylogenetic analysis of constituent ESAG families suggests that BESs are sequence mosaics and that extensive recombination has shaped the evolution of the BES repertoire. This work opens important perspectives in understanding the molecular mechanisms of antigenic variation, a widely used strategy for immune evasion in pathogens, and telomere biology.

  14. Antitrypanosomal effect of methanolic extract of Zingiber officinale (ginger on Trypanosoma brucei brucei-infected Wistar mice

    Directory of Open Access Journals (Sweden)

    P. I. Kobo

    2014-10-01

    Full Text Available Aim: The study was carried out to determine the in vivo antitrypanosomal effect of methanolic extract of Zingiber officinale (ginger in Trypanosoma brucei brucei-infected mice. Materials and Methods: Twenty-five mice were randomly allocated into five groups of five animals each. Group I and II were given Tween 80 (1 ml/kg and diminazene aceturate (3.5 mg/kg to serve as untreated and treated controls, respectively. Groups III-V received the extract at 200, 400 and 800 mg/kg body weight, respectively. All treatments were given for 6 consecutive days and through the oral route. The mean body weight, mean survival period and daily level of parasitaemia were evaluated. Results: Acute toxicity showed the extract to be relatively safe. There was an insignificant increase in body weight and survival rate of mice treated with the extract. The level of parasitaemia in the extract treated groups was decreased. Conclusion: This study shows the in vivo potential of methanolic extract of Z. officinale in the treatment of trypanosomiasis.

  15. Minimum Information Loss Based Multi-kernel Learning for Flagellar Protein Recognition in Trypanosoma Brucei

    KAUST Repository

    Wang, Jim Jing-Yan; Gao, Xin

    2014-01-01

    for the purposes of both biological research and drug design. In this paper, we investigate computationally recognizing flagellar proteins in T. Brucei by pattern recognition methods. It is argued that an optimal decision function can be obtained as the difference

  16. Novel molecular mechanism for targeting the parasite Trypanosoma brucei with snake venom toxins

    DEFF Research Database (Denmark)

    Martos Esteban, Andrea; Laustsen, Andreas Hougaard; Carrington, Mark

    Trypanosoma brucei is a parasitic protozoan species capable to infecting insect vectors whose bite further produces African sleeping sickness inhuman beings. During parasites’extracellular lives in the mammalian host, its outer coat, mainly composedof Variable surface glycoproteins (VSGs)[2...

  17. Deciphering RNA Regulatory Elements Involved in the Developmental and Environmental Gene Regulation of Trypanosoma brucei.

    Science.gov (United States)

    Gazestani, Vahid H; Salavati, Reza

    2015-01-01

    Trypanosoma brucei is a vector-borne parasite with intricate life cycle that can cause serious diseases in humans and animals. This pathogen relies on fine regulation of gene expression to respond and adapt to variable environments, with implications in transmission and infectivity. However, the involved regulatory elements and their mechanisms of actions are largely unknown. Here, benefiting from a new graph-based approach for finding functional regulatory elements in RNA (GRAFFER), we have predicted 88 new RNA regulatory elements that are potentially involved in the gene regulatory network of T. brucei. We show that many of these newly predicted elements are responsive to both transcriptomic and proteomic changes during the life cycle of the parasite. Moreover, we found that 11 of predicted elements strikingly resemble previously identified regulatory elements for the parasite. Additionally, comparison with previously predicted motifs on T. brucei suggested the superior performance of our approach based on the current limited knowledge of regulatory elements in T. brucei.

  18. Mosaic VSGs and the scale of Trypanosoma brucei antigenic variation.

    Directory of Open Access Journals (Sweden)

    James P J Hall

    Full Text Available A main determinant of prolonged Trypanosoma brucei infection and transmission and success of the parasite is the interplay between host acquired immunity and antigenic variation of the parasite variant surface glycoprotein (VSG coat. About 0.1% of trypanosome divisions produce a switch to a different VSG through differential expression of an archive of hundreds of silent VSG genes and pseudogenes, but the patterns and extent of the trypanosome diversity phenotype, particularly in chronic infection, are unclear. We applied longitudinal VSG cDNA sequencing to estimate variant richness and test whether pseudogenes contribute to antigenic variation. We show that individual growth peaks can contain at least 15 distinct variants, are estimated computationally to comprise many more, and that antigenically distinct 'mosaic' VSGs arise from segmental gene conversion between donor VSG genes or pseudogenes. The potential for trypanosome antigenic variation is probably much greater than VSG archive size; mosaic VSGs are core to antigenic variation and chronic infection.

  19. Conceptual Analysis of Causation in Legal Discourse

    Czech Academy of Sciences Publication Activity Database

    Doležal, Adam; Doležal, Tomáš

    2014-01-01

    Roč. 10, č. 7 (2014), s. 53-70 ISSN 1857-7881 Institutional support: RVO:68378122 Keywords : causation * tort law * legal liability Subject RIV: AG - Legal Sciences http://www.eujournal.org/index.php/esj/article/view/2968

  20. Characterization of Trypanosoma brucei brucei S-adenosyl-L-methionine decarboxylase and its inhibition by Berenil, pentamidine and methylglyoxal bis(guanylhydrazone).

    Science.gov (United States)

    Bitonti, A J; Dumont, J A; McCann, P P

    1986-01-01

    Trypanosoma brucei brucei S-adenosyl-L-methionine (AdoMet) decarboxylase was found to be relatively insensitive to activation by putrescine as compared with the mammalian enzyme, being stimulated by only 50% over a 10,000-fold range of putrescine concentrations. The enzyme was not stimulated by up to 10 mM-Mg2+. The Km for AdoMet was 30 microM, similar to that of other eukaryotic AdoMet decarboxylases. T.b. brucei AdoMet decarboxylase activity was apparently irreversibly inhibited in vitro by Berenil and reversibly by pentamidine and methylglyoxal bis(guanylhydrazone). Berenil also inhibited trypanosomal AdoMet decarboxylase by 70% within 4 h after administration to infected rats and markedly increased the concentration of putrescine in trypanosomes that were exposed to the drug in vivo. Spermidine and spermine blocked the curative effect of Berenil on model mouse T.b. brucei infections. This effect of the polyamines was probably not due to reversal of Berenil's inhibitory effects on the AdoMet decarboxylase. PMID:3800910

  1. Wrongful life: the problem of causation.

    Science.gov (United States)

    Mason, J K

    2004-01-01

    The paper considers the status of the wrongful life action particularly in the light of the recent acceptance of such actions in continental Europe. It is considered that the hurdle of causation is still not adequately overcome in these cases and, in a search for an answer to the difficulty, the author re-examines the Canadian case of Cherry v Borsman. This case was originally thought of as one of wrongful life associated with a negligently performed abortion and the paper attempts to overcome the problems of causation by comparing and contrasting the roles of the genetic counsellor and the abortionist. While the attempt is by no means wholly successful, it also serves to draw attention to some significant differences between wrongful life actions based on physical and mental disability in the neonate.

  2. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene

    2017-04-17

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  3. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene; Mohamad Razali, Rozaimi; Kulmanov, Maxat; Hashish, Yasmeen; Bajic, Vladimir B.; Goncalves-Serra, Eva; Schoenmakers, Nadia; Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

    2017-01-01

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  4. Exosome secretion affects social motility in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Dror Eliaz

    2017-03-01

    Full Text Available Extracellular vesicles (EV secreted by pathogens function in a variety of biological processes. Here, we demonstrate that in the protozoan parasite Trypanosoma brucei, exosome secretion is induced by stress that affects trans-splicing. Following perturbations in biogenesis of spliced leader RNA, which donates its spliced leader (SL exon to all mRNAs, or after heat-shock, the SL RNA is exported to the cytoplasm and forms distinct granules, which are then secreted by exosomes. The exosomes are formed in multivesicular bodies (MVB utilizing the endosomal sorting complexes required for transport (ESCRT, through a mechanism similar to microRNA secretion in mammalian cells. Silencing of the ESCRT factor, Vps36, compromised exosome secretion but not the secretion of vesicles derived from nanotubes. The exosomes enter recipient trypanosome cells. Time-lapse microscopy demonstrated that cells secreting exosomes or purified intact exosomes affect social motility (SoMo. This study demonstrates that exosomes are delivered to trypanosome cells and can change their migration. Exosomes are used to transmit stress signals for communication between parasites.

  5. Meiosis and haploid gametes in the pathogen Trypanosoma brucei.

    Science.gov (United States)

    Peacock, Lori; Bailey, Mick; Carrington, Mark; Gibson, Wendy

    2014-01-20

    In eukaryote pathogens, sex is an important driving force in spreading genes for drug resistance, pathogenicity, and virulence. For the parasitic trypanosomes that cause African sleeping sickness, mating occurs during transmission by the tsetse vector and involves meiosis, but haploid gametes have not yet been identified. Here, we show that meiosis is a normal part of development in the insect salivary glands for all subspecies of Trypanosoma brucei, including the human pathogens. By observing insect-derived trypanosomes during the window of peak expression of meiosis-specific genes, we identified promastigote-like (PL) cells that interacted with each other via their flagella and underwent fusion, as visualized by the mixing of cytoplasmic red and green fluorescent proteins. PL cells had a short, wide body, a very long anterior flagellum, and either one or two kinetoplasts, but only the anterior kinetoplast was associated with the flagellum. Measurement of nuclear DNA contents showed that PL cells were haploid relative to diploid metacyclics. Trypanosomes are among the earliest diverging eukaryotes, and our results support the hypothesis that meiosis and sexual reproduction are ubiquitous in eukaryotes and likely to have been early innovations. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Cancer in the parasitic protozoans Trypanosoma brucei and Toxoplasma gondii.

    Science.gov (United States)

    Lun, Zhao-Rong; Lai, De-Hua; Wen, Yan-Zi; Zheng, Ling-Ling; Shen, Ji-Long; Yang, Ting-Bo; Zhou, Wen-Liang; Qu, Liang-Hu; Hide, Geoff; Ayala, Francisco J

    2015-07-21

    Cancer is a general name for more than 100 malignant diseases. It is postulated that all cancers start from a single abnormal cell that grows out of control. Untreated cancers can cause serious consequences and deaths. Great progress has been made in cancer research that has significantly improved our knowledge and understanding of the nature and mechanisms of the disease, but the origins of cancer are far from being well understood due to the limitations of suitable model systems and to the complexities of the disease. In view of the fact that cancers are found in various species of vertebrates and other metazoa, here, we suggest that cancer also occurs in parasitic protozoans such as Trypanosoma brucei, a blood parasite, and Toxoplasma gondii, an obligate intracellular pathogen. Without treatment, these protozoan cancers may cause severe disease and death in mammals, including humans. The simpler genomes of these single-cell organisms, in combination with their complex life cycles and fascinating life cycle differentiation processes, may help us to better understand the origins of cancers and, in particular, leukemias.

  7. Neural Damage in Experimental Trypanosoma brucei gambiense Infection: The Suprachiasmatic Nucleus

    Directory of Open Access Journals (Sweden)

    Chiara Tesoriero

    2018-02-01

    Full Text Available Trypanosoma brucei (T. b. gambiense is the parasite subspecies responsible for most reported cases of human African trypanosomiasis (HAT or sleeping sickness. This severe infection leads to characteristic disruption of the sleep-wake cycle, recalling attention on the circadian timing system. Most animal models of the disease have been hitherto based on infection of laboratory rodents with the T. b. brucei subspecies, which is not infectious to humans. In these animal models, functional, rather than structural, alterations of the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN, have been reported. Information on the SCN after infection with the human pathogenic T. b. gambiense is instead lacking. The present study was aimed at the examination of the SCN after T. b. gambiense infection of a susceptible rodent, the multimammate mouse, Mastomys natalensis, compared with T. b. brucei infection of the same host species. The animals were examined at 4 and 8 weeks post-infection, when parasites (T. b. gambiense or T. b. brucei were detected in the brain parenchyma, indicating that the disease was in the encephalitic stage. Neuron and astrocyte changes were examined with Nissl staining, immunophenotyping and quantitative analyses. Interestingly, significant neuronal loss (about 30% reduction was documented in the SCN during the progression of T. b. gambiense infection. No significant neuronal density changes were found in the SCN of T. b. brucei-infected animals. Neuronal cell counts in the hippocampal dentate gyrus of T. b. gambiense-infected M. natalensis did not point out significant changes, indicating that no widespread neuron loss had occurred in the brain. Marked activation of astrocytes was detected in the SCN after both T. b. gambiense and T. b. brucei infections. Altogether the findings reveal that neurons of the biological clock are highly susceptible to the infection caused by human pathogenic African trypanosomes

  8. Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents

    Directory of Open Access Journals (Sweden)

    Jean J. Vanden Eynde

    2016-04-01

    Full Text Available A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b. subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54 and a chloroquine-resistant strain (K1. The in vitro cytotoxicity was determined against rat myoblast cells (L6. Seven compounds (5, 6, 10, 11, 12, 14, 15 showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50 in the nanomolar range (IC50 = 1–96 nM. None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11 were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002 or drug-resistant (KETRI 2538 and KETRI 1992 clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents.

  9. Causation and Responsibility: A New Direction

    Directory of Open Access Journals (Sweden)

    Matt Mortellaro

    2009-04-01

    Full Text Available In “Property, Causality, and Liability” and “Causation and Aggression,” Hans-Hermann Hoppe and Stephan Kinsella & Patrick Tinsley, respectively, argue against the Rothbardian position on criminal liability, especially with regard to the issue of incitement. This essay takes a critical look at the suggested approaches of both and attempts to defend the Rothbardian position on incitement from their criticisms. Further, this essay examines the views of Walter Block on incitement and attempts to correct inconsistencies in his position with regard to murder contracts and threats.

  10. Arterial blood pressure changes in acute T. brucei infection of dogs ...

    African Journals Online (AJOL)

    The aim of this study is to find out the usefulness of serial arterial blood pressure measurements in predicting severity and outcome of acute Trypanosoma brucei infection in dogs. Twenty adult dogs of mixed sexes and aged between 2 and 5 years were used for this study. The dogs were of good cardiac health and were ...

  11. The promoter for a variant surface glycoprotein gene expression site in Trypanosoma brucei

    NARCIS (Netherlands)

    Zomerdijk, J. C.; Ouellette, M.; ten Asbroek, A. L.; Kieft, R.; Bommer, A. M.; Clayton, C. E.; Borst, P.

    1990-01-01

    The variant-specific surface glycoprotein (VSG) gene 221 of Trypanosoma brucei is transcribed as part of a 60 kb expression site (ES). We have identified the promoter controlling this multigene transcription unit by the use of 221 chromosome-enriched DNA libraries and VSG gene 221 expression site

  12. Procyclic Trypanosoma brucei do not use Krebs cycle activity for energy generation

    NARCIS (Netherlands)

    Weelden, van S.W.H.; Fast, B.; Vogt, A.; Meer, van der P.; Saas, J.; Hellemond, van J.J.; Tielens, A.G.M.; Boshart, M.

    2003-01-01

    The importance of a functional Krebs cycle for energy generation in the procyclic stage of Trypanosoma brucei was investigated under physiological conditions during logarithmic phase growth of a pleomorphic parasite strain. Wild type procyclic cells and mutants with targeted deletion of the gene

  13. Interactions among Trypanosoma brucei RAD51 paralogues in DNA repair and antigenic variation

    Science.gov (United States)

    Dobson, Rachel; Stockdale, Christopher; Lapsley, Craig; Wilkes, Jonathan; McCulloch, Richard

    2011-01-01

    Homologous recombination in Trypanosoma brucei is used for moving variant surface glycoprotein (VSG) genes into expression sites during immune evasion by antigenic variation. A major route for such VSG switching is gene conversion reactions in which RAD51, a universally conserved recombinase, catalyses homology-directed strand exchange. In any eukaryote, RAD51-directed strand exchange in vivo is mediated by further factors, including RAD51-related proteins termed Rad51 paralogues. These appear to be ubiquitously conserved, although their detailed roles in recombination remain unclear. In T. brucei, four putative RAD51 paralogue genes have been identified by sequence homology. Here we show that all four RAD51 paralogues act in DNA repair, recombination and RAD51 subnuclear dynamics, though not equivalently, while mutation of only one RAD51 paralogue gene significantly impedes VSG switching. We also show that the T. brucei RAD51 paralogues interact, and that the complexes they form may explain the distinct phenotypes of the mutants as well as observed expression interdependency. Finally, we document the Rad51 paralogues that are encoded by a wide range of protists, demonstrating that the Rad51 paralogue repertoire in T. brucei is unusually large among microbial eukaryotes and that one member of the protein family corresponds with a key, conserved eukaryotic Rad51 paralogue. PMID:21615552

  14. Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei

    Czech Academy of Sciences Publication Activity Database

    Alkhaldi, A.A.M.; Martínek, Jan; Panicucci, Brian; Dardonville, C.; Zíková, Alena; de Koning, H.P.

    2016-01-01

    Roč. 6, č. 1 (2016), s. 23-34 ISSN 2211-3207 R&D Projects: GA MŠk LL1205 Institutional support: RVO:60077344 Keywords : Trypanosoma brucei * mitochondrion * FoF1 ATPase * succinate dehydrogenase * phosphonium salt * SDH complex Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.809, year: 2016

  15. Fibrosis and carcinoid syndrome: from causation to future therapy.

    Science.gov (United States)

    Druce, Maralyn; Rockall, Andrea; Grossman, Ashley B

    2009-05-01

    Carcinoid tumors are part of a heterogeneous group of gastrointestinal and pancreatic endocrine tumors that are characterized by their capacity to produce and secrete hormones, 5-hydroxytryptamine, tachykinins and other mediators. These substances are thought to be responsible for the collection of symptoms, which include diarrhea, flushing and wheezing, that is known as carcinoid syndrome. Fibrosis that occurs either local to or distant from the primary tumor is one of the hallmarks of carcinoid tumors that originate from the midgut. The fibrotic process can occur in the mesentery as a desmoplastic response and may lead to obstruction of the small bowel, but it can also occur in the lungs, skin or retroperitoneum. Importantly, up to one-third of patients develop cardiac valvulopathy. One or more products that are secreted by the tumor and enter into the circulation are likely to have a role in this process. This Review discusses the incidence and prevalence of fibrosis in carcinoid syndrome and explores evidence to date for causative agents, in particular the roles of 5-hydroxytryptamine and elements of the downstream signaling pathway. Improved understanding of the etiology of carcinoid-tumor-related fibrosis may lead to better treatments for this condition than those we currently have.

  16. Essential Assembly Factor Rpf2 Forms Novel Interactions within the 5S RNP in Trypanosoma brucei.

    Science.gov (United States)

    Kamina, Anyango D; Jaremko, Daniel; Christen, Linda; Williams, Noreen

    2017-01-01

    Ribosome biogenesis is a highly complex and conserved cellular process that is responsible for making ribosomes. During this process, there are several assembly steps that function as regulators to ensure proper ribosome formation. One of these steps is the assembly of the 5S ribonucleoprotein particle (5S RNP) in the central protuberance of the 60S ribosomal subunit. In eukaryotes, the 5S RNP is composed of 5S rRNA, ribosomal proteins L5 and L11, and assembly factors Rpf2 and Rrs1. Our laboratory previously showed that in Trypanosoma brucei , the 5S RNP is composed of 5S rRNA, L5, and trypanosome-specific RNA binding proteins P34 and P37. In this study, we characterize an additional component of the 5S RNP, the T. brucei homolog of Rpf2. This is the first study to functionally characterize interactions mediated by Rpf2 in an organism other than fungi. T . brucei Rpf2 (TbRpf2) was identified from tandem affinity purification using extracts prepared from protein A-tobacco etch virus (TEV)-protein C (PTP)-tagged L5, P34, and P37 cell lines, followed by mass spectrometry analysis. We characterized the binding interactions between TbRpf2 and the previously characterized members of the T. brucei 5S RNP. Our studies show that TbRpf2 mediates conserved binding interactions with 5S rRNA and L5 and that TbRpf2 also interacts with trypanosome-specific proteins P34 and P37. We performed RNA interference (RNAi) knockdown of TbRpf2 and showed that this protein is essential for the survival of the parasites and is critical for proper ribosome formation. These studies provide new insights into a critical checkpoint in the ribosome biogenesis pathway in T. brucei . IMPORTANCE Trypanosoma brucei is the parasitic protozoan that causes African sleeping sickness. Ribosome assembly is essential for the survival of this parasite through the different host environments it encounters during its life cycle. The assembly of the 5S ribonucleoprotein particle (5S RNP) functions as one of

  17. Novel 1,2-dihydroquinazolin-2-ones: Design, synthesis, and biological evaluation against Trypanosoma brucei.

    Science.gov (United States)

    Pham, ThanhTruc; Walden, Madeline; Butler, Christopher; Diaz-Gonzalez, Rosario; Pérez-Moreno, Guiomar; Ceballos-Pérez, Gloria; Gomez-Pérez, Veronica; García-Hernández, Raquel; Zecca, Henry; Krakoff, Emma; Kopec, Brian; Ichire, Ogar; Mackenzie, Caden; Pitot, Marika; Ruiz, Luis Miguel; Gamarro, Francisco; González-Pacanowska, Dolores; Navarro, Miguel; Dounay, Amy B

    2017-08-15

    In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to-lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability. The SAR developed on 24 provides new directions for further optimization of this novel scaffold for anti-trypanosomal drug discovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. The Development of the Causative Construction in Persian Child Language

    Science.gov (United States)

    Family, Neiloufar; Allen, Shanley E. M.

    2015-01-01

    The acquisition of systematic patterns and exceptions in different languages can be readily examined using the causative construction. Persian allows four types of causative structures, including one productive multiword structure (i.e. the light verb construction). In this study, we examine the development of all four structures in Persian child…

  19. Mental causation and Searle's impossible conception of unconscious intentionality

    NARCIS (Netherlands)

    Meijers, A.W.M.

    2000-01-01

    In my article I evaluate Searle's account of mental causation, in particular his account of the causal efficacy of unconscious intentional states. I argue that top-down causation and overdetermination are unsolved problems in Searle's philosophy of mind, despite his assurances to the contrary. I

  20. Mitochondrial tRNA import in Trypanosoma brucei is independent of thiolation and the Rieske protein

    Czech Academy of Sciences Publication Activity Database

    Paris, Zdeněk; RUBIO, M. A. T.; Lukeš, Julius; Alfonzo, J. D.

    2009-01-01

    Roč. 15, č. 7 (2009), s. 1398-1406 ISSN 1355-8382 R&D Projects: GA ČR GA204/06/1558; GA MŠk LC07032; GA MŠk 2B06129 Institutional research plan: CEZ:AV0Z60220518 Keywords : T. brucei * tRNA import * 2-thiolation * RIC * Rieske * Fe-S cluster Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.198, year: 2009

  1. A Trypanosoma brucei kinesin heavy chain promotes parasite growth by triggering host arginase activity.

    Directory of Open Access Journals (Sweden)

    Géraldine De Muylder

    2013-10-01

    Full Text Available In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells.By screening a cDNA library of T. brucei with an antibody neutralizing the arginase-inducing activity of parasite released factors, we identified a Kinesin Heavy Chain isoform, termed TbKHC1, as responsible for this effect. Following interaction with mouse myeloid cells, natural or recombinant TbKHC1 triggered SIGN-R1 receptor-dependent induction of IL-10 production, resulting in arginase-1 activation concomitant with reduction of nitric oxide (NO synthase activity. This TbKHC1 activity was IL-4Rα-independent and did not mirror M2 activation of myeloid cells. As compared to wild-type T. brucei, infection by TbKHC1 KO parasites was characterized by strongly reduced parasitaemia and prolonged host survival time. By treating infected mice with ornithine or with NO synthase inhibitor, we observed that during the first wave of parasitaemia the parasite growth-promoting effect of TbKHC1-mediated arginase activation resulted more from increased polyamine production than from reduction of NO synthesis. In late stage infection, TbKHC1-mediated reduction of NO synthesis appeared to contribute to liver damage linked to shortening of host survival time.A kinesin heavy chain released by T. brucei induces IL-10 and arginase-1 through SIGN-R1 signaling in myeloid cells, which promotes early trypanosome growth and favors parasite settlement in the host. Moreover, in the late stage of infection, the inhibition of NO synthesis by TbKHC1 contributes to liver pathogenicity.

  2. An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Juan P de Macêdo

    2015-05-01

    Full Text Available Elucidating the mechanism of action of trypanocidal compounds is an important step in the development of more efficient drugs against Trypanosoma brucei. In a screening approach using an RNAi library in T. brucei bloodstream forms, we identified a member of the mitochondrial carrier family, TbMCP14, as a prime candidate mediating the action of a group of anti-parasitic choline analogs. Depletion of TbMCP14 by inducible RNAi in both bloodstream and procyclic forms increased resistance of parasites towards the compounds by 7-fold and 3-fold, respectively, compared to uninduced cells. In addition, down-regulation of TbMCP14 protected bloodstream form mitochondria from a drug-induced decrease in mitochondrial membrane potential. Conversely, over-expression of the carrier in procyclic forms increased parasite susceptibility more than 13-fold. Metabolomic analyses of parasites over-expressing TbMCP14 showed increased levels of the proline metabolite, pyrroline-5-carboxylate, suggesting a possible involvement of TbMCP14 in energy production. The generation of TbMCP14 knock-out parasites showed that the carrier is not essential for survival of T. brucei bloodstream forms, but reduced parasite proliferation under standard culture conditions. In contrast, depletion of TbMCP14 in procyclic forms resulted in growth arrest, followed by parasite death. The time point at which parasite proliferation stopped was dependent on the major energy source, i.e. glucose versus proline, in the culture medium. Together with our findings that proline-dependent ATP production in crude mitochondria from TbMCP14-depleted trypanosomes was reduced compared to control mitochondria, the study demonstrates that TbMCP14 is involved in energy production in T. brucei. Since TbMCP14 belongs to a trypanosomatid-specific clade of mitochondrial carrier family proteins showing very poor similarity to mitochondrial carriers of mammals, it may represent an interesting target for drug

  3. A neural network model of causative actions

    Directory of Open Access Journals (Sweden)

    Jeremy eLee-Hand

    2015-06-01

    Full Text Available A common idea in models of action representation is that actions are represented in terms of their perceptual effects (see e.g. Prinz, 1997; Hommel et al., 2001; Sahin et al., 2007; Umilta et al., 2008; Hommel et al., 2013. In this paper we extend existing models of effect-based action representations to account for a novel distinction. Some actions bring about effects that are independent events in their own right: for instance, if John 'smashes' a cup, he brings about the event of 'the cup smashing'. Other actions do not bring about such effects. For instance, if John 'grabs' a cup, this action does not cause the cup to 'do' anything: a grab action has well-defined perceptual effects, but these are not registered by the perceptual system that detects independent events involving external objects in the world. In our model, effect-based actions are implemented in several distinct neural circuits, which are organised into a hierarchy based on the complexity of their associated perceptual effects. The circuit at the top of this hierarchy is responsible for actions that bring about independently perceivable events. This circuit receives input from the perceptual module that recognises arbitrary events taking place in the world, and learns movements that reliably cause such events. We assess our model against existing experimental observations about effect-based motor representations, and make some novel experimental predictions. We also consider the possibility that the 'causative actions' circuit in our model can be identified with a motor pathway reported in other work, specialising in 'functional' actions on manipulable tools (Bub et al., 2008; Binkofski and Buxbaum, 2013.

  4. A neural network model of causative actions.

    Science.gov (United States)

    Lee-Hand, Jeremy; Knott, Alistair

    2015-01-01

    A common idea in models of action representation is that actions are represented in terms of their perceptual effects (see e.g., Prinz, 1997; Hommel et al., 2001; Sahin et al., 2007; Umiltà et al., 2008; Hommel, 2013). In this paper we extend existing models of effect-based action representations to account for a novel distinction. Some actions bring about effects that are independent events in their own right: for instance, if John smashes a cup, he brings about the event of the cup smashing. Other actions do not bring about such effects. For instance, if John grabs a cup, this action does not cause the cup to "do" anything: a grab action has well-defined perceptual effects, but these are not registered by the perceptual system that detects independent events involving external objects in the world. In our model, effect-based actions are implemented in several distinct neural circuits, which are organized into a hierarchy based on the complexity of their associated perceptual effects. The circuit at the top of this hierarchy is responsible for actions that bring about independently perceivable events. This circuit receives input from the perceptual module that recognizes arbitrary events taking place in the world, and learns movements that reliably cause such events. We assess our model against existing experimental observations about effect-based motor representations, and make some novel experimental predictions. We also consider the possibility that the "causative actions" circuit in our model can be identified with a motor pathway reported in other work, specializing in "functional" actions on manipulable tools (Bub et al., 2008; Binkofski and Buxbaum, 2013).

  5. Structure of a Trypanosoma brucei α/β-hydrolase fold protein with unknown function

    International Nuclear Information System (INIS)

    Merritt, Ethan A.; Holmes, Margaret; Buckner, Frederick S.; Van Voorhis, Wesley C.; Quartly, Erin; Phizicky, Eric M.; Lauricella, Angela; Luft, Joseph; DeTitta, George; Neely, Helen; Zucker, Frank; Hol, Wim G. J.

    2008-01-01

    T. brucei gene Tb10.6k15.0140 codes for an α/β-hydrolase fold protein of unknown function. The 2.2 Å crystal structure shows that members of this sequence family retain a conserved Ser residue at the expected site of a catalytic nucleophile, but that trypanosomatid sequences lack structural homologs for the other expected residues of the catalytic triad. The structure of a structural genomics target protein, Tbru020260AAA from Trypanosoma brucei, has been determined to a resolution of 2.2 Å using multiple-wavelength anomalous diffraction at the Se K edge. This protein belongs to Pfam sequence family PF08538 and is only distantly related to previously studied members of the α/β-hydrolase fold family. Structural superposition onto representative α/β-hydrolase fold proteins of known function indicates that a possible catalytic nucleophile, Ser116 in the T. brucei protein, lies at the expected location. However, the present structure and by extension the other trypanosomatid members of this sequence family have neither sequence nor structural similarity at the location of other active-site residues typical for proteins with this fold. Together with the presence of an additional domain between strands β6 and β7 that is conserved in trypanosomatid genomes, this suggests that the function of these homologs has diverged from other members of the fold family

  6. Identification of TOEFAZ1-interacting proteins reveals key regulators of Trypanosoma brucei cytokinesis.

    Science.gov (United States)

    Hilton, Nicholas A; Sladewski, Thomas E; Perry, Jenna A; Pataki, Zemplen; Sinclair-Davis, Amy N; Muniz, Richard S; Tran, Holly L; Wurster, Jenna I; Seo, Jiwon; de Graffenried, Christopher L

    2018-05-21

    The protist parasite Trypanosoma brucei is an obligate extracellular pathogen that retains its highly-polarized morphology during cell division and has evolved a novel cytokinetic process independent of non-muscle myosin II. The polo-like kinase homolog TbPLK is essential for transmission of cell polarity during division and for cytokinesis. We previously identified a putative TbPLK substrate named Tip of the Extending FAZ 1 (TOEFAZ1) as an essential kinetoplastid-specific component of the T. brucei cytokinetic machinery. We performed a proximity-dependent biotinylation (BioID) screen using TOEFAZ1 as a means to identify additional proteins that are involved in cytokinesis. Using quantitative proteomic methods, we identified nearly 500 TOEFAZ1-proximal proteins and characterized 59 in further detail. Among the candidates, we identified an essential putative phosphatase that regulates the expression level and localization of both TOEFAZ1 and TbPLK, a previously uncharacterized protein that is necessary for the assembly of a new cell posterior, and a microtubule plus-end directed orphan kinesin that is required for completing cleavage furrow ingression. The identification of these proteins provides new insight into T. brucei cytokinesis and establishes TOEFAZ1 as a key component of this essential and uniquely-configured process in kinetoplastids. This article is protected by copyright. All rights reserved. © 2018 John Wiley & Sons Ltd.

  7. Novel sterol metabolic network of Trypanosoma brucei procyclic and bloodstream forms

    Science.gov (United States)

    Nes, Craigen R.; Singha, Ujjal K.; Liu, Jialin; Ganapathy, Kulothungan; Villalta, Fernando; Waterman, Michael R.; Lepesheva, Galina I.; Chaudhuri, Minu; Nes, W. David

    2012-01-01

    Trypanosoma brucei is the protozoan parasite that causes African trypanosomiasis, a neglected disease of people and animals. Co-metabolite analysis, labelling studies using [methyl-2H3]-methionine and substrate/product specificities of the cloned 24-SMT (sterol C24-methyltransferase) and 14-SDM (sterol C14-demethylase) from T. brucei afforded an uncommon sterol metabolic network that proceeds from lanosterol and 31-norlanosterol to ETO [ergosta-5,7,25(27)-trien-3β-ol], 24-DTO [dimethyl ergosta-5,7,25(27)-trienol] and ergosterol [ergosta-5,7,22(23)-trienol]. To assess the possible carbon sources of ergosterol biosynthesis, specifically 13C-labelled specimens of lanosterol, acetate, leucine and glucose were administered to T. brucei and the 13C distributions found were in accord with the operation of the acetate–mevalonate pathway, with leucine as an alternative precursor, to ergostenols in either the insect or bloodstream form. In searching for metabolic signatures of procyclic cells, we observed that the 13C-labelling treatments induce fluctuations between the acetyl-CoA (mitochondrial) and sterol (cytosolic) synthetic pathways detected by the progressive increase in 13C-ergosterol production (control sterol synthesis that is further fluctuated in the cytosol, yielding distinct sterol profiles in relation to cell demands on growth. PMID:22176028

  8. Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness.

    Science.gov (United States)

    Abdeen, Sanofar; Salim, Nilshad; Mammadova, Najiba; Summers, Corey M; Goldsmith-Pestana, Karen; McMahon-Pratt, Diane; Schultz, Peter G; Horwich, Arthur L; Chapman, Eli; Johnson, Steven M

    2016-11-01

    Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis-HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter-screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC 50 =7.9 and 3.1μM, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Methanolic leaf extract of Moringa oleifera improves the survivability rate, weight gain and histopathological changes of Wister rats infected with Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    A. Aremu

    2018-04-01

    Full Text Available Trypanosomosis is a major disease of Man and animals. This study investigated the effect of Moringa oleifera leaf extract on the survivability rate, weight gain and histopathological changes of Wister rats experimentally infected with Trypanosoma brucei. A total of thirty (30 rats randomly divided into six groups (A-F. Rats in group A remain untreated and uninfected while rates in group F were infected and untreated. Rats in groups B and C were treated with Moringa oleifera leave extract orally at 200 mg/kg for 14 days pre-infection and the treatment continued in B but not in C. Rats in groups D and E were treated with the extract orally for ninety days at 200 mg/kg (pre-infection and the treatment continued in D but not in E. The weight changes in all rats were monitored weekly. Rats in B-F groups were infected with 3 × 106 of Trypanosoma brucei per mL of blood. The results showed that all the infected rats died but the treated group survived extra two days when compared with the untreated group. The percentage weight gain of rats in groups B and C was high (23.9% and 21.1% respectively as against negative control (17.2%. The groups with chronic administration of the extract (D and E had a lower percentage weight gains (64.3% and 60.3% respectively when compared with negative control (71.8%. The histopathology results showed that the extract was a potent ameliorative agent that reduced neuronal degeneration and congestion in the brain and the spleen of the infected rats respectively. In conclusion, Moringa Oleifera leave extract has mitigative effects on the pathogenesis of trypanosomosis. Keywords: Histopathology, Moringa, Survivability, Trypanosoma, Weight, Wister rats

  10. Changes in blood sugar levels of rats experimentally infected with Trypanosoma brucei and treated with imidocarb dipropionate and diminazene aceturate

    Directory of Open Access Journals (Sweden)

    Nwoha Rosemary Ijeoma Ogechi

    2016-01-01

    Full Text Available Objective: To determine the effect of Trypanosoma brucei (T. brucei on blood sugar level of infected rats. Methods: The experiment was done with 42 albino rats grouped into 3 groups of 14 members each. Group A was uninfected (control group, Group B was infected with T. brucei and treated with diminazene aceturate, and Group C was infected with T. brucei and treated with imidocarb dipropionate. Blood samples were collected from the media canthus of the experimental rats on Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 for the assessment of change in blood sugar levels. The blood sugar levels were determined with a glucometer (Accu-chek active serial No. GN: 10023338. Results: By 4 to 5 days post infection, there was a significant increase (P 0.05 was observed in the groups when compared with the control group till Day 12 of the experiment. Conclusions: T. brucei caused a significant increase in blood sugar of infected rats.

  11. Perceived Role Of Dietary Factors In Cancer Causation And ...

    African Journals Online (AJOL)

    Perceived Role Of Dietary Factors In Cancer Causation And Prevention Among ... The impact of cancer on patients, care givers and family could be ... as well as social support programmes including subsidized cancer-limiting feeding of ...

  12. Coarse-graining as a downward causation mechanism

    Science.gov (United States)

    Flack, Jessica C.

    2017-11-01

    Downward causation is the controversial idea that `higher' levels of organization can causally influence behaviour at `lower' levels of organization. Here I propose that we can gain traction on downward causation by being operational and examining how adaptive systems identify regularities in evolutionary or learning time and use these regularities to guide behaviour. I suggest that in many adaptive systems components collectively compute their macroscopic worlds through coarse-graining. I further suggest we move from simple feedback to downward causation when components tune behaviour in response to estimates of collectively computed macroscopic properties. I introduce a weak and strong notion of downward causation and discuss the role the strong form plays in the origins of new organizational levels. I illustrate these points with examples from the study of biological and social systems and deep neural networks. This article is part of the themed issue 'Reconceptualizing the origins of life'.

  13. Nocardia harenae, an uncommon causative organism of mycetoma: report on two patients.

    Science.gov (United States)

    Kresch-Tronik, Nicole S; Carrillo-Casas, Erika M; Arenas, Roberto; Atoche, Carlos; Ochoa-Carrera, Luis A; Xicohtencatl-Cortes, Juan; Manjarrez-Hernández, Angel H; Hernández-Castro, Rigoberto

    2012-08-01

    Mycetoma is the most frequently diagnosed deep mycosis in Mexico and is caused, in 86% of cases, by Nocardia brasiliensis. Worldwide, Nocardia harenae has not been previously reported as a causative agent of human mycetoma. Herein we report, to our knowledge, the first two human cases of mycetoma due to N. harenae in a clinical setting. The strains were identified by phenotypic and molecular techniques. Both cases were characterized by long-lasting mycetoma that had previously been failed to be cured and had shown resistance to therapy. However, in our hospital, a multidrug therapy proved to be effective in these cases.

  14. Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice.

    Directory of Open Access Journals (Sweden)

    Jean Rodgers

    Full Text Available Invasion of the central nervous system (CNS by African trypanosomes represents a critical step in the development of human African trypanosomiasis. In both clinical cases and experimental mouse infections it has been demonstrated that predisposition to CNS invasion is associated with a type 1 systemic inflammatory response. Using the Trypanosoma brucei brucei GVR35 experimental infection model, we demonstrate that systemic delivery of the counter-inflammatory cytokine IL-10 lowers plasma IFN-γ and TNF-α concentrations, CNS parasitosis and ameliorates neuro-inflammatory pathology and clinical symptoms of disease. The results provide evidence that CNS invasion may be susceptible to immunological attenuation.

  15. Functional characterisation and drug target validation of a mitotic kinesin-13 in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Kuan Yoow Chan

    2010-08-01

    Full Text Available Mitotic kinesins are essential for faithful chromosome segregation and cell proliferation. Therefore, in humans, kinesin motor proteins have been identified as anti-cancer drug targets and small molecule inhibitors are now tested in clinical studies. Phylogenetic analyses have assigned five of the approximately fifty kinesin motor proteins coded by Trypanosoma brucei genome to the Kinesin-13 family. Kinesins of this family have unusual biochemical properties because they do not transport cargo along microtubules but are able to depolymerise microtubules at their ends, therefore contributing to the regulation of microtubule length. In other eukaryotic genomes sequenced to date, only between one and three Kinesin-13s are present. We have used immunolocalisation, RNAi-mediated protein depletion, biochemical in vitro assays and a mouse model of infection to study the single mitotic Kinesin-13 in T. brucei. Subcellular localisation of all five T. brucei Kinesin-13s revealed distinct distributions, indicating that the expansion of this kinesin family in kinetoplastids is accompanied by functional diversification. Only a single kinesin (TbKif13-1 has a nuclear localisation. Using active, recombinant TbKif13-1 in in vitro assays we experimentally confirm the depolymerising properties of this kinesin. We analyse the biological function of TbKif13-1 by RNAi-mediated protein depletion and show its central role in regulating spindle assembly during mitosis. Absence of the protein leads to abnormally long and bent mitotic spindles, causing chromosome mis-segregation and cell death. RNAi-depletion in a mouse model of infection completely prevents infection with the parasite. Given its essential role in mitosis, proliferation and survival of the parasite and the availability of a simple in vitro activity assay, TbKif13-1 has been identified as an excellent potential drug target.

  16. Chemical characterisation of Nigerian red propolis and its biological activity against Trypanosoma Brucei.

    Science.gov (United States)

    Omar, Ruwida M K; Igoli, John; Gray, Alexander I; Ebiloma, Godwin Unekwuojo; Clements, Carol; Fearnley, James; Ebel, Ru Angeli Edrada; Zhang, Tong; De Koning, Harry P; Watson, David G

    2016-01-01

    A previous study showed the unique character of Nigerian red propolis from Rivers State, Nigeria (RSN), with regards to chemical composition and activity against Trypanosoma brucei in comparison with other African propolis. To carry out fractionation and biological testing of Nigerian propolis in order to isolate compounds with anti-trypanosomal activity. To compare the composition of the RSN propolis with the composition of Brazilian red propolis. Profiling was carried out using HPLC-UV-ELSD and HPLC-Orbitrap-FTMS on extracts of two samples collected from RSN with data extraction using MZmine software. Isolation was carried out by normal phase and reversed phase MPLC. Elucidation of the compounds with a purity > 95% was performed by 1D/2D NMR HRMS and HRLC-MS(n) . Ten phenolic compounds were isolated or in the case of liquiritigenin partially purified. Data for nine of these correlated with literature reports of known compounds i.e. one isoflavanone, calycosin (1); two flavanones, liquiritigenin (2) and pinocembrin (5); an isoflavan, vestitol (3); a pterocarpan, medicarpin (4); two prenylflavanones, 8-prenylnaringenin (7) and 6-prenylnaringenin (8); and two geranyl flavonoids, propolin D (9) and macarangin (10). The tenth was elucidated as a previously undescribed dihydrobenzofuran (6). The isolated compounds were tested against Trypanosoma brucei and displayed moderate to high activity. Some of the compounds tested had similar activity against wild type T. brucei and two strains displaying pentamidine resistance. Nigerian propolis from RSN has some similarities with Brazilian red propolis. The propolis displayed anti-trypanosomal activity at a potentially useful level. Copyright © 2015 John Wiley & Sons, Ltd.

  17. Trypanosoma brucei Co-opts NK Cells to Kill Splenic B2 B Cells.

    Directory of Open Access Journals (Sweden)

    Deborah Frenkel

    2016-07-01

    Full Text Available After infection with T. brucei AnTat 1.1, C57BL/6 mice lost splenic B2 B cells and lymphoid follicles, developed poor parasite-specific antibody responses, lost weight, became anemic and died with fulminating parasitemia within 35 days. In contrast, infected C57BL/6 mice lacking the cytotoxic granule pore-forming protein perforin (Prf1-/- retained splenic B2 B cells and lymphoid follicles, developed high-titer antibody responses against many trypanosome polypeptides, rapidly suppressed parasitemia and did not develop anemia or lose weight for at least 60 days. Several lines of evidence show that T. brucei infection-induced splenic B cell depletion results from natural killer (NK cell-mediated cytotoxicity: i B2 B cells were depleted from the spleens of infected intact, T cell deficient (TCR-/- and FcγRIIIa deficient (CD16-/- C57BL/6 mice excluding a requirement for T cells, NKT cell, or antibody-dependent cell-mediated cytotoxicity; ii administration of NK1.1 specific IgG2a (mAb PK136 but not irrelevant IgG2a (myeloma M9144 prevented infection-induced B cell depletion consistent with a requirement for NK cells; iii splenic NK cells but not T cells or NKT cells degranulated in infected C57BL/6 mice co-incident with B cell depletion evidenced by increased surface expression of CD107a; iv purified NK cells from naïve C57BL/6 mice killed purified splenic B cells from T. brucei infected but not uninfected mice in vitro indicating acquisition of an NK cell activating phenotype by the post-infection B cells; v adoptively transferred C57BL/6 NK cells prevented infection-induced B cell population growth in infected Prf1-/- mice consistent with in vivo B cell killing; vi degranulated NK cells in infected mice had altered gene and differentiation antigen expression and lost cytotoxic activity consistent with functional exhaustion, but increased in number as infection progressed indicating continued generation. We conclude that NK cells in T. brucei

  18. A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans

    DEFF Research Database (Denmark)

    Vanhollebeke, Benoit; De Muylder, Géraldine; Nielsen, Marianne J

    2008-01-01

    The protozoan parasite Trypanosoma brucei is lysed by apolipoprotein L-I, a component of human high-density lipoprotein (HDL) particles that are also characterized by the presence of haptoglobin-related protein. We report that this process is mediated by a parasite glycoprotein receptor, which...... binds the haptoglobin-hemoglobin complex with high affinity for the uptake and incorporation of heme into intracellular hemoproteins. In mice, this receptor was required for optimal parasite growth and the resistance of parasites to the oxidative burst by host macrophages. In humans, the trypanosome...... immunity against the parasite....

  19. Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors.

    Science.gov (United States)

    Bayliss, Tracy; Robinson, David A; Smith, Victoria C; Brand, Stephen; McElroy, Stuart P; Torrie, Leah S; Mpamhanga, Chido; Norval, Suzanne; Stojanovski, Laste; Brenk, Ruth; Frearson, Julie A; Read, Kevin D; Gilbert, Ian H; Wyatt, Paul G

    2017-12-14

    N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a starting point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

  20. Hierarchy, causation and explanation: ubiquity, locality and pluralism

    Science.gov (United States)

    Love, Alan C.

    2012-01-01

    The ubiquity of top-down causal explanations within and across the sciences is prima facie evidence for the existence of top-down causation. Much debate has been focused on whether top-down causation is coherent or in conflict with reductionism. Less attention has been given to the question of whether these representations of hierarchical relations pick out a single, common hierarchy. A negative answer to this question undermines a commonplace view that the world is divided into stratified ‘levels’ of organization and suggests that attributions of causal responsibility in different hierarchical representations may not have a meaningful basis for comparison. Representations used in top-down and bottom-up explanations are primarily ‘local’ and tied to distinct domains of science, illustrated here by protein structure and folding. This locality suggests that no single metaphysical account of hierarchy for causal relations to obtain within emerges from the epistemology of scientific explanation. Instead, a pluralist perspective is recommended—many different kinds of top-down causation (explanation) can exist alongside many different kinds of bottom-up causation (explanation). Pluralism makes plausible why different senses of top-down causation can be coherent and not in conflict with reductionism, thereby illustrating a productive interface between philosophical analysis and scientific inquiry. PMID:23386966

  1. Causative species and serotypes of shigellosis in mainland China: systematic review and meta-analysis.

    Science.gov (United States)

    Chang, Zhili; Lu, Shuting; Chen, Lihong; Jin, Qi; Yang, Jian

    2012-01-01

    Shigella, the causative agent of shigellosis, is a major global public health concern, particularly in developing countries with poor sanitation. A comprehensive and current understanding of the prevalent species and serotypes of shigellosis is essential for both disease prevention and vaccine development. However, no current data are available on the causative species/serotypes of shigellosis in mainland China during the past decade. Relevant studies addressing the prevalent species of shigellosis in mainland China from January 2001 to December 2010 were identified from PubMed and the Chinese BioMedical Literature Database (in Chinese) until April 2012. A total of 131 eligible articles (136 studies) were included in this review. Meta-analyses showed that the prevalences of S. flexneri and S. sonnei were 76.2% (95% CI, 73.7%-78.5%) and 21.3% (95% CI, 19.0%-23.7%), respectively. Stratified analyses indicated a decrease in the prevalence of S. flexneri cases and an increase in the prevalence of S. sonnei cases concurrent with the rapid economic growth experienced by China in recent years. Moreover, significantly higher rates of S. sonnei were observed in the East, North and Northeast regions of China, as compared to the rest of the country. These phenomena imply the possible association between the prevalent species of Shigella and regional economic status; however, additional factors also exist and require further investigations. Moreover, the two major serotypes S. flexneri 2a and 4c accounted for 21.5% (95% CI, 16.7%-27.4%) and 12.9% (95% CI 9.8%-16.9%) of S. flexneri infections, respectively, in the past decade. However, these results were found to be frequently heterogeneous (p for Q tests review of the causative agents of shigellosis in mainland China and focuses on the importance of strengthening prevention and research efforts on S. sonnei and the newly emerged S. flexneri serotype 4c.

  2. Causation of severe and fatal accidents in the manufacturing sector.

    Science.gov (United States)

    Carrillo-Castrillo, Jesús A; Rubio-Romero, Juan C; Onieva, Luis

    2013-01-01

    The main purpose of this paper is to identify the most frequent causes of accidents in the manufacturing sector in Andalusia, Spain, to help safety practitioners in the task of prioritizing preventive actions. Official accident investigation reports are analyzed. A causation pattern is identified with the proportion of causes of each of the different possible groups of causes. We found evidence of a differential causation between slight and nonslight accidents. We have also found significant differences in accident causation depending on the mechanism of the accident. These results can be used to prioritize preventive actions to combat the most likely causes of each accident mechanism. We have also done research on the associations of certain latent causes with specific active (immediate) causes. These relationships show how organizational and safety management can contribute to the prevention of active failures.

  3. A theory of biological relativity: no privileged level of causation.

    Science.gov (United States)

    Noble, Denis

    2012-02-06

    Must higher level biological processes always be derivable from lower level data and mechanisms, as assumed by the idea that an organism is completely defined by its genome? Or are higher level properties necessarily also causes of lower level behaviour, involving actions and interactions both ways? This article uses modelling of the heart, and its experimental basis, to show that downward causation is necessary and that this form of causation can be represented as the influences of initial and boundary conditions on the solutions of the differential equations used to represent the lower level processes. These insights are then generalized. A priori, there is no privileged level of causation. The relations between this form of 'biological relativity' and forms of relativity in physics are discussed. Biological relativity can be seen as an extension of the relativity principle by avoiding the assumption that there is a privileged scale at which biological functions are determined.

  4. Investigating the Chaperone Properties of a Novel Heat Shock Protein, Hsp70.c, from Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Adélle Burger

    2014-01-01

    Full Text Available The neglected tropical disease, African Trypanosomiasis, is fatal and has a crippling impact on economic development. Heat shock protein 70 (Hsp70 is an important molecular chaperone that is expressed in response to stress and Hsp40 acts as its co-chaperone. These proteins play a wide range of roles in the cell and they are required to assist the parasite as it moves from a cold blooded insect vector to a warm blooded mammalian host. A novel cytosolic Hsp70, from Trypanosoma brucei, TbHsp70.c, contains an acidic substrate binding domain and lacks the C-terminal EEVD motif. The ability of a cytosolic Hsp40 from Trypanosoma brucei J protein 2, Tbj2, to function as a co-chaperone of TbHsp70.c was investigated. The main objective was to functionally characterize TbHsp70.c to further expand our knowledge of parasite biology. TbHsp70.c and Tbj2 were heterologously expressed and purified and both proteins displayed the ability to suppress aggregation of thermolabile MDH and chemically denatured rhodanese. ATPase assays revealed a 2.8-fold stimulation of the ATPase activity of TbHsp70.c by Tbj2. TbHsp70.c and Tbj2 both demonstrated chaperone activity and Tbj2 functions as a co-chaperone of TbHsp70.c. In vivo heat stress experiments indicated upregulation of the expression levels of TbHsp70.c.

  5. Blocking variant surface glycoprotein synthesis alters endoplasmic reticulum exit sites/Golgi homeostasis in Trypanosoma brucei.

    Science.gov (United States)

    Ooi, Cher-Pheng; Smith, Terry K; Gluenz, Eva; Wand, Nadina Vasileva; Vaughan, Sue; Rudenko, Gloria

    2018-06-01

    The predominant secretory cargo of bloodstream form Trypanosoma brucei is variant surface glycoprotein (VSG), comprising ~10% total protein and forming a dense protective layer. Blocking VSG translation using Morpholino oligonucleotides triggered a precise pre-cytokinesis arrest. We investigated the effect of blocking VSG synthesis on the secretory pathway. The number of Golgi decreased, particularly in post-mitotic cells, from 3.5 ± 0.6 to 2.0 ± 0.04 per cell. Similarly, the number of endoplasmic reticulum exit sites (ERES) in post-mitotic cells dropped from 3.9 ± 0.6 to 2.7 ± 0.1 eight hours after blocking VSG synthesis. The secretory pathway was still functional in these stalled cells, as monitored using Cathepsin L. Rates of phospholipid and glycosylphosphatidylinositol-anchor biosynthesis remained relatively unaffected, except for the level of sphingomyelin which increased. However, both endoplasmic reticulum and Golgi morphology became distorted, with the Golgi cisternae becoming significantly dilated, particularly at the trans-face. Membrane accumulation in these structures is possibly caused by reduced budding of nascent vesicles due to the drastic reduction in the total amount of secretory cargo, that is, VSG. These data argue that the total flux of secretory cargo impacts upon the biogenesis and maintenance of secretory structures and organelles in T. brucei, including the ERES and Golgi. © 2018 The Authors. Traffic published by John Wiley & Sons Ltd.

  6. The Chemical Characterization of Nigerian Propolis samples and Their Activity Against Trypanosoma brucei.

    Science.gov (United States)

    Omar, Ruwida; Igoli, John O; Zhang, Tong; Gray, Alexander I; Ebiloma, Godwin U; Clements, Carol J; Fearnley, James; Edrada Ebel, RuAngeli; Paget, Tim; de Koning, Harry P; Watson, David G

    2017-04-19

    Profiling of extracts from twelve propolis samples collected from eight regions in Nigeria was carried out using high performance liquid chromatography (LC) coupled with evaporative light scattering (ELSD), ultraviolet detection (UV) and mass spectrometry (MS), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). Principal component analysis (PCA) of the processed LC-MS data demonstrated the varying chemical composition of the samples. Most of the samples were active against Trypanosoma b. brucei with the highest activity being in the samples from Southern Nigeria. The more active samples were fractionated in order to isolate the component(s) responsible for their activity using medium pressure liquid chromatography (MPLC). Three xanthones, 1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl)xanthone, 1,3,7-trihydroxy-4,8-di-(3-methylbut-2-enyl)xanthone a previously undescribed xanthone and three triterpenes: ambonic acid, mangiferonic acid and a mixture of α-amyrin with mangiferonic acid (1:3) were isolated and characterised by NMR and LC-MS. These compounds all displayed strong inhibitory activity against T.b. brucei but none of them had higher activity than the crude extracts. Partial least squares (PLS) modelling of the anti-trypanosomal activity of the sample extracts using the LC-MS data indicated that high activity in the extracts, as judged from LCMS 2 data, could be correlated to denticulatain isomers in the extracts.

  7. KREX2 is not essential for either procyclic or bloodstream form Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Jason Carnes

    Full Text Available Most mitochondrial mRNAs in Trypanosoma brucei require RNA editing for maturation and translation. The edited RNAs primarily encode proteins of the oxidative phosphorylation system. These parasites undergo extensive changes in energy metabolism between the insect and bloodstream stages which are mirrored by alterations in RNA editing. Two U-specific exonucleases, KREX1 and KREX2, are both present in protein complexes (editosomes that catalyze RNA editing but the relative roles of each protein are not known.The requirement for KREX2 for RNA editing in vivo was assessed in both procyclic (insect and bloodstream form parasites by methods that use homologous recombination for gene elimination. These studies resulted in null mutant cells in which both alleles were eliminated. The viability of these cells demonstrates that KREX2 is not essential in either life cycle stage, despite certain defects in RNA editing in vivo. Furthermore, editosomes isolated from KREX2 null cells require KREX1 for in vitro U-specific exonuclease activity.KREX2 is a U-specific exonuclease that is dispensable for RNA editing in vivo in T. brucei BFs and PFs. This result suggests that the U deletion activity, which is required for RNA editing, is primarily mediated in vivo by KREX1 which is normally found associated with only one type of editosome. The retention of the KREX2 gene implies a non-essential role or a role that is essential in other life cycle stages or conditions.

  8. Diversity and spation distribution of vectors and hosts of T. brucei gambiense in forest zones of Southern Cameroon: Epidemiological implications

    NARCIS (Netherlands)

    Massussi, J.A.; Mbida Mbida, J.A.; Djieto-Lordon, C.; Njiokou, F.; Laveissière, C.; Ploeg, van der J.D.

    2010-01-01

    Host and vector distribution of Trypanosoma brucei gambiense was studied in relation to habitat types and seasons. Six (19.35%) of the 31 mammal species recorded in Bipindi were reservoir hosts. Cercopithecus nictitans was confined to the undisturbed forest and the low intensive shifting cultivation

  9. Studies on the localization of Trypanosoma brucei in the female reproductive tract of bka mice and hooded lister rats

    International Nuclear Information System (INIS)

    Chipepa, J.A.S.; Brown, H.; Holmes, P.

    1991-01-01

    A study was conducted to establish whether Trypanosoma brucei migrated preferentially to the reproductive tracts of female BKA mice, or Hooded Lister rats and lodged there as the site of choice compared to other organs. Blood flow to the reproductive tracts, the liver and spleen was measured using red blood cells labelled with chromium- 51. The distribution of trypanosomes labelled with 75 Se-methionine. The average percentage of the blood flow to the reproductive tract was 0.21Plus or minus0.08 in mice, while the mean concentration of trypanosomes there was 0.30% in both mice and rats. Blood flow to the liver was lower than the percentage distribution of Se-labelled T.Brucei(5.17Plus or minus1.34 versus 8.1Plus or Minus1.2). There were, on the contrary, less labelled trypanosomes as compared to the mean blood flow to the spleen (0.54% plus or minus0.18 versus 2.10%pPlus or minus0.88). After 24 hours there were adequate numbers of T. brucei in the reproductive tract to cause parasitaemia in recipient mice. From these preliminary data it was concluded that T. brucei did not lodge in the reproductive organ system a site of choice. (author). 9 refs., 3 tabs

  10. THE CYTOSOLIC AND GLYCOSOMAL GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE FROM TRYPANOSOMA-BRUCEI - KINETIC-PROPERTIES AND COMPARISON WITH HOMOLOGOUS ENZYMES

    NARCIS (Netherlands)

    LAMBEIR, AM; LOISEAU, AM; KUNTZ, DA; VELLIEUX, FM; MICHELS, PAM; OPPERDOES, FR

    1991-01-01

    The protozoan haemoflagellate Trypanosoma brucei has two NAD-dependent glyceraldehyde-3-phosphate dehydrogenase isoenzymes, each with a different localization within the cell. One isoenzyme is found in the cytosol, as in other eukaryotes, while the other is found in the glycosome, a microbody-like

  11. Mitochondrial translation factors of Trypanosoma brucei: elongation factor-Tu has a unique subdomain that is essential for its function

    Czech Academy of Sciences Publication Activity Database

    Cristodero, M.; Mani, J.; Oeljeklaus, S.; Aeberhard, L.; Hashimi, Hassan; Ramrath, D.J.F.; Lukeš, Julius; Warscheid, B.; Schneider, A.

    2013-01-01

    Roč. 90, č. 4 (2013), s. 744-755 ISSN 0950-382X R&D Projects: GA ČR GAP305/12/2261 Institutional support: RVO:60077344 Keywords : mitochondrial translation * Trypanosoma brucei * EF-Tu Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.026, year: 2013

  12. Adaptations in the glucose metabolism of procyclic Trypanosoma brucei isolates from Tsetse flies and during differentiation of bloodstream forms.

    NARCIS (Netherlands)

    van Grinsven, K.W.A.; van den Abbeele, J.; van den Bossche, P.; van Hellemond, J.J.; Tielens, A.G.M.

    2009-01-01

    Procyclic forms of Trypanosoma brucei isolated from the midguts of infected tsetse flies, or freshly transformed from a strain that is close to field isolates, do not use a complete Krebs cycle. Furthermore, short stumpy bloodstream forms produce acetate and are apparently metabolically preadapted

  13. Haematological indices in Trypanosoma brucei brucei (Federe isolate infected Nigerian donkeys (Equus asinus treated with homidium and isometamidium chloride of ciprofloxacin in broiler chickens after single intravenous and intraingluvial administration

    Directory of Open Access Journals (Sweden)

    Queen Nneka Oparah

    2017-03-01

    Full Text Available The efficacy of intramuscular administration of Homidium chloride (Novidium® and Isometamidium chloride (Sécuridium® in Nigerian donkeys (Equus asinus experimentally infected with T. b. brucei (Federe isolate was investigated. Changes in haematological and serum biochemical indices were evaluated using clinical haematology and biochemistry methods. Red blood cell (RBC count for the negative control group was significantly higher than for the positive control, Novidium® and Sécuridium®-treatment groups. Haemoglobin (Hb concentration significantly reduced in the infected untreated group compared with other groups. Packed cell volume (PCV was significantly different between negative and positive controls, and also between the infected untreated and treatment groups. There was significant reduction in platelet counts post-infection and post-treatment. Mean corpuscular volume (MCV increased significantly in the treatment groups while mean corpuscular haemoglobin concentration (MCHC significantly reduced only in the Sécuridium®-treatment group. Lymphocyte count for infected untreated was non-significantly higher than for the uninfected controls, but treatment with both trypanocides recorded further increases, which were higher compared with that of the uninfected group. Post infection and treatment, aspartate aminotransferase (AST levels increased significantly. There were non-significant differences in electrolyte ion concentrations across the groups except for chloride ion which recorded a significant reduction in the Novidium®-treatment group. This experiment revealed that Nigerian donkeys infected with T. brucei brucei (Federe isolate developed symptoms of trypanosomosis; anaemia, lymphocytosis and thrombocytopenia. Treatment with the trypanocides ameliorated effects of the infection, and results suggest that immunosuppression may not be a substantial clinical manifestation of T. brucei brucei (Federe isolate trypanosomosis in Nigerian

  14. ATG24 Represses Autophagy and Differentiation and Is Essential for Homeostasy of the Flagellar Pocket in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Ana Brennand

    Full Text Available We have previously identified homologs for nearly half of the approximately 30 known yeast Atg's in the genome database of the human sleeping sickness parasite Trypanosoma brucei. So far, only a few of these homologs have their role in autophagy experimentally confirmed. Among the candidates was the ortholog of Atg24 that is involved in pexophagy in yeast. In T. brucei, the peroxisome-like organelles named glycosomes harbor core metabolic processes, especially glycolysis. In the autotrophic yeast, autophagy is essential for adaptation to different nutritional environments by participating in the renewal of the peroxisome population. We hypothesized that autophagic turnover of the parasite's glycosomes plays a role in differentiation during its life cycle, which demands adaptation to different host environments and associated dramatic changes in nutritional conditions. We therefore characterized T. brucei ATG24, the T. brucei ortholog of yeast Atg24 and mammalian SNX4, and found it to have a regulatory role in autophagy and differentiation as well as endocytic trafficking. ATG24 partially localized on endocytic membranes where it was recruited via PI3-kinase III/VPS34. ATG24 silencing severely impaired receptor-mediated endocytosis of transferrin, but not adsorptive uptake of a lectin, and caused a major enlargement of the flagellar pocket. ATG24 silencing approximately doubled the number of autophagosomes, suggesting a role in repressing autophagy, and strongly accelerated differentiation, in accordance with a role of autophagy in parasite differentiation. Overexpression of the two isoforms of T. brucei ATG8 fused to GFP slowed down differentiation, possibly by a dominant-negative effect. This was overcome by ATG24 depletion, further supporting its regulatory role.

  15. The Concurrentism of Thomas Aquinas: Divine Causation and Human Freedom

    Czech Academy of Sciences Publication Activity Database

    Dvořák, Petr

    2013-01-01

    Roč. 41, č. 3 (2013), s. 617-634 ISSN 0048-3893 R&D Projects: GA ČR(CZ) GAP401/11/0371 Institutional support: RVO:67985955 Keywords : divine causation * free will * concurrentism * Thomas Aquinas Subject RIV: AA - Philosophy ; Religion

  16. Concepts Concerning 'Disease\\' Causation, Control, and the current ...

    African Journals Online (AJOL)

    There is an ethical necessity that doctors understand the complex social, political, environmental and economic dynamics involved in infectious disease outbreaks. This article discusses some important concepts concerning 'disease' causation and control with specific reference to the current cholera outbreak in Zimbabwe ...

  17. Transitivity and the ontology of causation | Unwin | South African ...

    African Journals Online (AJOL)

    It is argued that it is very hard to analyse causation in such a way that prevents everything from causing everything else. This is particularly true if we assume that the causal relation is transitive, for it all too often happens that causal chains that we wish to keep separate pass through common intermediate events. It is also ...

  18. Diabetes Causation Beliefs Among Spanish-Speaking Patients.

    Science.gov (United States)

    Concha, Jeannie Belinda; Mayer, Sallie D; Mezuk, Briana R; Avula, Danielle

    2016-02-01

    The purpose of this study was to explore how the inquiry of cultural diabetes causation beliefs can improve Hispanic/Latino patient self-management. Two semistructured focus groups were conducted with 13 Hispanic/Latinos adults diagnosed with type 2 diabetes mellitus. Prior to taking part in the group discussion, participants completed a demographic survey and the Illness Perception Questionnaire-Revised. The top 5 diabetes causation items endorsed by participants per the questionnaire included stress or worry, behavior, hereditary, diet/eating habits, and family problems/worries. The qualitative analysis revealed stress as a recurring theme for a cause of diabetes. Work stress was specifically identified as a contributor to unhealthy eating and diabetes. Most participants were aware of and believed in susto and referred to it as coraje (anger). Participants believed that asking patients about their diabetes causation beliefs and emotional status can help health professionals (1) better understand the patient and (2) identify and prioritize diabetes treatments. Participants also indicated that the role of doctors is important and the encouragement that they give to patients is clinically and spiritually valued. Stress was identified as a cause of diabetes in addition to unhealthy diets and heredity. Asking patients about diabetes causation beliefs and emotional status may help prioritize treatment and management goals. © 2015 The Author(s).

  19. CGRP may play a causative role in migraine

    DEFF Research Database (Denmark)

    Lassen, L H; Haderslev, P A; Jacobsen, V B

    2002-01-01

    Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP...... attacks may play a causative role....

  20. Development of a methodology for accident causation research

    Science.gov (United States)

    1983-06-01

    The obj ective of this study was to fully develop and apply a me thodology to : study accident causation, uhich was outlined in a previous study . " Causal" factors : are those pre-crash factors, which are statistically related to the accident rate :...

  1. Standard Javanese Causatives in online editorials and short stories

    Directory of Open Access Journals (Sweden)

    Noor Malihah

    2014-06-01

    Full Text Available This paper explores the distinctive features of the standard Javanese causatives in on-line editorials and short stories. This research is based on written corpus. This written corpus was compiled from articles published in an online newspaper Solo Pos. To analyze the corpus, I have developed a system of manual annotation to identify the features of verb transitivity, the animacy and humanness of the verb, the presence of active, passive and ergative-like clauses and the number of other grammatical and semantic features using a system of tags. Using this annotation, I analyze the data based on dua anlaysis: genre analysis, functional analysis using a quantitative method. The findings show that genre influences the selection of causative types (markers. Also, there exists gawe used as a verb of causation in both editorials and short stories which contradicts to the canonical rule of the Javanese active verb and Malihah’s (2014 findings. The finding also shows that the standard Javanese causative in online editorials and short stories occurs with intransitive verbs. The last finding is that active clause is the relative prominent type of clause which occurs in all marker. In conclusion, the above findings have made contributions to knowledge to Javanese grammar.

  2. Characterization of a Novel Class I Transcription Factor A (CITFA) Subunit That Is Indispensable for Transcription by the Multifunctional RNA Polymerase I of Trypanosoma brucei

    KAUST Repository

    Nguyen, T. N.; Nguyen, B. N.; Lee, J. H.; Panigrahi, A. K.; Gunzl, A.

    2012-01-01

    Trypanosoma brucei is the only organism known to have evolved a multifunctional RNA polymerase I (pol I) system that is used to express the parasite's ribosomal RNAs, as well as its major cell surface antigens, namely, the variant surface

  3. Chimerization at the AQP2–AQP3 locus is the genetic basis of melarsoprol–pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates

    Directory of Open Access Journals (Sweden)

    Fabrice E. Graf

    2015-08-01

    Full Text Available Aquaglyceroporin-2 is a known determinant of melarsoprol–pentamidine cross-resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2–AQP3 tandem locus was described from melarsoprol–pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2–aqp3 null T. b. brucei does not. This proves that AQP2–AQP3 chimerization is the cause of melarsoprol–pentamidine cross-resistance in the T. b. gambiense isolates.

  4. A geo-information system approach for forest fire likelihood based on causative and anti - causative factors

    NARCIS (Netherlands)

    Srivastava, Sanjay K.; Saran, Sameer; de By, R.A.; Dadhwal, V.K.

    2014-01-01

    Innumerable forest fire spread models exist for taking a decision, but far less focus is on the real causative factors which initiate/ignite fire in an area. It has been observed that the majority of the forest fires in India are initiated due to anthropogenic factors. In this study, we develop a

  5. Enhanced succinic acid production in Aspergillus saccharolyticus by heterologous expression of fumarate reductase from Trypanosoma brucei

    DEFF Research Database (Denmark)

    Yang, Lei; Lübeck, Mette; Ahring, Birgitte K.

    2015-01-01

    production medium as well as the complete medium, but the measured enzyme activities were different depending on the media. Furthermore, a soluble NADH-dependent fumarate reductase gene (frd) from Trypanosoma brucei was inserted and expressed in A. saccharolyticus. The expression of the frd gene led......Aspergillus saccharolyticus exhibits great potential as a cell factory for industrial production of dicarboxylic acids. In the analysis of the organic acid profile, A. saccharolyticus was cultivated in an acid production medium using two different pH conditions. The specific activities...... of the enzymes, pyruvate carboxylase (PYC), malate dehydrogenase (MDH), and fumarase (FUM), involved in the reductive tricarboxylic acid (rTCA) branch, were examined and compared in cells harvested from the acid production medium and a complete medium. The results showed that ambient pH had a significant impact...

  6. Trypanosoma brucei gambiense trypanosomiasis in Terego county, northern Uganda, 1996: a lot quality assurance sampling survey.

    Science.gov (United States)

    Hutin, Yvan J F; Legros, Dominique; Owini, Vincent; Brown, Vincent; Lee, Evan; Mbulamberi, Dawson; Paquet, Christophe

    2004-04-01

    We estimated the pre-intervention prevalence of Trypanosoma brucei gambiense (Tbg) trypanosomiasis using the lot quality assurance sampling (LQAS) methods in 14 parishes of Terego County in northern Uganda. A total of 826 participants were included in the survey sample in 1996. The prevalence of laboratory confirmed Tbg trypanosomiasis adjusted for parish population sizes was 2.2% (95% confidence interval =1.1-3.2). This estimate was consistent with the 1.1% period prevalence calculated on the basis of cases identified through passive and active screening in 1996-1999. Ranking of parishes in four categories according to LQAS analysis of the 1996 survey predicted the prevalences observed during the first round of active screening in the population in 1997-1998 (P LQAS were validated by the results of the population screening, suggesting that these survey methods may be useful in the pre-intervention phase of sleeping sickness control programs.

  7. [Causation in the court: the complex case of malignant mesothelioma].

    Science.gov (United States)

    Lageard, Giovanni

    2011-01-01

    The aim of this paper is to carry out an analysis of the legal evolution in Italy of the assessment of causation i.e. cause and effect, in oncological diseases, a question taken into consideration by the High Court almost exclusively with reference to pleural mesothelioma. The most debated question when defining the causal association between asbestos exposure and mesothelioma is the possible role that any multiple potentially causative exposures could assume in the induction and development of the disease, and in particular the role of any asbestos exposure over the successive employment periods. Indeed, this is a subject on which, to date, no agreement has yet been reached in scientific doctrine: these divergences bear important practical significance from a legal point of view, since sustaining one thesis or another may constitute determining factors when ascertaining responsibility for individuals who, in the past, had decisional statuses in the workplace. Jurisprudence in the High Court took on an oscillating position on this question as from the early 2000s, which was divided into those who sustained the thesis of the relevance of any asbestos exposure over the successive employment periods and those who were of a different opinion, i.e. only the first exposure period has relevant causative effect. The point under discussion concerns, in particular, the adequacy of a probabilistic law only governing such a question. An important turning point was made in the year 2010 when two sentences were announced in the High Court, reiterating, in strict compliance with the principles affirmed by the United Sections in 2002, that a judge cannot, and must not, be satisfied with a general causation, but must rather reach a judgment on the basis of an individual causation. In particular, not only did the second of these two sentences recognise the multifactorial nature of mesothelioma, something which had almost always been denied in jurisprudence in the past, but it also

  8. Secondary Metabolites from Vietnamese Marine Invertebrates with Activity against Trypanosoma brucei and T. cruzi

    Directory of Open Access Journals (Sweden)

    Nguyen Phuong Thao

    2014-06-01

    Full Text Available Marine-derived natural products from invertebrates comprise an extremely diverse and promising source of the compounds from a wide variety of structural classes. This study describes the discovery of five marine natural products with activity against Trypanosoma species by natural product library screening using whole cell in vitro assays. We investigated the anti-trypanosomal activity of the extracts from the soft corals and echinoderms living in Vietnamese seas. Of the samples screened, the methanolic extracts of several marine organisms exhibited potent activities against cultures of Trypanosoma brucei and T. cruzi (EC50 < 5.0 μg/mL. Among the compounds isolated from these extracts, laevigatol B (1 from Lobophytum crassum and L. laevigatum, (24S-ergost-4-ene-3-one (2 from Sinularia dissecta, astropectenol A (3 from Astropecten polyacanthus, and cholest-8-ene-3β,5α,6β,7α-tetraol (4 from Diadema savignyi showed inhibitory activity against T. brucei with EC50 values ranging from 1.57 ± 0.14 to 14.6 ± 1.36 μM, relative to the positive control, pentamidine (EC50 = 0.015 ± 0.003 μM. Laevigatol B (1 and 5α-cholest-8(14-ene-3β,7α-diol (5 exhibited also significant inhibitory effects on T. cruzi. The cytotoxic activity of the pure compounds on mammalian cells was also assessed and found to be insignificant in all cases. This is the first report on the inhibitory effects of marine organisms collected in Vietnamese seas against Trypanosoma species responsible for neglected tropical diseases.

  9. Population genetics of Trypanosoma brucei rhodesiense: clonality and diversity within and between foci.

    Directory of Open Access Journals (Sweden)

    Craig W Duffy

    2013-11-01

    Full Text Available African trypanosomes are unusual among pathogenic protozoa in that they can undergo their complete morphological life cycle in the tsetse fly vector with mating as a non-obligatory part of this development. Trypanosoma brucei rhodesiense, which infects humans and livestock in East and Southern Africa, has classically been described as a host-range variant of the non-human infective Trypanosoma brucei that occurs as stable clonal lineages. We have examined T. b. rhodesiense populations from East (Uganda and Southern (Malawi Africa using a panel of microsatellite markers, incorporating both spatial and temporal analyses. Our data demonstrate that Ugandan T. b. rhodesiense existed as clonal populations, with a small number of highly related genotypes and substantial linkage disequilibrium between pairs of loci. However, these populations were not stable as the dominant genotypes changed and the genetic diversity also reduced over time. Thus these populations do not conform to one of the criteria for strict clonality, namely stability of predominant genotypes over time, and our results show that, in a period in the mid 1990s, the previously predominant genotypes were not detected but were replaced by a novel clonal population with limited genetic relationship to the original population present between 1970 and 1990. In contrast, the Malawi T. b. rhodesiense population demonstrated significantly greater diversity and evidence for frequent genetic exchange. Therefore, the population genetics of T. b. rhodesiense is more complex than previously described. This has important implications for the spread of the single copy T. b. rhodesiense gene that allows human infectivity, and therefore the epidemiology of the human disease, as well as suggesting that these parasites represent an important organism to study the influence of optional recombination upon population genetic dynamics.

  10. Processing of the glycosomal matrix-protein import receptor PEX5 of Trypanosoma brucei

    International Nuclear Information System (INIS)

    Gualdrón-López, Melisa; Michels, Paul A.M.

    2013-01-01

    Highlights: ► Most eukaryotic cells have a single gene for the peroxin PEX5. ► PEX5 is sensitive to in vitro proteolysis in distantly related organisms. ► TbPEX5 undergoes N-terminal truncation in vitro and possibly in vivo. ► Truncated TbPEX5 is still capable of binding PTS1-containing proteins. ► PEX5 truncation is physiologically relevant or an evolutionary conserved artifact. -- Abstract: Glycolysis in kinetoplastid protists such as Trypanosoma brucei is compartmentalized in peroxisome-like organelles called glycosomes. Glycosomal matrix-protein import involves a cytosolic receptor, PEX5, which recognizes the peroxisomal-targeting signal type 1 (PTS1) present at the C-terminus of the majority of matrix proteins. PEX5 appears generally susceptible to in vitro proteolytic processing. On western blots of T. brucei, two PEX5 forms are detected with apparent M r of 100 kDa and 72 kDa. 5′-RACE-PCR showed that TbPEX5 is encoded by a unique transcript that can be translated into a protein of maximally 72 kDa. However, recombinant PEX5 migrates aberrantly in SDS–PAGE with an apparent M r of 100 kDa, similarly as observed for the native peroxin. In vitro protease susceptibility analysis of native and 35 S-labelled PEX5 showed truncation of the 100 kDa form at the N-terminal side by unknown parasite proteases, giving rise to the 72 kDa form which remains functional for PTS1 binding. The relevance of these observations is discussed

  11. Processing of the glycosomal matrix-protein import receptor PEX5 of Trypanosoma brucei

    Energy Technology Data Exchange (ETDEWEB)

    Gualdrón-López, Melisa [Research Unit for Tropical Diseases, de Duve Institute, Université catholique de Louvain, Brussels (Belgium); Michels, Paul A.M., E-mail: paul.michels@uclouvain.be [Research Unit for Tropical Diseases, de Duve Institute, Université catholique de Louvain, Brussels (Belgium)

    2013-02-01

    Highlights: ► Most eukaryotic cells have a single gene for the peroxin PEX5. ► PEX5 is sensitive to in vitro proteolysis in distantly related organisms. ► TbPEX5 undergoes N-terminal truncation in vitro and possibly in vivo. ► Truncated TbPEX5 is still capable of binding PTS1-containing proteins. ► PEX5 truncation is physiologically relevant or an evolutionary conserved artifact. -- Abstract: Glycolysis in kinetoplastid protists such as Trypanosoma brucei is compartmentalized in peroxisome-like organelles called glycosomes. Glycosomal matrix-protein import involves a cytosolic receptor, PEX5, which recognizes the peroxisomal-targeting signal type 1 (PTS1) present at the C-terminus of the majority of matrix proteins. PEX5 appears generally susceptible to in vitro proteolytic processing. On western blots of T. brucei, two PEX5 forms are detected with apparent M{sub r} of 100 kDa and 72 kDa. 5′-RACE-PCR showed that TbPEX5 is encoded by a unique transcript that can be translated into a protein of maximally 72 kDa. However, recombinant PEX5 migrates aberrantly in SDS–PAGE with an apparent M{sub r} of 100 kDa, similarly as observed for the native peroxin. In vitro protease susceptibility analysis of native and {sup 35}S-labelled PEX5 showed truncation of the 100 kDa form at the N-terminal side by unknown parasite proteases, giving rise to the 72 kDa form which remains functional for PTS1 binding. The relevance of these observations is discussed.

  12. Public awareness of human papillomavirus as a causative factor for oropharyngeal cancer.

    Science.gov (United States)

    Williams, Michael U; Carr, Michele M; Goldenberg, David

    2015-06-01

    To assess the public's awareness of human papillomavirus (HPV) as a causative factor for oropharyngeal cancer. Twenty-three-item survey. Local shopping malls and Maxwell Air Force Base in 2012. Respondents were randomly chosen to participate in 23-item survey at various local shopping malls and at Maxwell Air Force Base in 2012. The χ(2) test was used in statistical analysis. The majority of respondents (n = 319) were civilians; 158 were military officer trainees (MOTs). All MOTs had a bachelor's degree or higher, while 37% of civilian respondents had a bachelor's degree or higher. Most MOTs (82%) were aware of oropharyngeal cancer, and 53% of civilians had not heard of oropharyngeal cancer (P aware of the association between HPV and cervical cancer. Conversely, 75% of civilian population and 49% of MOTs were not aware of the association between HPV and oropharyngeal cancer (P aware that HPV is a causative agent of cervical cancer. However, the majority were not aware of the association between oropharyngeal cancer and HPV. Furthermore, many respondents were not aware that HPV equally affects males and females and that the vaccine is available for both sexes. This underscores the need to educate the public on the availability of HPV vaccine and the association between HPV and oropharyngeal cancer. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

  13. A cascading failure model for analyzing railway accident causation

    Science.gov (United States)

    Liu, Jin-Tao; Li, Ke-Ping

    2018-01-01

    In this paper, a new cascading failure model is proposed for quantitatively analyzing the railway accident causation. In the model, the loads of nodes are redistributed according to the strength of the causal relationships between the nodes. By analyzing the actual situation of the existing prevention measures, a critical threshold of the load parameter in the model is obtained. To verify the effectiveness of the proposed cascading model, simulation experiments of a train collision accident are performed. The results show that the cascading failure model can describe the cascading process of the railway accident more accurately than the previous models, and can quantitatively analyze the sensitivities and the influence of the causes. In conclusion, this model can assist us to reveal the latent rules of accident causation to reduce the occurrence of railway accidents.

  14. Game of Objects: vicarious causation and multi-modal media

    Directory of Open Access Journals (Sweden)

    Aaron Pedinotti

    2013-09-01

    Full Text Available This paper applies philosopher Graham Harman's object-oriented theory of "vicarious causation" to an analysis of the multi-modal media phenomenon known as "Game of Thrones." Examining the manner in which George R.R. Martin's best-selling series of fantasy novels has been adapted into a board game, a video game, and a hit HBO television series, it uses the changes entailed by these processes to trace the contours of vicariously generative relations. In the course of the resulting analysis, it provides new suggestions concerning the eidetic dimensions of Harman's causal model, particularly with regard to causation in linear networks and in differing types of game systems.

  15. Causation at Different Levels: Tracking the Commitments of Mechanistic Explanations

    DEFF Research Database (Denmark)

    Fazekas, Peter; Kertész, Gergely

    2011-01-01

    connections transparent. These general commitments get confronted with two claims made by certain proponents of the mechanistic approach: William Bechtel often argues that within the mechanistic framework it is possible to balance between reducing higher levels and maintaining their autonomy at the same time...... their autonomy at the same time than standard reductive accounts are, and that what mechanistic explanations are able to do at best is showing that downward causation does not exist....

  16. Research advances in probability of causation calculation of radiogenic neoplasms

    International Nuclear Information System (INIS)

    Ning Jing; Yuan Yong; Xie Xiangdong; Yang Guoshan

    2009-01-01

    Probability of causation (PC) was used to facilitate the adjudication of compensation claims for cancers diagnosed following exposure to ionizing radiation. In this article, the excess cancer risk assessment models used for PC calculation are reviewed. Cancer risk transfer models between different populations, dependence of cancer risk on dose and dose rate, modification by epidemiological risk factors and application of PC are also discussed in brief. (authors)

  17. Medical negligence. An overview of legal theory and neurosurgical practice: causation.

    Science.gov (United States)

    Todd, Nicholas V

    2014-06-01

    This article discusses the principles of the law in relation to legal causation as applied to neurosurgical practice. Causation is a causal link between a breach of duty of care and the final harm. The fundamental "but-for" test for causation will be discussed, together with Chester v Afshar modified causation, prospective and retrospective probabilities of harm, loss of a chance, causation following breach of duty of care by omission, breaking the chain of causation, material contribution and the law in relation to multiple defendants, with neurosurgical examples.

  18. Distribution territories and causative mechanisms of ischemic stroke

    Energy Technology Data Exchange (ETDEWEB)

    Rovira, A.; Grive, E.; Alvarez-Sabin, J. [Unidad de Resonancia Magnetica, Hospital Vall d' Hebron, Barcelona (Spain)

    2005-03-01

    Ischemic stroke prognosis, risk of recurrence, clinical assessment, and treatment decisions are influenced by stroke subtype (anatomic distribution and causative mechanism of infarction). Stroke subtype diagnosis is better achieved in the early phase of acute ischemia with the use of multimodal MR imaging. The pattern of brain lesions as shown by brain MR imaging can be classified according to a modified Oxfordshire method, based on the anatomic distribution of the infarcts into six groups: (1) total anterior circulation infarcts, (2) partial anterior circulation infarcts, (3) posterior circulation infarcts, (4) watershed infarcts, (5) centrum ovale infarcts, and (6) lacunar infarcts. The subtype of stroke according to its causative mechanism is based on the TOAST method, which classifies stroke into five major etiologic groups: (1) large-vessel atherosclerotic disease, (2) small-vessel atherosclerotic disease, (3) cardioembolic source, (4) other determined etiologies, and (5) undetermined or multiple possible etiologies. The different MR imaging patterns of acute ischemic brain lesions visualized using diffusion-weighted imaging and the pattern of vessel involvement demonstrated with MR angiography are essential factors that can suggest the most likely causative mechanism of infarction. This information may have an impact on decisions regarding therapy and the performance of additional diagnostic tests. (orig.)

  19. Downward Causation and the Neurobiology of Free Will

    CERN Document Server

    Murphy, Nancey; O’Connor, Timothy

    2009-01-01

    How is free will possible in the light of the physical and chemical underpinnings of brain activity and recent neurobiological experiments? How can the emergence of complexity in hierarchical systems such as the brain, based at the lower levels in physical interactions, lead to something like genuine free will? The nature of our understanding of free will in the light of present-day neuroscience is becoming increasingly important because of remarkable discoveries on the topic being made by neuroscientists at the present time, on the one hand, and its crucial importance for the way we view ourselves as human beings, on the other. A key tool in understanding how free will may arise in this context is the idea of downward causation in complex systems, happening coterminously with bottom up causation, to form an integral whole. Top-down causation is usually neglected, and is therefore emphasized in the other part of the book’s title. The concept is explored in depth, as are the ethical and legal implications of...

  20. Shifting accountability: a longitudinal qualitative study of diabetes causation accounts.

    Science.gov (United States)

    Lawton, Julia; Peel, Elizabeth; Parry, Odette; Douglas, Margaret

    2008-07-01

    We undertook a longitudinal qualitative study involving of 20 patients from Scotland who had type 2 diabetes. We looked at their perceptions and understandings of why they had developed diabetes and how, and why, their causation accounts had changed or remained stable over time. Respondents, all of whom were white, were interviewed four times over a 4-year period (at baseline, 6, 12 and 48 months). Their causation accounts often shifted, sometimes subtly, sometimes radically, over the 4 years. The experiential dimensions of living with, observing, and managing their disease over time were central to understanding the continuities and changes we observed. We also highlight how, through a process of removing, adding and/or de-emphasising explanatory factors, causation accounts could be used as "resources" to justify or enable present treatment choices. We use our work to support critiques of social cognition theories, with their emphasis upon beliefs being antecedent to behaviours. We also provide reflections upon the implications of our findings for qualitative research designs and sampling strategies.

  1. No gold standard estimation of the sensitivity and specificity of two molecular diagnostic protocols for Trypanosoma brucei spp. in Western Kenya.

    Directory of Open Access Journals (Sweden)

    Barend Mark de Clare Bronsvoort

    2010-01-01

    Full Text Available African animal trypanosomiasis is caused by a range of tsetse transmitted protozoan parasites includingTrypanosoma vivax, Trypanosoma congolense and Trypansoma brucei. In Western Kenya and other parts of East Africa two subspecies of T. brucei, T.b. brucei and the zoonoticT.b. rhodesiense, co-circulate in livestock. A range of polymerase chain reactions (PCR have been developed as important molecular diagnostic tools for epidemiological investigations of T. brucei s.l. in the animal reservoir and of its zoonotic potential. Quantification of the relative performance of different diagnostic PCRs is essential to ensure comparability of studies. This paper describes an evaluation of two diagnostic test systems for T. brucei using a T. brucei s.l. specific PCR [1] and a single nested PCR targeting the Internal Transcribed Spacer (ITS regions of trypanosome ribosomal DNA [2]. A Bayesian formulation of the Hui-Walter latent class model was employed to estimate their test performance in the absence of a gold standard test for detecting T.brucei s.l. infections in ear-vein blood samples from cattle, pig, sheep and goat populations in Western Kenya, stored on Whatman FTA cards. The results indicate that the system employing the T. brucei s.l. specific PCR (Se1=0.760 had a higher sensitivity than the ITS-PCR (Se2=0.640; both have high specificity (Sp1=0.998; Sp2=0.997. The true prevalences for livestock populations were estimated (pcattle=0.091, ppigs=0.066, pgoats=0.005, psheep=0.006, taking into account the uncertainties in the specificity and sensitivity of the two test systems. Implications of test performance include the required survey sample size; due to its higher sensitivity and specificity, the T. brucei s.l. specific PCR requires a consistently smaller sample size than the ITS-PCR for the detection of T. brucei s.l. However the ITS-PCR is able to simultaneously screen samples for other pathogenic trypanosomes and may thus be, overall, a better

  2. Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

    Science.gov (United States)

    Giroud, Maude; Dietzel, Uwe; Anselm, Lilli; Banner, David; Kuglstatter, Andreas; Benz, Jörg; Blanc, Jean-Baptiste; Gaufreteau, Delphine; Liu, Haixia; Lin, Xianfeng; Stich, August; Kuhn, Bernd; Schuler, Franz; Kaiser, Marcel; Brun, Reto; Schirmeister, Tanja; Kisker, Caroline; Diederich, François; Haap, Wolfgang

    2018-04-26

    Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( K i < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC 50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.

  3. Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei.

    Science.gov (United States)

    Turrens, J F; Bickar, D; Lehninger, A L

    1986-06-01

    The cyanide-insensitive respiration of bloodstream trypomastigote forms of Trypanosoma brucei (75 +/- 8 nmol O2 min-1(mg protein)-1) is completely inhibited by the mitochondrial ubiquinone-like inhibitors 2-hydroxy-3-undecyl-1,4-naphthoquinone (UHNQ) and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). The Ki values for UHDBT (30 nM) and UHNQ (2 microM) are much lower than the reported Ki for salicylhydroxamic acid (SHAM) (5 microM), a widely used inhibitor of the cyanide-insensitive oxidase. UHNQ also stimulated the glycerol-3-phosphate-dependent reduction of phenazine methosulfate, demonstrating that the site of UHNQ inhibition is on the terminal oxidase of the cyanide-insensitive respiration of T. brucei. These results suggest that a ubiquinone-like compound may act as an electron carrier between the two enzymatic components of the cyanide-insensitive glycerol-3-phosphate oxidase.

  4. A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.

    Directory of Open Access Journals (Sweden)

    Elizabeth R Sharlow

    2010-04-01

    Full Text Available The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK, an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay.Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were approximately 20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics.The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome.

  5. Dynamics of Mitochondrial RNA-Binding Protein Complex in Trypanosoma brucei and Its Petite Mutant under Optimized Immobilization Conditions

    Czech Academy of Sciences Publication Activity Database

    Huang, Zhenqiu; Kaltenbrunner, S.; Šimková, Eva; Staněk, David; Lukeš, Julius; Hashimi, Hassan

    2014-01-01

    Roč. 13, č. 9 (2014), s. 1232-1240 ISSN 1535-9778 R&D Projects: GA ČR GAP305/12/2261; GA MŠk(CZ) EE2.3.30.0032 Institutional support: RVO:60077344 ; RVO:68378050 Keywords : mitochondrion * Trypanosoma brucei * YFP Subject RIV: EB - Genetics ; Molecular Biology; EB - Genetics ; Molecular Biology (UMG-J) Impact factor: 2.820, year: 2014

  6. The F1 -ATPase from Trypanosoma brucei is elaborated by three copies of an additional p18-subunit.

    Science.gov (United States)

    Gahura, Ondřej; Šubrtová, Karolína; Váchová, Hana; Panicucci, Brian; Fearnley, Ian M; Harbour, Michael E; Walker, John E; Zíková, Alena

    2018-02-01

    The F-ATPases (also called the F 1 F o -ATPases or ATP synthases) are multi-subunit membrane-bound molecular machines that produce ATP in bacteria and in eukaryotic mitochondria and chloroplasts. The structures and enzymic mechanisms of their F 1 -catalytic domains are highly conserved in all species investigated hitherto. However, there is evidence that the F-ATPases from the group of protozoa known as Euglenozoa have novel features. Therefore, we have isolated pure and active F 1 -ATPase from the euglenozoan parasite, Trypanosoma brucei, and characterized it. All of the usual eukaryotic subunits (α, β, γ, δ, and ε) were present in the enzyme, and, in addition, two unique features were detected. First, each of the three α-subunits in the F 1 -domain has been cleaved by proteolysis in vivo at two sites eight residues apart, producing two assembled fragments. Second, the T. brucei F 1 -ATPase has an additional subunit, called p18, present in three copies per complex. Suppression of expression of p18 affected in vitro growth of both the insect and infectious mammalian forms of T. brucei. It also reduced the levels of monomeric and multimeric F-ATPase complexes and diminished the in vivo hydrolytic activity of the enzyme significantly. These observations imply that p18 plays a role in the assembly of the F 1 domain. These unique features of the F 1 -ATPase extend the list of special characteristics of the F-ATPase from T. brucei, and also, demonstrate that the architecture of the F 1 -ATPase complex is not strictly conserved in eukaryotes. © 2017 Federation of European Biochemical Societies.

  7. ANALYTIC CAUSATIVES IN JAVANESE: A LEXICAL- FUNCTIONAL APPROACH

    Directory of Open Access Journals (Sweden)

    Agus Subiyanto

    2014-01-01

    Full Text Available Analytic  causatives  are  the  type  of  causatives  formed  by  separate predicates  expressing the cause and the effect, that is, the causing notion  is  realized  by  a  word  separate  from  the  word  denoting  the caused activity. This paper aims to discuss the forms and syntactic structure  of  analytic  causatives  in  Javanese.  To  discuss  the syntactic structure, the theory of lexical functional grammar (LFG is  employed.  The  data  used  in  this  study  is  the  „ngoko‟  level  of Javanese of the Surakarta dialect. By using a negation marker and modals  as  the  syntactic  operators to test mono-  or bi-clausality  of analytic  causatives,  the  writer  found  that  analytic  causatives  in Javanese form biclausal constructions. These constructions have an X-COMP  structure,  in  that  the  SUBJ  of  the  second  verb  is controlled  by  the  OBJ  of  the  causative  verb  (Ngawe  „make‟.  In terms  of  the  constituent  structure,  analytic  causatives  have  two kinds of structures, which are V-cause OBJ X-COMP and V-cause X-COMP OBJ. Kausatif  analitik  adalah  tipe  kausatif  yang  dibentuk  oleh  dua predikat  atau  dua  kata  terpisah  untuk  mengungkapkan  makna sebab dan akibat, yakni makna sebab direalisasikan oleh kata yang berbeda  dengan  kata  yang  menyatakan  makna  akibat.  Tulisan  ini membahas  bentuk  dan  struktur  sintaksis  kausatif  analitik  dalam bahasa Jawa. Untuk menjelaskan struktur sintaksis digunakan teori Tata  Bahasa  Leksikal  Fungsional.  Data  yang  digunakan  dalam penelitian  ini  adalah  bahasa  Jawa  dialek  Surakarta  ragam  ngoko. Dengan  menggunakan  alat  uji  pemarkah  negasi  dan  penggunaaan modalitas,  penulis  menemukan  bahwa  kausatif  analitik  dalam bahasa Jawa membentuk struktur biklausa. Konstruksi ini memiliki struktur  X

  8. VNTR analysis reveals unexpected genetic diversity within Mycoplasma agalactiae, the main causative agent of contagious agalactia

    Directory of Open Access Journals (Sweden)

    Ayling Roger D

    2008-11-01

    Full Text Available Abstract Background Mycoplasma agalactiae is the main cause of contagious agalactia, a serious disease of sheep and goats, which has major clinical and economic impacts. Previous studies of M. agalactiae have shown it to be unusually homogeneous and there are currently no available epidemiological techniques which enable a high degree of strain differentiation. Results We have developed variable number tandem repeat (VNTR analysis using the sequenced genome of the M. agalactiae type strain PG2. The PG2 genome was found to be replete with tandem repeat sequences and 4 were chosen for further analysis. VNTR 5 was located within the hypothetical protein MAG6170 a predicted lipoprotein. VNTR 14 was intergenic between the hypothetical protein MAG3350 and the hypothetical protein MAG3340. VNTR 17 was intergenic between the hypothetical protein MAG4060 and the hypothetical protein MAG4070 and VNTR 19 spanned the 5' end of the pseudogene for a lipoprotein MAG4310 and the 3' end of the hypothetical lipoprotein MAG4320. We have investigated the genetic diversity of 88 M. agalactiae isolates of wide geographic origin using VNTR analysis and compared it with pulsed field gel electrophoresis (PFGE and random amplified polymorphic DNA (RAPD analysis. Simpson's index of diversity was calculated to be 0.324 for PFGE and 0.574 for VNTR analysis. VNTR analysis revealed unexpected diversity within M. agalactiae with 9 different VNTR types discovered. Some correlation was found between geographical origin and the VNTR type of the isolates. Conclusion VNTR analysis represents a useful, rapid first-line test for use in molecular epidemiological analysis of M. agalactiae for outbreak tracing and control.

  9. On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer

    Directory of Open Access Journals (Sweden)

    Doig Kenneth D

    2012-06-01

    Full Text Available Abstract Background Mycobacterium ulcerans is an unusual bacterial pathogen with elusive origins. While closely related to the aquatic dwelling M. marinum, M. ulcerans has evolved the ability to produce the immunosuppressive polyketide toxin mycolactone and cause the neglected tropical disease Buruli ulcer. Other mycolactone-producing mycobacteria (MPM have been identified in fish and frogs and given distinct species designations (M. pseudoshottsii, M. shinshuense, M. liflandii and M. marinum, however the evolution of M. ulcerans and its relationship to other MPM has not been defined. Here we report the comparative analysis of whole genome sequences from 30 MPM and five M. marinum. Results A high-resolution phylogeny based on genome-wide single nucleotide polymorphisms (SNPs showed that M. ulcerans and all other MPM represent a single clonal group that evolved from a common M. marinum progenitor. The emergence of the MPM was driven by the acquisition of the pMUM plasmid encoding genes for the biosynthesis of mycolactones. This change was accompanied by the loss of at least 185 genes, with a significant overrepresentation of genes associated with cell wall functions. Cell wall associated genes also showed evidence of substantial adaptive selection, suggesting cell wall remodeling has been critical for the survival of MPM. Fine-grain analysis of the MPM complex revealed at least three distinct lineages, one of which comprised a highly clonal group, responsible for Buruli ulcer in Africa and Australia. This indicates relatively recent transfer of M. ulcerans between these continents, which represent the vast majority of the global Buruli ulcer burden. Our data provide SNPs and gene sequences that can differentiate M. ulcerans lineages, suitable for use in the diagnosis and surveillance of Buruli ulcer. Conclusions M. ulcerans and all mycolactone-producing mycobacteria are specialized variants of a common Mycobacterium marinum progenitor that have adapted to live in restricted environments. Examination of genes lost or retained and now under selective pressure suggests these environments might be aerobic, and extracellular, where slow growth, production of an immune suppressor, cell wall remodeling, loss or modification of cell wall antigens, and biofilm-forming ability provide a survival advantage. These insights will guide our efforts to find the elusive reservoir(s of M. ulcerans and to understand transmission of Buruli ulcer.

  10. [ON THE ORIGIN OF HYPERVIRULENCE OF THE CAUSATIVE AGENT OF PLAGUE].

    Science.gov (United States)

    Anisimov, N V; Kislichkina, A A; Platonov, M E; Evseeva, V V; Kadnikova, L A; Lipatnikova, N A; Bogun, A G; Dentovskaya, S V; Anisimov, A P

    2016-01-01

    The attempt to combine Yersinia pseudotuberculosis and Yersinia pestis into one species has been unsupported by microbiologists due to the specific features of the epidemiology and clinical presentations of their induced diseases and to basic differences in their virulence. Pseudotuberculosis is predominantly a relatively mild human intestinal infection transmitted through contaminated food and plague is an acute generalized disease with high mortality, which is most frequently transmitted by the bites of infected fleas. Y. pestis hypervirulence, the ability of single bacteria to ensure the development of predagonal bacteriemia in rodents, which is sufficient to contaminate the fleas, is one of the main events during pathogen adaptation to a new ecological niche. By analyzing the data of molecular typing of the representative kits of naturally occurring Y. pestis isolates, the authois consider the issues of formation of intraspecies groups with universal hypervirulence, as well as biovars that are highly virulent only to their major host. A strategy for searching for selective virulence factors, the potential molecular targets for vaccination and etiotropic treatment of plague, is discussed.

  11. Genomic analysis of the causative agents of coccidiosis in domestic chickens

    DEFF Research Database (Denmark)

    Reid, Adam J.; Blake, Damer P.; Ansari, Hifzur R.

    2014-01-01

    of the genus Eimeria, is one of the most important poultry diseases. Understanding the biology of Eimeria parasites underpins development of new drugs and vaccines needed to improve global food security. We have produced annotated genome sequences of all seven species of Eimeria that infect domestic chickens....... Analysis of Eimeria genes involved in basic biology and host-parasite interaction highlights adaptations to a relatively simple developmental life cycle and a complex array of co-expressed surface proteins involved in host cell binding....

  12. Emerging infectious diseases: a guide to diseases, causative agents, and surveillance

    National Research Council Canada - National Science Library

    Beltz, Lisa A

    2011-01-01

    "This important resource offers a comprehensive introduction to emerging and reemerging infectious disease, including the underlying mechanisms of microbial emergence, the technology used to detect...

  13. First dengue haemorrhagic fever epidemic in the Americas, 1981: insights into the causative agent.

    Science.gov (United States)

    Rodriguez-Roche, Rosmari; Hinojosa, Yoandri; Guzman, Maria G

    2014-12-01

    Historical records describe a disease in North America that clinically resembled dengue haemorrhagic fever during the latter part of the slave-trading period. However, the dengue epidemic that occurred in Cuba in 1981 was the first laboratory-confirmed and clinically diagnosed outbreak of dengue haemorrhagic fever in the Americas. At that time, the presumed source of the dengue type 2 strain isolated during this epidemic was considered controversial, partly because of the limited sequence data and partly because the origin of the virus appeared to be southern Asia. Here, we present a molecular characterisation at the whole-genome level of the original strains isolated at different time points during the epidemic. Phylogenetic trees constructed using Bayesian methods indicated that 1981 Cuban strains group within the Asian 2 genotype. In addition, the study revealed that viral evolution occurred during the epidemic - a fact that could be related to the increasing severity from month to month. Moreover, the Cuban strains exhibited particular amino acid substitutions that differentiate them from the New Guinea C prototype strain as well as from dengue type 2 strains isolated globally.

  14. Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis

    NARCIS (Netherlands)

    Rodrigues, Anderson Messias; de Hoog, G Sybren; de Cássia Pires, Débora; Brihante, Raimunda Sâmia Nogueira; Sidrim, José Júlio da Costa; Gadelha, Marcos Fabio; Colombo, Arnaldo Lopes; de Camargo, Zoilo Pires

    2014-01-01

    BACKGROUND: Sporotrichosis is a chronic subcutaneous mycosis of humans and animals, which is typically acquired by traumatic inoculation of plant material contaminated with Sporothrix propagules, or via animals, mainly felines. Sporothrix infections notably occur in outbreaks, with large epidemics

  15. [The morphology of the causative agent of human diphyllobothriasis in the Far East].

    Science.gov (United States)

    Dovgalev, A S; Valovaia, M A; Piskunova, Iu A; Romanenko, N A; Khodakova, V I; Artamoshin, A S

    1991-01-01

    The morphology of types F, A, C plerocercoids, and mature Diphyllobothriidae of the Far Eastern populations (USSR) was studied by using scanning electron microscopy. New data were obtained on structure the skin muscular sac of plerocercoids type F (presence of tegumental microvilli, multi poly-layer of longitudinal subtegumental musculature, and variation of quantity of muscular filaments along strobila. The morphological identity of mature Diphyllobothriidae from the volunteer (self-infection of plerocercoid "type F"), infested men and seagulls from focuses of diphyllobothriasis in the Pacific Ocean regions in the Far East of the USSR was proved.

  16. Purification of a Recombinant Glutathione Transferase from the Causative Agent of Hydatidosis, "Echinococcus granulosus"

    Science.gov (United States)

    Fleitas, Andrea L.; Randall, Lía M.; Möller, Matías N.; Denicola, Ana

    2016-01-01

    This practical class activity was designed to introduce students to recombinant protein expression and purification. The principal goal is to shed light on basic aspects concerning recombinant protein production, in particular protein expression, chromatography methods for protein purification, and enzyme activity as a tool to evaluate purity and…

  17. Streptobacillus moniliformis as the causative agent in spondylodiscitis and psoas abscess after rooster scratches.

    Science.gov (United States)

    Dubois, Damien; Robin, Frédéric; Bouvier, Damien; Delmas, Julien; Bonnet, Richard; Lesens, Olivier; Hennequin, Claire

    2008-08-01

    We report a case of Streptobacillus moniliformis spondylodiscitis accompanied by a psoas abscess in an 80-year-old man scratched by a rooster. S. moniliformis was identified from abscess fluid by use of 16S rRNA gene sequencing. After 18 weeks of antimicrobial therapy, the clinical condition of the patient improved.

  18. Streptobacillus moniliformis as the Causative Agent in Spondylodiscitis and Psoas Abscess after Rooster Scratches▿

    Science.gov (United States)

    Dubois, Damien; Robin, Frédéric; Bouvier, Damien; Delmas, Julien; Bonnet, Richard; Lesens, Olivier; Hennequin, Claire

    2008-01-01

    We report a case of Streptobacillus moniliformis spondylodiscitis accompanied by a psoas abscess in an 80-year-old man scratched by a rooster. S. moniliformis was identified from abscess fluid by use of 16S rRNA gene sequencing. After 18 weeks of antimicrobial therapy, the clinical condition of the patient improved. PMID:18562588

  19. Detection of single bacteria - causative agents of meningitis using raman microscopy

    Science.gov (United States)

    Baikova, T. V.; Minaeva, S. A.; Sundukov, A. V.; Svistunova, T. S.; Bagratashvili, V. N.; Alushin, M. V.; Gonchukov, S. A.

    2015-03-01

    Early diagnostics of meningitis is a very topical problem as it is a fulminant disease with a high level of mortality. The progress of this disease is, as a rule, accompanied by the appearance of bacteria in the cerebrospinal fluid (CSF) composition. The examination of the CSF is well known to be the only reliable approach to the identification of meningitis. However, the traditional biochemical analyses are time consuming and not always reliable, simple, and inexpensive, whereas the optical methods are poorly developed. This work is devoted to the study of Raman spectra of several bacterial cultures which are mainly present during meningitis. Raman microscopy is a prompt and noninvasive technique capable of providing reliable information about molecular-level alterations of biological objects at their minimal quantity and size. It was shown that there are characteristic lines in Raman spectra which can be the reliable markers for determination of bacterial form of meningitis at a level of a single bacterium.

  20. Schizophyllum commune a causative agent of fungal sinusitis: a case report.

    Science.gov (United States)

    Premamalini, T; Ambujavalli, B T; Anitha, S; Somu, L; Kindo, Anupma J

    2011-01-01

    We present a case of maxillary sinusitis caused by Schizophyllum commune, in a 50-year-old female. The patient presented with nasal obstruction, purulent nasal discharge from right side of the nose, cough, headache, and sneezing. Computed tomography revealed extensive opacity of the right maxillary sinus as well as erosion of the nasal wall and maxillary bone. Functional endoscopic sinus surgery was done, and fungal debris present on right side of the maxillary sinus was removed and sent to laboratory. Potassium hydroxide (KOH) examination of the nasal discharge showed hyaline, septate hyphae. Primary isolation on Sabouraud's dextrose agar (SDA) yielded a white woolly mould. Banana peel culture after 8 weeks showed macroscopically visible fan-shaped fruiting bodies. Lactophenol cotton blue (LPCB) mount of the same revealed hyaline septate hyphae, often with clamp connections. Identification was confirmed by the presence of clamp connections formed on the hyphae and by vegetative compatibility with known isolates.

  1. Schizophyllum Commune a Causative Agent of Fungal Sinusitis: A Case Report

    Directory of Open Access Journals (Sweden)

    T. Premamalini

    2011-01-01

    Full Text Available We present a case of maxillary sinusitis caused by Schizophyllum commune, in a 50-year-old female. The patient presented with nasal obstruction, purulent nasal discharge from right side of the nose, cough, headache, and sneezing. Computed tomography revealed extensive opacity of the right maxillary sinus as well as erosion of the nasal wall and maxillary bone. Functional endoscopic sinus surgery was done, and fungal debris present on right side of the maxillary sinus was removed and sent to laboratory. Potassium hydroxide (KOH examination of the nasal discharge showed hyaline, septate hyphae. Primary isolation on Sabouraud's dextrose agar (SDA yielded a white woolly mould. Banana peel culture after 8 weeks showed macroscopically visible fan-shaped fruiting bodies. Lactophenol cotton blue (LPCB mount of the same revealed hyaline septate hyphae, often with clamp connections. Identification was confirmed by the presence of clamp connections formed on the hyphae and by vegetative compatibility with known isolates.

  2. Relapsing fever causative agent in Southern Iran is a closely related species to East African borreliae.

    Science.gov (United States)

    Naddaf, Saied Reza; Ghazinezhad, Behnaz; Kazemirad, Elham; Cutler, Sally Jane

    2017-10-01

    We obtained two blood samples from relapsing fever patients residing in Jask County, Hormozgan Province, southern Iran in 2013. Sequencing of a partial fragment of glpQ from two samples, and further characterization of one of them by analyzing flaB gene, and 16S-23S spacer (IGS) revealed the greatest sequence identity with East African borreliae, Borrelia recurrentis, and Borrelia duttonii, and Borrelia microti from Iran. Phylogenetic analyses of glpQ, flaB, and concatenated sequences (glpQ, flab, and IGS) clustered these sequences amongst East African Relapsing fever borreliae and B. microti from Iran. However, the more discriminatory IGS disclosed a unique 8-bp signature (CAGCCTAA) separating these from B. microti and indeed other relapsing fever borreliae. In southern Iran, relapsing fever cases are mostly from localities in which O. erraticus ticks, the notorious vector of B. microti, prevail. There are chances that this argasid tick serves as a host and vector of several closely related species or ecotypes including the one we identified in the present study. The distribution of this Borrelia species remains to be elucidated, but it is assumed to be endemic to lowland areas of the Hormozgan Province, as well as Sistan va Baluchistan in the southeast and South Khorasan (in Persian: Khorasan-e Jonobi) in the east of Iran. Copyright © 2017 Elsevier GmbH. All rights reserved.

  3. Eggs as a Suitable Tool for Species Diagnosis of Causative Agents of Human Diphyllobothriosis (Cestoda)

    Czech Academy of Sciences Publication Activity Database

    Leštinová, Kateřina; Soldánová, Miroslava; Scholz, Tomáš; Kuchta, Roman

    2016-01-01

    Roč. 10, č. 5 (2016), č. článku e0004721. ISSN 1935-2735 R&D Projects: GA ČR GAP506/12/1632 Institutional support: RVO:60077344 Keywords : Adenocephalus pacificus * helminth fauna * infection Subject RIV: EG - Zoology Impact factor: 3.834, year: 2016

  4. Viruses as Sole Causative Agents of Severe Acute Respiratory Tract Infections in Children.

    Science.gov (United States)

    Moesker, Fleur M; van Kampen, Jeroen J A; van Rossum, Annemarie M C; de Hoog, Matthijs; Koopmans, Marion P G; Osterhaus, Albert D M E; Fraaij, Pieter L A

    2016-01-01

    Respiratory syncytial virus (RSV) and influenza A viruses are known to cause severe acute respiratory tract infections (SARIs) in children. For other viruses like human rhinoviruses (HRVs) this is less well established. Viral or bacterial co-infections are often considered essential for severe manifestations of these virus infections. The study aims at identifying viruses that may cause SARI in children in the absence of viral and bacterial co-infections, at identifying disease characteristics associated with these single virus infections, and at identifying a possible correlation between viral loads and disease severities. Between April 2007 and March 2012, we identified children (acute respiratory tract infection (ARTI) (controls). Data were extracted from the clinical and laboratory databases of our tertiary care paediatric hospital. Patient specimens were tested for fifteen respiratory viruses with real-time reverse transcriptase PCR assays and we selected patients with a single virus infection only. Typical bacterial co-infections were considered unlikely to have contributed to the PICU or MC admission based on C-reactive protein-levels or bacteriological test results if performed. We identified 44 patients admitted to PICU with SARI and 40 patients admitted to MC with ARTI. Twelve viruses were associated with SARI, ten of which were also associated with ARTI in the absence of typical bacterial and viral co-infections, with RSV and HRV being the most frequent causes. Viral loads were not different between PICU-SARI patients and MC-ARTI patients. Both SARI and ARTI may be caused by single viral pathogens in previously healthy children as well as in children with a medical history. No relationship between viral load and disease severity was identified.

  5. Postharvest control of anthracnose lesions and its causative agent, Colletotrichum musae by some oils.

    Science.gov (United States)

    Rizwana, Humaira

    2018-03-31

    Anthracnose of banana is incited by Colletotrichum  musae. It is recognized as one the most destructive diseases of mature and immature banana fruits, resulting in huge economic losses all over the world. Present research deals with screening some oils both in vitro and in vivo for their antifungal activity against C.musae. Clove oil (0.1µl/ml) completely arrested the conidial germination and mycelial growth of C. musae. Fenugreek and almond oil exhibited significant inhibition of mycelial growth, 61% and 57% at a concentration of 2µl/ml. However, olive oil was least inhibitory on the test fungi. Clove oil also a showed marked reduction in anthracnose lesions on banana fruits, thereby suggesting disease control. Scanning electron microscopy revealed severely damaged mycelium and conidia. FTIR studies show the presence of important bands representing phenols, terpenes, aldehydes, and ketones. Based on our findings; clove, fenugreek and almond oil demonstrated fungicidal and fungistatic activities against anthracnose pathogen. Hence, these oils can be considered as potential alternatives to chemical treatments.

  6. Pacific Broad Tapeworm Adenocephalus pacificus as a Causative Agent of Globally Reemerging Diphyllobothriosis

    Czech Academy of Sciences Publication Activity Database

    Kuchta, Roman; Serrano-Martínez, M.E.; Scholz, Tomáš

    2015-01-01

    Roč. 21, č. 10 (2015), s. 1697-1703 ISSN 1080-6040 R&D Projects: GA ČR GAP506/12/1632 Institutional support: RVO:60077344 Keywords : megaloblastic anemia * identification * populations Subject RIV: EG - Zoology Impact factor: 6.994, year: 2015

  7. Genomic analysis of the causative agents of coccidiosis in domestic chickens

    KAUST Repository

    Reid, Adam J.; Blake, Damer P.; Ansari, Hifzur R.; Billington, Karen; Browne, Hilary P.; Bryant, Josephine; Dunn, Matt; Hung, Stacy S.; Kawahara, Fumiya; Miranda-Saavedra, Diego; Malas, Tareq B.; Mourier, Tobias; Naghra, Hardeep; Nair, Mridul; Otto, Thomas D.; Rawlings, Neil D.; Rivailler, Pierre; Sanchez-Flores, Alejandro; Sanders, Mandy; Subramaniam, Chandra; Tay, Yea-Ling; Woo, Yong; Wu, Xikun; Barrell, Bart; Dear, Paul H.; Doerig, Christian; Gruber, Arthur; Ivens, Alasdair C.; Parkinson, John; Rajandream, Marie-Adè le; Shirley, Martin W.; Wan, Kiew-Lian; Berriman, Matthew; Tomley, Fiona M.; Pain, Arnab

    2014-01-01

    Global production of chickens has trebled in the past two decades and they are now the most important source of dietary animal protein worldwide. Chickens are subject to many infectious diseases that reduce their performance and productivity. Coccidiosis, caused by apicomplexan protozoa of the genus Eimeria, is one of the most important poultry diseases. Understanding the biology of Eimeria parasites underpins development of new drugs and vaccines needed to improve global food security. We have produced annotated genome sequences of all seven species of Eimeria that infect domestic chickens, which reveal the full extent of previously described repeat-rich and repeat-poor regions and show that these parasites possess the most repeat-rich proteomes ever described. Furthermore, while no other apicomplexan has been found to possess retrotransposons, Eimeria is home to a family of chromoviruses. Analysis of Eimeria genes involved in basic biology and host-parasite interaction highlights adaptations to a relatively simple developmental life cycle and a complex array of co-expressed surface proteins involved in host cell binding.

  8. Encephalitozoon cuniculi Genotype I as a Causative Agent of Brain Abscess in an Immunocompetent Patient

    Czech Academy of Sciences Publication Activity Database

    Ditrich, Oleg; Chrdle, A.; Sak, Bohumil; Chmelík, V.; Kubale, J.; Dyková, Iva; Kváč, Martin

    2011-01-01

    Roč. 49, č. 7 (2011), 2769-2771 ISSN 0095-1137 R&D Projects: GA ČR GA206/09/0927; GA ČR(CZ) GAP505/11/1163 Institutional research plan: CEZ:AV0Z60220518 Keywords : AIDS PATIENT * MICROSPORIDIOSIS * ALBENDAZOLE * INFECTION Subject RIV: GJ - Animal Vermins ; Diseases, Veterinary Medicine Impact factor: 4.153, year: 2011

  9. Incidence, CauSative Agents and Strategy of Control of Mastitis

    African Journals Online (AJOL)

    little knowledge on dairy! husbandry and thus / the economic significance of mastitis 011 their. , dairy enterprises (Mchaui, 1995). Hence, the extent of mastitis as a problem in small holder dairy farms in: Tanzania'iis not well known. ,This 'is ironical, bearing in mind that small- holder dairy farmers own ~bout 60 % of the es-.

  10. H3N2 Virus as Causative Agent of ARDS Requiring Extracorporeal Membrane Oxygenation Support

    Directory of Open Access Journals (Sweden)

    Adriano Peris

    2014-01-01

    Full Text Available Pandemic influenza virus A(H1N1 2009 was associated with a higher risk of viral pneumonia in comparison with seasonal influenza viruses. The influenza season 2011-2012 was characterized by the prevalent circulation of influenza A(H3N2 viruses. Whereas most H3N2 patients experienced mild, self-limited influenza-like illness, some patients were at increased risk for influenza complications because of age or underlying medical conditions. Cases presented were patients admitted to the Intensive Care Unit (ICU of ECMO referral center (Careggi Teaching Hospital, Florence, Italy. Despite extracorporeal membrane oxygenation treatment (ECMO, one patient with H3N2-induced ARDS did not survive. Our experience suggests that viral aetiology is becoming more important and hospitals should be able to perform a fast differential diagnosis between bacterial and viral aetiology.

  11. Can a simple urinalysis predict the causative agent and the antibiotic sensitivities?

    Science.gov (United States)

    Waseem, Muhammad; Chen, Justin; Paudel, Govinda; Sharma, Nirdesh; Castillo, Manuel; Ain, Yumna; Leber, Mark

    2014-04-01

    The objective of this study was (1) to determine the reliability of urinalysis (UA) for predicting urinary tract infection (UTI) in febrile children, (2) to determine whether UA findings can predict Escherichia coli versus non-E. coli urinary tract infection, and (3) to determine if empiric antibiotics should be selected based on E. coli versus non-E. coli infection predictions. This was a retrospective chart review of children from 2 months to 2 years of age who presented to the emergency department with fever (rectal temperature >100.4°F) and had a positive urine culture. This study was conducted between January 2004 and December 2007. Negative UA was defined as urine white blood cell count less than 5 per high-power field, negative leukocyte esterase, and negative nitrites. Urine cultures were classified into E. coli and non-E. coli groups. These groups were compared for sex, race, and UA findings. Multivariate forward logistic regression, using the Wald test, was performed to calculate the likelihood ratio (LR) of each variable (eg, sex, race, UA parameters) in predicting UTI. In addition, antibiotic sensitivities between both groups were compared. Of 749 medical records reviewed, 608 were included; negative UA(-) was present in 183 cases, and positive UA(+) was observed in 425 cases. Furthermore, 424 cases were caused by E. coli, and 184 were due to non-E. coli organisms. Among 425 UA(+) cases, E. coli was identified in 349 (82.1%), whereas non-E. coli organisms were present in 76 (17.9%); in contrast, in 183 UA(-) cases, 108 (59%) were due to non-E. coli organisms versus 75 (41%), which were caused by E. coli. Urinalysis results were shown to be associated with organism group (P Antibiotic sensitivity compared between UA groups demonstrated equivalent superiority of cefazolin (94.7% sensitive in UA(+) vs 84.0% in UA(-) group; P sensitivity to trimethoprim-sulfamethoxazole (82.2% vs 71.3% in UA(+); P = 0.008). Urinalysis is not an accurate predictor of UTI. A positive urine culture in the presence of negative UA most likely grew non-E. coli organisms, whereas most UA(+) results were associated with E. coli. This study also highlighted local patterns of antibiotic resistance between E. coli and non-E. coli groups. Negative UA results in the presence of strong suspicion of a UTI suggest a non-E. coli organism, which may be best treated with trimethoprim-sulfamethoxazole. Conversely, UA(+) results suggest E. coli, which calls for treatment with cefazolin or cefuroxime.

  12. Draft genome of neurotropic nematode parasite Angiostrongylus cantonensis, causative agent of human eosinophilic meningitis.

    Science.gov (United States)

    Yong, Hoi-Sen; Eamsobhana, Praphathip; Lim, Phaik-Eem; Razali, Rozaimi; Aziz, Farhanah Abdul; Rosli, Nurul Shielawati Mohamed; Poole-Johnson, Johan; Anwar, Arif

    2015-08-01

    Angiostrongylus cantonensis is a bursate nematode parasite that causes eosinophilic meningitis (or meningoencephalitis) in humans in many parts of the world. The genomic data from A. cantonensis will form a useful resource for comparative genomic and chemogenomic studies to aid the development of diagnostics and therapeutics. We have sequenced, assembled and annotated the genome of A. cantonensis. The genome size is estimated to be ∼260 Mb, with 17,280 genomic scaffolds, 91X coverage, 81.45% for complete and 93.95% for partial score based on CEGMA analysis of genome completeness. The number of predicted genes of ≥300 bp was 17,482. A total of 7737 predicted protein-coding genes of ≥50 amino acids were identified in the assembled genome. Among the proteins of known function, kinases are the most abundant followed by transferases. The draft genome contains 34 excretory-secretory proteins (ES), a minimum of 44 Nematode Astacin (NAS) metalloproteases, 12 Homeobox (HOX) genes, and 30 neurotransmitters. The assembled genome size (260 Mb) is larger than those of Pristionchus pacificus, Caenorhabditis elegans, Necator americanus, Caenorhabditis briggsae, Trichinella spiralis, Brugia malayi and Loa loa, but smaller than Haemonchus contortus and Ascaris suum. The repeat content (25%) is similar to H. contortus. The GC content (41.17%) is lower compared to P. pacificus (42.7%) and H. contortus (43.1%) but higher compared to C. briggsae (37.69%), A. suum (37.9%) and N. americanus (40.2%) while the scaffold N50 is 42,191. This draft genome will facilitate the understanding of many unresolved issues on the parasite and the disorder it causes. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. The etiological structure, biological properties of causative agents of peri-implant mucositis

    Directory of Open Access Journals (Sweden)

    M. O. Faustova

    2017-10-01

    Full Text Available The purpose was to examine the peri-implant mucositis microflora and sensitivity of dominant pathogens to antibiotics and antiseptics. Materials and methods. The study involved 43 patients with peri-implant mucositis. During the study 162 clinical strains of microorganisms were isolated and identified. Cultivation of clinical isolates was performed by the standard method, final identification was carried out with using bacteriological automatic analyzer Vitec – 2compact bioMérieux (France. Determination of sensitivity to antibiotics of pathogens was carried with disc-diffusion method; the study of sensitivity to antiseptics was carried by means of double serial dilutions method by the standard procedure approved by the Order № 167 of the Ministry of Public Health of Ukraine on “On Approval of Training Guidance “Assessment of the sensitivity of microorganisms to antibiotics”, dated by April, 5, 2007. Results. It is The microflora of peri-implant area of patients with mucositis was revealed to consist of opportunistic species. Representatives of Streptococcus spp. and Staphylococcus spp. were dominating among them, although Kocuria spp., Enterobacter spp. and yeast-like fungi Candida spp. were detected quite common. Investigated clinical strains of microorganisms had different sensitivity to antibiotics. All cultures were sensitive to fluoroquinolones, but very significant number of them showed resistance to penicillins, macrolides and lincosamides. In turn, horosten, dekasan and chlorhexidine had powerful antimicrobial effect on dominant pathogens of periimplant mucositis in patients. Moreover, the effect of decametoxine-based antiseptics on some of them significantly exceeded the activity of chlorhexidine. Conclusions. Microflora from peri-implant area of patients with peri-implant mucositis consists mainly of aerobic and facultative anaerobic microorganisms, belonging to normal oral microflora. Most of pathogens of mucositis obtaine resistance to antibiotics (penicillins, macrolides, lincosamides. Modern antiseptics horosten, decasan and chlorhexidine provide a strong antimicrobial activity against etiological pathogens of mucositis, that makes them promising for use in dental implantology.

  14. Genomic analysis of the causative agents of coccidiosis in domestic chickens

    KAUST Repository

    Reid, Adam J.

    2014-10-01

    Global production of chickens has trebled in the past two decades and they are now the most important source of dietary animal protein worldwide. Chickens are subject to many infectious diseases that reduce their performance and productivity. Coccidiosis, caused by apicomplexan protozoa of the genus Eimeria, is one of the most important poultry diseases. Understanding the biology of Eimeria parasites underpins development of new drugs and vaccines needed to improve global food security. We have produced annotated genome sequences of all seven species of Eimeria that infect domestic chickens, which reveal the full extent of previously described repeat-rich and repeat-poor regions and show that these parasites possess the most repeat-rich proteomes ever described. Furthermore, while no other apicomplexan has been found to possess retrotransposons, Eimeria is home to a family of chromoviruses. Analysis of Eimeria genes involved in basic biology and host-parasite interaction highlights adaptations to a relatively simple developmental life cycle and a complex array of co-expressed surface proteins involved in host cell binding.

  15. Detection of single bacteria – causative agents of meningitis using Raman microscopy

    International Nuclear Information System (INIS)

    Baikova, T V; Alushin, M V; Gonchukov, S A; Minaeva, S A; Bagratashvili, V N; Sundukov, A V; Svistunova, T S

    2015-01-01

    Early diagnostics of meningitis is a very topical problem as it is a fulminant disease with a high level of mortality. The progress of this disease is, as a rule, accompanied by the appearance of bacteria in the cerebrospinal fluid (CSF) composition. The examination of the CSF is well known to be the only reliable approach to the identification of meningitis. However, the traditional biochemical analyses are time consuming and not always reliable, simple, and inexpensive, whereas the optical methods are poorly developed. This work is devoted to the study of Raman spectra of several bacterial cultures which are mainly present during meningitis. Raman microscopy is a prompt and noninvasive technique capable of providing reliable information about molecular-level alterations of biological objects at their minimal quantity and size. It was shown that there are characteristic lines in Raman spectra which can be the reliable markers for determination of bacterial form of meningitis at a level of a single bacterium

  16. [Invasive fungal infections in immunocompromised patients with focus on aspergillosis and its causative agents].

    Science.gov (United States)

    Paloušová, Dita; Lengerová, Martina; Volfová, Pavlína; Bejdák, Petr; Kocmanová, Iva; Mayer, Jiří; Ráčil, Zdeněk

    2012-08-01

    Invasive fungal diseases (IFD) are a life-threatening infectious complications in immunocompromised patients and are associated with high rate of morbidity and mortality. The most common invasive mycosis in patients who underwent an allogeneic hematopoietic stem cell transplantation is invasive aspergilosis (IA), most frequently caused by the clinically dominant species Aspergillus fumigatus and, rarely, also by Aspergillus flavus, Aspergillus terreus and Aspergillus niger. In recent years, other related Aspergillus species were also reported to cause IFD, phenotypically similar to A. fumigatus and moreover, frequently exhibiting resistance towards various antifungals. For example, it is Aspergillus lentulus, Aspergillus viridinutans, Neosartoya fischeri, etc. Classical microbiological methods such as direct microscopy or culture are usually used for the identification of Aspergillus species. The application of PCR-based molecular techniques and monitoring of secondary metabolites production enable detection and identification of species, which are not distinguishable solely by their morphology. PCR methods are also useful for molecular strain typing of aspergilli and can reveal the genetic diversity of isolates.

  17. Lactobacilli and tartrazine as causative agents of red-color spoilage in cucumber pickle products.

    Science.gov (United States)

    Pérez-Díaz, I M; Kelling, R E; Hale, S; Breidt, F; McFeeters, R F

    2007-09-01

    The cucumber pickling industry has sporadically experienced spoilage outbreaks in pickled cucumber products characterized by development of red color on the surface of the fruits. Lactobacillus casei and Lactobacillus paracasei were isolated from 2 outbreaks of this spoilage that occurred about 15 y apart during the last 3 decades. Both organisms were shown to produce this spoilage when inoculated into pickled cucumbers while concomitantly degrading the azo dye tartrazine (FD&C yellow nr 5). This food dye is used as a yellow coloring in the brine cover solutions of commercial pickled cucumber products. The red color does not occur in the absence of tartrazine, nor when turmeric is used as a yellow coloring in the pickles. Addition of sodium benzoate to the brine cover solutions of a pickled cucumber product, more specifically hamburger dill pickles, prevented growth of these lactic acid bacteria and the development of the red spoilage.

  18. Antimycobacterial activity of medicinal plants against the causative agent of buruli ulcer: Mycobacterium ulcerans

    Directory of Open Access Journals (Sweden)

    R Keumoe

    2016-01-01

    Conclusion: The obtained results further strengthened the exploitation of these extracts as potent hits in the treatment of Buruli ulcer. Meanwhile, further studies are required to fully characterize the bioactive compounds.

  19. Rapid Quantitative Serological Test for Detection of Infection with Mycobacterium leprae, the Causative Agent of Leprosy

    Science.gov (United States)

    Balagon, Marivic F.; Maghanoy, Armi; Orcullo, Florenda M.; Cang, Marjorie; Dias, Ronaldo Ferreira; Collovati, Marco; Reed, Steven G.

    2014-01-01

    Leprosy remains an important health problem in a number of regions. Early detection of infection, followed by effective treatment, is critical to reduce disease progression. New sensitive and specific tools for early detection of infection will be a critical component of an effective leprosy elimination campaign. Diagnosis is made by recognizing clinical signs and symptoms, but few clinicians are able to confidently identify these. Simple tests to facilitate referral to leprosy experts are not widely available, and the correct diagnosis of leprosy is often delayed. In this report, we evaluate the performance of a new leprosy serological test (NDO-LID). As expected, the test readily detected clinically confirmed samples from patients with multibacillary (MB) leprosy, and the rate of positive results declined with bacterial burden. NDO-LID detected larger proportions of MB and paucibacillary (PB) leprosy than the alternative, the Standard Diagnostics leprosy test (87.0% versus 81.7% and 32.3% versus 6.5%, respectively), while also demonstrating improved specificity (97.4% versus 90.4%). Coupled with a new cell phone-based test reader platform (Smart Reader), the NDO-LID test provided consistent, objective test interpretation that could facilitate wider use in nonspecialized settings. In addition, results obtained from sera at the time of diagnosis, versus at the end of treatment, indicated that the quantifiable nature of this system can also be used to monitor treatment efficacy. Taken together, these data indicate that the NDO-LID/Smart Reader system can assist in the diagnosis and monitoring of MB leprosy and can detect a significant number of earlier-stage infections. PMID:24478496

  20. Anti-Parasitic Activities of Allium sativum and Allium cepa against Trypanosoma b. brucei and Leishmania tarentolae.

    Science.gov (United States)

    Krstin, Sonja; Sobeh, Mansour; Braun, Markus Santhosh; Wink, Michael

    2018-04-21

    Background: Garlics and onions have been used for the treatment of diseases caused by parasites and microbes since ancient times. Trypanosomiasis and leishmaniasis are a concern in many areas of the world, especially in poor countries. Methods: Trypanosoma brucei brucei and Leishmania tarentolae were used to investigate the anti-parasitic effects of dichloromethane extracts of Allium sativum (garlic) and Allium cepa (onion) bulbs. As a confirmation of known antimicrobial activities, they were studied against a selection of G-negative, G-positive bacteria and two fungi. Chemical analyses were performed using high-performance liquid chromatography (HPLC) and electrospray ionization-mass spectrometry (LC-ESI-MS/MS). Results: Chemical analyses confirmed the abundance of several sulfur secondary metabolites in garlic and one (zwiebelane) in the onion extract. Both extracts killed both types of parasites efficiently and inhibited the Trypanosoma brucei trypanothione reductase irreversibly. In addition, garlic extract decreased the mitochondrial membrane potential in trypanosomes. Garlic killed the fungi C. albicans and C. parapsilosis more effectively than the positive control. The combinations of garlic and onion with common trypanocidal and leishmanicidal drugs resulted in a synergistic or additive effect in 50% of cases. Conclusion: The mechanism for biological activity of garlic and onion appears to be related to the amount and the profile of sulfur-containing compounds. It is most likely that vital substances inside the parasitic cell, like trypanothione reductase, are inhibited through disulfide bond formation between SH groups of vital redox compounds and sulfur-containing secondary metabolites.

  1. Trypanosoma brucei metabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion.

    Science.gov (United States)

    McGettrick, Anne F; Corcoran, Sarah E; Barry, Paul J G; McFarland, Jennifer; Crès, Cécile; Curtis, Anne M; Franklin, Edward; Corr, Sinéad C; Mok, K Hun; Cummins, Eoin P; Taylor, Cormac T; O'Neill, Luke A J; Nolan, Derek P

    2016-11-29

    The parasite Trypanasoma brucei causes African trypanosomiasis, known as sleeping sickness in humans and nagana in domestic animals. These diseases are a major burden in the 36 sub-Saharan African countries where the tsetse fly vector is endemic. Untreated trypanosomiasis is fatal and the current treatments are stage-dependent and can be problematic during the meningoencephalitic stage, where no new therapies have been developed in recent years and the current drugs have a low therapeutic index. There is a need for more effective treatments and a better understanding of how these parasites evade the host immune response will help in this regard. The bloodstream form of T. brucei excretes significant amounts of aromatic ketoacids, including indolepyruvate, a transamination product of tryptophan. This study demonstrates that this process is essential in bloodstream forms, is mediated by a specialized isoform of cytoplasmic aminotransferase and, importantly, reveals an immunomodulatory role for indolepyruvate. Indolepyruvate prevents the LPS-induced glycolytic shift in macrophages. This effect is the result of an increase in the hydroxylation and degradation of the transcription factor hypoxia-inducible factor-1α (HIF-1α). The reduction in HIF-1α levels by indolepyruvate, following LPS or trypanosome activation, results in a decrease in production of the proinflammatory cytokine IL-1β. These data demonstrate an important role for indolepyruvate in immune evasion by T. brucei.

  2. Major surface glycoproteins of insect forms of Trypanosoma brucei are not essential for cyclical transmission by tsetse.

    Directory of Open Access Journals (Sweden)

    Erik Vassella

    Full Text Available Procyclic forms of Trypanosoma brucei reside in the midgut of tsetse flies where they are covered by several million copies of glycosylphosphatidylinositol-anchored proteins known as procyclins. It has been proposed that procyclins protect parasites against proteases and/or participate in tropism, directing them from the midgut to the salivary glands. There are four different procyclin genes, each subject to elaborate levels of regulation. To determine if procyclins are essential for survival and transmission of T. brucei, all four genes were deleted and parasite fitness was compared in vitro and in vivo. When co-cultured in vitro, the null mutant and wild type trypanosomes (tagged with cyan fluorescent protein maintained a near-constant equilibrium. In contrast, when flies were infected with the same mixture, the null mutant was rapidly overgrown in the midgut, reflecting a reduction in fitness in vivo. Although the null mutant is patently defective in competition with procyclin-positive parasites, on its own it can complete the life cycle and generate infectious metacyclic forms. The procyclic form of T. brucei thus differs strikingly from the bloodstream form, which does not tolerate any perturbation of its variant surface glycoprotein coat, and from other parasites such as Plasmodium berghei, which requires the circumsporozoite protein for successful transmission to a new host.

  3. The γ-tubulin complex in Trypanosoma brucei: molecular composition, subunit interdependence and requirement for axonemal central pair protein assembly

    Science.gov (United States)

    Zhou, Qing; Li, Ziyin

    2015-01-01

    The γ-tubulin complex constitutes a key component of the microtubule-organizing center and nucleates microtubule assembly. This complex differs in complexity in different organisms: the budding yeast contains the γ-tubulin small complex (γTuSC) composed of γ-tubulin, GCP2 and GCP3, whereas animals contain the γ-tubulin ring complex (γTuRC) composed of γTuSC and three additional proteins, GCP4, GCP5 and GCP6. In Trypanosoma brucei, the composition of the γ-tubulin complex remains elusive, and it is not known whether it also regulates assembly of the subpellicular microtubules and the spindle microtubules. Here we report that the γ-tubulin complex in T. brucei is composed of γ-tubulin and three GCP proteins, GCP2-GCP4, and is primarily localized in the basal body throughout the cell cycle. Depletion of GCP2 and GCP3, but not GCP4, disrupted the axonemal central pair microtubules, but not the subpellicular microtubules and the spindle microtubules. Furthermore, we showed that the γTuSC is required for assembly of two central pair proteins and that γTuSC subunits are mutually required for stability. Together, these results identified an unusual γ-tubulin complex in T. brucei, uncovered an essential role of γTuSC in central pair protein assembly, and demonstrated the interdependence of individual γTuSC components for maintaining a stable complex. PMID:26224545

  4. The discovery and development of antiretroviral agents

    NARCIS (Netherlands)

    Lange, Joep M. A.; Ananworanich, Jintanat

    2014-01-01

    Since the discovery of HIV as the causative agent of AIDS in 1983/1984, remarkable progress has been made in finding antiretroviral drugs (ARVs) that are effective against it. A major breakthrough occurred in 1996 when it was found that triple drug therapy (HAART) could durably suppress viral

  5. 77 FR 5711 - Guidelines for Determining Probability of Causation Under the Energy Employees Occupational...

    Science.gov (United States)

    2012-02-06

    ... Guidelines for Determining Probability of Causation Under the Energy Employees Occupational Illness... provide a technical review of a proposed amendment to the probability of causation guidelines.\\2\\ All of..., and hence had required DOL to assign a probability of causation value of ``zero.'' There were two...

  6. Regularity and counterfactuality in Hume's treatment of causation

    Directory of Open Access Journals (Sweden)

    José Oscar de Almeida Marques

    2011-12-01

    Full Text Available Of the several theories of causation current in our days, Hume is said to be the inspiration of two of the most influential and accepted: the regularity theory, first clearly formulated by Thomas Brown in 1822, and the counterfactual theory, proposed by David Lewis in 1973. After a brief outline of the comparative merits and difficulties of these two views, I proceed to examine whether Hume's own treatment of causation actually corresponds to any of them. I will show that his first definition of cause, coupled with his rules by which to judge about causes and effects, contains elements that, properly developed, allow us to address successfully some traditional difficulties of the regularity view of causation, without resorting to the conceptual resources employed in the counterfactual approach. Therefore, we can properly classify Hume as an advocate of the conception of causation as regularity, noting however that his primary goal in his research and definitions of the concept was to provide not so much an analysis of causation as such, but of causation as we apprehend it, in the form of our ability to make causal inferences and refine them to reach the more sophisticated causal reasonings that are required in the theoretical and practical issues of life.Das diversas teorias da causação existentes em nossos dias, Hume pode ser considerado o precursor de duas das mais influentes e aceitas: a teoria regularista, formulada claramente pela primeira vez por Thomas Brown, em 1822, e a teoria contrafatualista, proposta por David Lewis em 1973. Depois de um breve resumo dos méritos e dificuldades comparativos dessas duas perspectivas, passo a examinar se o tratamento de Hume da causação corresponde, na verdade a algum deles. Mostro que a sua primeira definição de causa, juntamente com suas regras para julgar sobre as causas e efeitos, contém elementos que, devidamente desenvolvidos, permitem-nos abordar com sucesso algumas dificuldades

  7. Bias and Causation Models and Judgment for Valid Comparisons

    CERN Document Server

    Weisberg, Herbert I

    2010-01-01

    A one-of-a-kind resource on identifying and dealing with bias in statistical research on causal effects. Do cell phones cause cancer? Can a new curriculum increase student achievement? Determining what the real causes of such problems are, and how powerful their effects may be, are central issues in research across various fields of study. Some researchers are highly skeptical of drawing causal conclusions except in tightly controlled randomized experiments, while others discount the threats posed by different sources of bias, even in less rigorous observational studies. Bias and Causation pre

  8. Critical review of the probability of causation method

    International Nuclear Information System (INIS)

    Cox, L.A. Jr.; Fiksel, J.R.

    1985-01-01

    In a more controversial report than the others in the study, the authors use one scientific discipline to review the work of another discipline. Their proposal recognizes the imprecision that develops in moving from group to individual interpretations of causal effects by substituting the term assigned share for probability of causation. The authors conclude that the use of a formula will not provide reliable measures of risk attribution in individual cases. The gap between scientific certainty and assigning shares of responsibility must be filled by subjective value judgments supplied by the scientists. 22 references, 2 figures, 4 tables

  9. Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Ward Pauline N

    2005-09-01

    Full Text Available Abstract Background The trypanosomatids Leishmania major, Trypanosoma brucei and Trypanosoma cruzi cause some of the most debilitating diseases of humankind: cutaneous leishmaniasis, African sleeping sickness, and Chagas disease. These protozoa possess complex life cycles that involve development in mammalian and insect hosts, and a tightly coordinated cell cycle ensures propagation of the highly polarized cells. However, the ways in which the parasites respond to their environment and coordinate intracellular processes are poorly understood. As a part of an effort to understand parasite signaling functions, we report the results of a genome-wide analysis of protein kinases (PKs of these three trypanosomatids. Results Bioinformatic searches of the trypanosomatid genomes for eukaryotic PKs (ePKs and atypical PKs (aPKs revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L. major, most of which are orthologous across the three species. This is approximately 30% of the number in the human host and double that of the malaria parasite, Plasmodium falciparum. The representation of various groups of ePKs differs significantly as compared to humans: trypanosomatids lack receptor-linked tyrosine and tyrosine kinase-like kinases, although they do possess dual-specificity kinases. A relative expansion of the CMGC, STE and NEK groups has occurred. A large number of unique ePKs show no strong affinity to any known group. The trypanosomatids possess few ePKs with predicted transmembrane domains, suggesting that receptor ePKs are rare. Accessory Pfam domains, which are frequently present in human ePKs, are uncommon in trypanosomatid ePKs. Conclusion Trypanosomatids possess a large set of PKs, comprising approximately 2% of each genome, suggesting a key role for phosphorylation in parasite biology. Whilst it was possible to place most of the trypanosomatid ePKs into the seven established groups using bioinformatic analyses, it has not been

  10. Channel-forming activities in the glycosomal fraction from the bloodstream form of Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Melisa Gualdron-López

    Full Text Available BACKGROUND: Glycosomes are a specialized form of peroxisomes (microbodies present in unicellular eukaryotes that belong to the Kinetoplastea order, such as Trypanosoma and Leishmania species, parasitic protists causing severe diseases of livestock and humans in subtropical and tropical countries. The organelles harbour most enzymes of the glycolytic pathway that is responsible for substrate-level ATP production in the cell. Glycolysis is essential for bloodstream-form Trypanosoma brucei and enzymes comprising this pathway have been validated as drug targets. Glycosomes are surrounded by a single membrane. How glycolytic metabolites are transported across the glycosomal membrane is unclear. METHODS/PRINCIPAL FINDINGS: We hypothesized that glycosomal membrane, similarly to membranes of yeast and mammalian peroxisomes, contains channel-forming proteins involved in the selective transfer of metabolites. To verify this prediction, we isolated a glycosomal fraction from bloodstream-form T. brucei and reconstituted solubilized membrane proteins into planar lipid bilayers. The electrophysiological characteristics of the channels were studied using multiple channel recording and single channel analysis. Three main channel-forming activities were detected with current amplitudes 70-80 pA, 20-25 pA, and 8-11 pA, respectively (holding potential +10 mV and 3.0 M KCl as an electrolyte. All channels were in fully open state in a range of voltages ±150 mV and showed no sub-conductance transitions. The channel with current amplitude 20-25 pA is anion-selective (P(K+/P(Cl-∼0.31, while the other two types of channels are slightly selective for cations (P(K+/P(Cl- ratios ∼1.15 and ∼1.27 for the high- and low-conductance channels, respectively. The anion-selective channel showed an intrinsic current rectification that may suggest a functional asymmetry of the channel's pore. CONCLUSIONS/SIGNIFICANCE: These results indicate that the membrane of glycosomes

  11. Deletion Mutagenesis and Identification of Causative Mutations in Maize.

    Science.gov (United States)

    Jia, Shangang; Li, Aixia; Zhang, Chi; Holding, David

    2018-01-01

    We describe a method for gamma-irradiation of mature maize seeds to generate mutants with opaque endosperm and reduced kernel fill phenotypes. We also describe methods for mapping mutants and identifying causal gene mutations. Using this method, a population of 1788M2 families and 47 Mo17 × F2s showing stable, segregating, and viable kernel phenotypes was developed. For molecular characterization of the mutants, we utilized a novel functional genomics platform that combines separate Bulked Segregant RNA and exome sequencing data sets (BSREx-seq) to map causative mutations and identify candidate genes within mapping intervals. We also describe the use of exome capture sequencing of F2 mutant and normal pools to perform mapping and candidate gene identification without the need for separate RNA-seq (BSEx-seq). To exemplify the utility of the deletion mutants for functional genomics and provide proof-of-concept for the bioinformatics platform, we summarize the identification of the causative deletion in two mutants. Mutant 937, which was characterized by BSREx-seq, harbors a 6203-bp in-frame deletion covering six exons within the Opaque-1 gene on chromosome 4. Preliminary investigation of opaque mutant 1486 with BSEx-seq shows a tight mapping interval and associated deletion on chromosome 10.

  12. Communities, self-causation and the natural lottery.

    Science.gov (United States)

    Loewy, E H

    1988-01-01

    This paper examines the various notions of community, and of the 'natural lottery' as well as investigating the role that 'self-causation' plays in communal obligations. In examining community, two opposing views are juxtaposed: (1) the view that community consists merely of persons united by duties of refraining from harm one to another, resulting in autonomy based justice which makes freedom an absolute condition of mortality; and (2) a broader view which sees the concept of community as entailing obligations of beneficence, resulting in beneficence based justice and which, therefore, sees freedom as a value to be cautiously traded with other values. In examining the 'natural lottery' in the light of community, the various consequences of viewing the lottery in various ways and the impact that our view of community has on these consequences, is explored. A third option, the option that the 'natural lottery' as the cause of illness and health is a shaky concept, is offered. Self-causation of illness and its linkage to concepts of community and of the 'natural lottery' is then briefly examined. It is concluded that (1) community implies a social contract which, in order to be conceived in the first place, necessitates more than a minimalist ethic: to come about, a degree of beneficence inspiring trust is presupposed; (2) conceiving community narrowly is neither what we ordinarily do when we think of the term nor, for that matter, workable in our world.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Acute appendicitis: most common clinical presentation and causative microorganism

    International Nuclear Information System (INIS)

    Awan, M.Y.; Shukr, I.; Mahmood, M.A.; Qasmi, S.A.

    2013-01-01

    Objective: To determine the most common clinical presentation and causative microorganism for acute appendicitis. Study Design: Descriptive. Place and duration of study: Department of Surgery, Combined Military Hospital Multan, from June 2002 to May 2004. Patients and Methods: Clinical features of all the patients, older than 5 years of age diagnosed with acute appendicitis were recorded. Patients presented with other pathology which mimic acute appendicitis were excluded from the study. Surgery was done under general anaesthesia. Appendices of all the patient as well as pus swabs from abdominal cavity were sent to the laboratory for histopathology and microbiological cultures to confirm the diagnoses of acute appendicitis and causative organism. Results: The mean age of 75 subjects was 32.56 +- 11.93 years. The most common symptom was pain in right iliac fossa (80 % cases) and the most common physical sign was tenderness (92% cases). Some of the patients(9.3%) had a histologically normal appendix. Maximum isolates on culture were E. coli. Conclusion: The most common presentation of acute appendicitis was pain in right iliac fossa while the most sensitive sign was tenderness. Proper history and sharp clinical examination is the key to diagnosis. The most frequent organism of appendicitis was Escherichia Coli. (author)

  14. Chronic multifocal osteomyelitis: Is infectious causation a moot point?

    Directory of Open Access Journals (Sweden)

    Nevio Cimolai

    2011-09-01

    Full Text Available Summary: Chronic multifocal osteomyelitis (CMO is an uncommon disease entity with descriptions possibly emanating from the medical literature over one century ago, and there are numerous disease entities which have been historically detailed and which are probably synonymous. The illness is one of chronicity with exacerbating and remitting focal bony lesions. The differential diagnosis for a bony lesion which ultimately proves to be CMO is initially quite broad. There is no absolute pathognomonic clinical finding, and the diagnosis is highly dependent on clinical course, histopathology, and an absence of microbial infection. Recent studies have focused on immune dysfunction or dysregulation, and there are now many other diseases which are inflammatory in nature and which have been diagnosed among patients with CMO. Despite the aforementioned, the potential for direct infectious causation or indirect causation by infectious stimulation of immunity cannot be entirely excluded. Infection as a mechanism for pathogenesis must continue to be entertained. Multi-centre studies are key to future research. Key words: Osteomyelitis, Infection, SAPHO, Immunity

  15. Differential Editosome Protein Function between Life Cycle Stages of Trypanosoma brucei.

    Science.gov (United States)

    McDermott, Suzanne M; Guo, Xuemin; Carnes, Jason; Stuart, Kenneth

    2015-10-09

    Uridine insertion and deletion RNA editing generates functional mitochondrial mRNAs in Trypanosoma brucei. The mRNAs are differentially edited in bloodstream form (BF) and procyclic form (PF) life cycle stages, and this correlates with the differential utilization of glycolysis and oxidative phosphorylation between the stages. The mechanism that controls this differential editing is unknown. Editing is catalyzed by multiprotein ∼20S editosomes that contain endonuclease, 3'-terminal uridylyltransferase, exonuclease, and ligase activities. These editosomes also contain KREPB5 and KREPA3 proteins, which have no functional catalytic motifs, but they are essential for parasite viability, editing, and editosome integrity in BF cells. We show here that repression of KREPB5 or KREPA3 is also lethal in PF, but the effects on editosome structure differ from those in BF. In addition, we found that point mutations in KREPB5 or KREPA3 differentially affect cell growth, editosome integrity, and RNA editing between BF and PF stages. These results indicate that the functions of KREPB5 and KREPA3 editosome proteins are adjusted between the life cycle stages. This implies that these proteins are involved in the processes that control differential editing and that the 20S editosomes differ between the life cycle stages. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Isothermal microcalorimetry, a new tool to monitor drug action against Trypanosoma brucei and Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Tanja Wenzler

    Full Text Available Isothermal microcalorimetry is an established tool to measure heat flow of physical, chemical or biological processes. The metabolism of viable cells produces heat, and if sufficient cells are present, their heat production can be assessed by this method. In this study, we investigated the heat flow of two medically important protozoans, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Heat flow signals obtained for these pathogens allowed us to monitor parasite growth on a real-time basis as the signals correlated with the number of viable cells. To showcase the potential of microcalorimetry for measuring drug action on pathogenic organisms, we tested the method with three antitrypanosomal drugs, melarsoprol, suramin and pentamidine and three antiplasmodial drugs, chloroquine, artemether and dihydroartemisinin, each at two concentrations on the respective parasite. With the real time measurement, inhibition was observed immediately by a reduced heat flow compared to that in untreated control samples. The onset of drug action, the degree of inhibition and the time to death of the parasite culture could conveniently be monitored over several days. Microcalorimetry is a valuable element to be added to the toolbox for drug discovery for protozoal diseases such as human African trypanosomiasis and malaria. The method could probably be adapted to other protozoan parasites, especially those growing extracellularly.

  17. Flux Analysis of the Trypanosoma brucei Glycolysis Based on a Multiobjective-Criteria Bioinformatic Approach

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    Amine Ghozlane

    2012-01-01

    Full Text Available Trypanosoma brucei is a protozoan parasite of major of interest in discovering new genes for drug targets. This parasite alternates its life cycle between the mammal host(s (bloodstream form and the insect vector (procyclic form, with two divergent glucose metabolism amenable to in vitro culture. While the metabolic network of the bloodstream forms has been well characterized, the flux distribution between the different branches of the glucose metabolic network in the procyclic form has not been addressed so far. We present a computational analysis (called Metaboflux that exploits the metabolic topology of the procyclic form, and allows the incorporation of multipurpose experimental data to increase the biological relevance of the model. The alternatives resulting from the structural complexity of networks are formulated as an optimization problem solved by a metaheuristic where experimental data are modeled in a multiobjective function. Our results show that the current metabolic model is in agreement with experimental data and confirms the observed high metabolic flexibility of glucose metabolism. In addition, Metaboflux offers a rational explanation for the high flexibility in the ratio between final products from glucose metabolism, thsat is, flux redistribution through the malic enzyme steps.

  18. Identification and characterization of a stage specific membrane protein involved in flagellar attachment in Trypanosoma brucei.

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    Katherine Woods

    Full Text Available Flagellar attachment is a visibly striking morphological feature of African trypanosomes but little is known about the requirements for attachment at a molecular level. This study characterizes a previously undescribed membrane protein, FLA3, which plays an essential role in flagellar attachment in Trypanosoma brucei. FLA3 is heavily N-glycosylated, locates to the flagellar attachment zone and appears to be a bloodstream stage specific protein. Ablation of the FLA3 mRNA rapidly led to flagellar detachment and a concomitant failure of cytokinesis in the long slender bloodstream form but had no effect on the procyclic form. Flagellar detachment was obvious shortly after induction of the dsRNA and the newly synthesized flagellum was often completely detached after it emerged from the flagellar pocket. Within 12 h most cells possessed detached flagella alongside the existing attached flagellum. These results suggest that proteins involved in attachment are not shared between the new and old attachment zones. In other respects the detached flagella appear normal, they beat rapidly although directional motion was lost, and they possess an apparently normal axoneme and paraflagellar rod structure. The flagellar attachment zone appeared to be disrupted when FLA3 was depleted. Thus, while flagellar attachment is a constitutive feature of the life cycle of trypanosomes, attachment requires stage specific elements at the protein level.

  19. Relationship between Trypanosoma brucei rhodesiense genetic diversity and clinical spectrum among sleeping sickness patients in Uganda.

    Science.gov (United States)

    Kato, Charles D; Mugasa, Claire M; Nanteza, Ann; Matovu, Enock; Alibu, Vincent P

    2017-10-27

    Human African trypanosomiasis (HAT) due to Trypanosoma brucei rhodesiense in East and southern Africa is reported to be clinically diverse. We tested the hypothesis that this clinical diversity is associated with a variation in trypanosome genotypes. Trypanosome DNA isolated from HAT patients was genotyped using 7 microsatellite markers directly from blood spotted FTA cards following a whole genome amplification. All markers were polymorphic and identified 17 multi-locus genotypes with 56% of the isolates having replicate genotypes. We did not observe any significant clustering between isolates and bootstrap values across major tree nodes were insignificant. When genotypes were compared among patients with varying clinical presentation or outcome, replicate genotypes were observed at both extremes showing no significant association between genetic diversity and clinical outcome. Our study shows that T. b. rhodesiense isolates are homogeneous within a focus and that observed clinical diversity may not be associated with parasite genetic diversity. Other factors like host genetics and environmental factors might be involved in determining clinical diversity. Our study may be important in designing appropriate control measures that target the parasite.

  20. Three Redox States of Trypanosoma brucei Alternative Oxidase Identified by Infrared Spectroscopy and Electrochemistry

    Science.gov (United States)

    Maréchal, Amandine; Kido, Yasutoshi; Kita, Kiyoshi; Moore, Anthony L.; Rich, Peter R.

    2009-01-01

    Electrochemistry coupled with Fourier transform infrared (IR) spectroscopy was used to investigate the redox properties of recombinant alternative ubiquinol oxidase from Trypanosoma brucei, the organism responsible for African sleeping sickness. Stepwise reduction of the fully oxidized resting state of recombinant alternative ubiquinol oxidase revealed two distinct IR redox difference spectra. The first of these, signal 1, titrates in the reductive direction as an n = 2 Nernstian component with an apparent midpoint potential of 80 mV at pH 7.0. However, reoxidation of signal 1 in the same potential range under anaerobic conditions did not occur and only began with potentials in excess of 500 mV. Reoxidation by introduction of oxygen was also unsuccessful. Signal 1 contained clear features that can be assigned to protonation of at least one carboxylate group, further perturbations of carboxylic and histidine residues, bound ubiquinone, and a negative band at 1554 cm−1 that might arise from a radical in the fully oxidized protein. A second distinct IR redox difference spectrum, signal 2, appeared more slowly once signal 1 had been reduced. This component could be reoxidized with potentials above 100 mV. In addition, when both signals 1 and 2 were reduced, introduction of oxygen caused rapid oxidation of both components. These data are interpreted in terms of the possible active site structure and mechanism of oxygen reduction to water. PMID:19767647

  1. Overproduction, purification, crystallization and preliminary X-ray diffraction analysis of Trypanosoma brucei gambiense glycerol kinase

    International Nuclear Information System (INIS)

    Balogun, Emmanuel Oluwadare; Inaoka, Daniel Ken; Kido, Yasutoshi; Shiba, Tomoo; Nara, Takeshi; Aoki, Takashi; Honma, Teruki; Tanaka, Akiko; Inoue, Masayuki; Matsuoka, Shigeru; Michels, Paul A. M.; Harada, Shigeharu; Kita, Kiyoshi

    2010-01-01

    Glycerol kinase from human African trypanosomes has been purified and crystallized for X-ray structure analysis. In the bloodstream forms of human trypanosomes, glycerol kinase (GK; EC 2.7.1.30) is one of the nine glycosomally compartmentalized enzymes that are essential for energy metabolism. In this study, a recombinant Trypanosoma brucei gambiense GK (rTbgGK) with an N-terminal cleavable His 6 tag was overexpressed, purified to homogeneity and crystallized by the sitting-drop vapour-diffusion method using PEG 400 as a precipitant. A complete X-ray diffraction data set to 2.75 Å resolution indicated that the crystals belonged to the orthorhombic space group P2 1 2 1 2 1 , with unit-cell parameters a = 63.84, b = 121.50, c = 154.59 Å. The presence of two rTbgGK molecules in the asymmetric unit gives a Matthews coefficient (V M ) of 2.5 Å 3 Da −1 , corresponding to 50% solvent content

  2. Biological Agents

    Science.gov (United States)

    ... E-Tools Safety and Health Topics / Biological Agents Biological Agents This page requires that javascript be enabled ... 202) 693-2300 if additional assistance is required. Biological Agents Menu Overview In Focus: Ebola Frederick A. ...

  3. Profiles in medical courage: causation and Austin Bradford Hill

    Directory of Open Access Journals (Sweden)

    Robbins RA

    2012-09-01

    Full Text Available Austin Bradford Hill was a British epidemiologist and statistician who is best remembered for two landmark pulmonary studies. He was the statistician on the Medical Research Council Streptomycin in Tuberculosis Trial. This is regarded as the first randomized clinical trial. The second was the demonstration of the connection between cigarette smoking and lung cancer. However, Hill’s most lasting contribution may be his establishment of a group of conditions necessary to provide adequate evidence of a causal relationship between an incidence and a consequence, widely known as the Bradford Hill Criteria of Causation. In this profile of medical courage we examine his remarkable background that led to the epidemiological equivalent of Koch’s postulates.

  4. Probability of causation for radiogenic cancer in Indian population

    International Nuclear Information System (INIS)

    Bhatia, D.P.; Murthy, M.S.S.

    1992-01-01

    The National Institute of Health (NIH), USA has generated tables for probability of causation (PC) for various radiogenic cancers for the population of United States, (NIH 1985). These are based on cancer incidence rates derived from data on the Japanese survivors of atomic bomb, followed up to 1977 and T65D dosimetry system. In 1987, Radiation Effects Research Foundation (RERF), a cooperative Japan-United States research organisation published radiation induced risk estimates (absolute and relative) using revised system of dosimetry DS86 and extended follow up of 35 years (Yukiko et al., 1988). In this paper PC has been calculated for the Indian population: i) using absolute risk estimates of RERF and NIH methodology, and ii) using the constant relative risk coefficients (CRR) of RERF. Calculations with new risk coefficients have been extended to the American population and results compared with Indian population. (author). 3 refs., 2 figs

  5. Causation and the origin of life. Metabolism or replication first?

    Science.gov (United States)

    Pross, Addy

    2004-06-01

    The conceptual gulf that separates the 'metabolism first' and 'replication first' mechanisms for the emergence of life continues to cloud the origin of life debate. In the present paper we analyze this aspect of the origin of life problem and offer arguments in favor of the 'replication first' school. Utilizing Wicken's two-tier approach to causation we argue that a causal connection between replication and metabolism can only be demonstrated if replication would have preceded metabolism. In conjunction with existing empirical evidence and theoretical reasoning, our analysis concludes that there is no substantive evidence for a 'metabolism first' mechanism for life's emergence, while a coherent case can be made for the 'replication first' group of mechanisms. The analysis reaffirms our conviction that life is an extreme expression of kinetic control, and that the emergence of metabolic pathways can be understood by considering life as a manifestation of 'replicative chemistry'.

  6. γ-Tubulin complex in Trypanosoma brucei: molecular composition, subunit interdependence and requirement for axonemal central pair protein assembly.

    Science.gov (United States)

    Zhou, Qing; Li, Ziyin

    2015-11-01

    γ-Tubulin complex constitutes a key component of the microtubule-organizing center and nucleates microtubule assembly. This complex differs in complexity in different organisms: the budding yeast contains the γ-tubulin small complex (γTuSC) composed of γ-tubulin, gamma-tubulin complex protein (GCP)2 and GCP3, whereas animals contain the γ-tubulin ring complex (γTuRC) composed of γTuSC and three additional proteins, GCP4, GCP5 and GCP6. In Trypanosoma brucei, the composition of the γ-tubulin complex remains elusive, and it is not known whether it also regulates assembly of the subpellicular microtubules and the spindle microtubules. Here we report that the γ-tubulin complex in T. brucei is composed of γ-tubulin and three GCP proteins, GCP2-GCP4, and is primarily localized in the basal body throughout the cell cycle. Depletion of GCP2 and GCP3, but not GCP4, disrupted the axonemal central pair microtubules, but not the subpellicular microtubules and the spindle microtubules. Furthermore, we showed that the γTuSC is required for assembly of two central pair proteins and that γTuSC subunits are mutually required for stability. Together, these results identified an unusual γ-tubulin complex in T. brucei, uncovered an essential role of γTuSC in central pair protein assembly, and demonstrated the interdependence of individual γTuSC components for maintaining a stable complex. © 2015 John Wiley & Sons Ltd.

  7. Trypanosoma brucei TbIF1 inhibits the essential F1-ATPase in the infectious form of the parasite.

    Directory of Open Access Journals (Sweden)

    Brian Panicucci

    2017-04-01

    Full Text Available The mitochondrial (mt FoF1-ATP synthase of the digenetic parasite, Trypanosoma brucei, generates ATP during the insect procyclic form (PF, but becomes a perpetual consumer of ATP in the mammalian bloodstream form (BF, which lacks a canonical respiratory chain. This unconventional dependence on FoF1-ATPase is required to maintain the essential mt membrane potential (Δψm. Normally, ATP hydrolysis by this rotary molecular motor is restricted to when eukaryotic cells experience sporadic hypoxic conditions, during which this compulsory function quickly depletes the cellular ATP pool. To protect against this cellular treason, the highly conserved inhibitory factor 1 (IF1 binds the enzyme in a manner that solely inhibits the hydrolytic activity. Intriguingly, we were able to identify the IF1 homolog in T. brucei (TbIF1, but determined that its expression in the mitochondrion is tightly regulated throughout the life cycle as it is only detected in PF cells. TbIF1 appears to primarily function as an emergency brake in PF cells, where it prevented the restoration of the Δψm by FoF1-ATPase when respiration was chemically inhibited. In vitro, TbIF1 overexpression specifically inhibits the hydrolytic activity but not the synthetic capability of the FoF1-ATP synthase in PF mitochondria. Furthermore, low μM amounts of recombinant TbIF1 achieve the same inhibition of total mt ATPase activity as the FoF1-ATPase specific inhibitors, azide and oligomycin. Therefore, even minimal ectopic expression of TbIF1 in BF cells proved lethal as the indispensable Δψm collapsed due to inhibited FoF1-ATPase. In summary, we provide evidence that T. brucei harbors a natural and potent unidirectional inhibitor of the vital FoF1-ATPase activity that can be exploited for future structure-based drug design.

  8. Processing of metacaspase 2 from Trypanosoma brucei (TbMCA2) broadens its substrate specificity.

    Science.gov (United States)

    Gilio, Joyce M; Marcondes, Marcelo F; Ferrari, Débora; Juliano, Maria A; Juliano, Luiz; Oliveira, Vitor; Machado, Maurício F M

    2017-04-01

    Metacaspases are members of the cysteine peptidase family and may be implicated in programmed cell death in plants and lower eukaryotes. These proteases exhibit calcium-dependent activity and specificity for arginine residues at P 1 . In contrast to caspases, they do not require processing or dimerization for activity. Indeed, unprocessed metacaspase-2 of Trypanosoma brucei (TbMCA2) is active; however, it has been shown that cleavages at Lys 55 and Lys 268 increase TbMCA2 hydrolytic activity on synthetic substrates. The processed TbMCA2 comprises 3 polypeptide chains that remain attached by non-covalent bonds. Replacement of Lys 55 and Lys 268 with Gly via site-directed mutagenesis results in non-processed but enzymatically active mutant, TbMCA2 K55/268G. To investigate the importance of this processing for the activity and specificity of TbMCA2, we performed activity assays comparing the non-processed mutant (TbMCA2 K55/268G) with the processed TbMCA2 form. Significant differences between TbMCA2 WT (processed form) and TbMCA2 K55/268G (non-processed form) were observed. Specifically, we verified that although non-processed TbMCA2 is active when assayed with small synthetic substrates, the TbMCA2 form does not exhibit hydrolytic activity on large substrates such as azocasein, while processed TbMCA2 is able to readily digest this protein. Such differences can be relevant for understanding the physiological regulation and function of TbMCA2. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. 3D Architecture of the Trypanosoma brucei Flagella Connector, a Mobile Transmembrane Junction.

    Directory of Open Access Journals (Sweden)

    Johanna L Höög

    2016-01-01

    Full Text Available Cellular junctions are crucial for the formation of multicellular organisms, where they anchor cells to each other and/or supportive tissue and enable cell-to-cell communication. Some unicellular organisms, such as the parasitic protist Trypanosoma brucei, also have complex cellular junctions. The flagella connector (FC is a three-layered transmembrane junction that moves with the growing tip of a new flagellum and attaches it to the side of the old flagellum. The FC moves via an unknown molecular mechanism, independent of new flagellum growth. Here we describe the detailed 3D architecture of the FC suggesting explanations for how it functions and its mechanism of motility.We have used a combination of electron tomography and cryo-electron tomography to reveal the 3D architecture of the FC. Cryo-electron tomography revealed layers of repetitive filamentous electron densities between the two flagella in the interstitial zone. Though the FC does not change in length and width during the growth of the new flagellum, the interstitial zone thickness decreases as the FC matures. This investigation also shows interactions between the FC layers and the axonemes of the new and old flagellum, sufficiently strong to displace the axoneme in the old flagellum. We describe a novel filament, the flagella connector fibre, found between the FC and the axoneme in the old flagellum.The FC is similar to other cellular junctions in that filamentous proteins bridge the extracellular space and are anchored to underlying cytoskeletal structures; however, it is built between different portions of the same cell and is unique because of its intrinsic motility. The detailed description of its structure will be an important tool to use in attributing structure / function relationships as its molecular components are discovered in the future. The FC is involved in the inheritance of cell shape, which is important for the life cycle of this human parasite.

  10. Trypanosoma brucei gambiense adaptation to different mammalian sera is associated with VSG expression site plasticity.

    Science.gov (United States)

    Cordon-Obras, Carlos; Cano, Jorge; González-Pacanowska, Dolores; Benito, Agustin; Navarro, Miguel; Bart, Jean-Mathieu

    2013-01-01

    Trypanosoma brucei gambiense infection is widely considered an anthroponosis, although it has also been found in wild and domestic animals. Thus, fauna could act as reservoir, constraining the elimination of the parasite in hypo-endemic foci. To better understand the possible maintenance of T. b. gambiense in local fauna and investigate the molecular mechanisms underlying adaptation, we generated adapted cells lines (ACLs) by in vitro culture of the parasites in different mammalian sera. Using specific antibodies against the Variant Surface Glycoproteins (VSGs) we found that serum ACLs exhibited different VSG variants when maintained in pig, goat or human sera. Although newly detected VSGs were independent of the sera used, the consistent appearance of different VSGs suggested remodelling of the co-transcribed genes at the telomeric Expression Site (VSG-ES). Thus, Expression Site Associated Genes (ESAGs) sequences were analysed to investigate possible polymorphism selection. ESAGs 6 and 7 genotypes, encoding the transferrin receptor (TfR), expressed in different ACLs were characterised. In addition, we quantified the ESAG6/7 mRNA levels and analysed transferrin (Tf) uptake. Interestingly, the best growth occurred in pig and human serum ACLs, which consistently exhibited a predominant ESAG7 genotype and higher Tf uptake than those obtained in calf and goat sera. We also detected an apparent selection of specific ESAG3 genotypes in the pig and human serum ACLs, suggesting that other ESAGs could be involved in the host adaptation processes. Altogether, these results suggest a model whereby VSG-ES remodelling allows the parasite to express a specific set of ESAGs to provide selective advantages in different hosts. Finally, pig serum ACLs display phenotypic adaptation parameters closely related to human serum ACLs but distinct to parasites grown in calf and goat sera. These results suggest a better suitability of swine to maintain T. b. gambiense infection supporting

  11. Proximity Interactions among Basal Body Components in Trypanosoma brucei Identify Novel Regulators of Basal Body Biogenesis and Inheritance

    Directory of Open Access Journals (Sweden)

    Hung Quang Dang

    2017-01-01

    Full Text Available The basal body shares similar architecture with centrioles in animals and is involved in nucleating flagellar axonemal microtubules in flagellated eukaryotes. The early-branching Trypanosoma brucei possesses a motile flagellum nucleated from the basal body that consists of a mature basal body and an adjacent pro-basal body. Little is known about the basal body proteome and its roles in basal body biogenesis and flagellar axoneme assembly in T. brucei. Here, we report the identification of 14 conserved centriole/basal body protein homologs and 25 trypanosome-specific basal body proteins. These proteins localize to distinct subdomains of the basal body, and several of them form a ring-like structure surrounding the basal body barrel. Functional characterization of representative basal body proteins revealed distinct roles in basal body duplication/separation and flagellar axoneme assembly. Overall, this work identified novel proteins required for basal body duplication and separation and uncovered new functions of conserved basal body proteins in basal body duplication and separation, highlighting an unusual mechanism of basal body biogenesis and inheritance in this early divergent eukaryote.

  12. In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase

    Directory of Open Access Journals (Sweden)

    Fabian C. Herrmann

    2015-09-01

    Full Text Available As part of our ongoing efforts to identify natural products with activity against pathogens causing neglected tropical diseases, we are currently performing an extensive screening of natural product (NP databases against a multitude of protozoan parasite proteins. Within this project, we screened a database of NPs from a commercial supplier, AnalytiCon Discovery (Potsdam, Germany, against Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH, a glycolytic enzyme whose inhibition deprives the parasite of energy supply. NPs acting as potential inhibitors of the mentioned enzyme were identified using a pharmacophore-based virtual screening and subsequent docking of the identified hits into the active site of interest. In a set of 700 structures chosen for the screening, 13 (1.9% were predicted to possess significant affinity towards the enzyme and were therefore tested in an in vitro enzyme assay using recombinant TbGAPDH. Nine of these in silico hits (69% showed significant inhibitory activity at 50 µM, of which two geranylated benzophenone derivatives proved to be particularly active with IC50 values below 10 µM. These compounds also showed moderate in vitro activity against T. brucei rhodesiense and may thus represent interesting starting points for further optimization.

  13. In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase.

    Science.gov (United States)

    Herrmann, Fabian C; Lenz, Mairin; Jose, Joachim; Kaiser, Marcel; Brun, Reto; Schmidt, Thomas J

    2015-09-03

    As part of our ongoing efforts to identify natural products with activity against pathogens causing neglected tropical diseases, we are currently performing an extensive screening of natural product (NP) databases against a multitude of protozoan parasite proteins. Within this project, we screened a database of NPs from a commercial supplier, AnalytiCon Discovery (Potsdam, Germany), against Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH), a glycolytic enzyme whose inhibition deprives the parasite of energy supply. NPs acting as potential inhibitors of the mentioned enzyme were identified using a pharmacophore-based virtual screening and subsequent docking of the identified hits into the active site of interest. In a set of 700 structures chosen for the screening, 13 (1.9%) were predicted to possess significant affinity towards the enzyme and were therefore tested in an in vitro enzyme assay using recombinant TbGAPDH. Nine of these in silico hits (69%) showed significant inhibitory activity at 50 µM, of which two geranylated benzophenone derivatives proved to be particularly active with IC50 values below 10 µM. These compounds also showed moderate in vitro activity against T. brucei rhodesiense and may thus represent interesting starting points for further optimization.

  14. Independent Analysis of the Flagellum Surface and Matrix Proteomes Provides Insight into Flagellum Signaling in Mammalian-infectious Trypanosoma brucei*

    Science.gov (United States)

    Oberholzer, Michael; Langousis, Gerasimos; Nguyen, HoangKim T.; Saada, Edwin A.; Shimogawa, Michelle M.; Jonsson, Zophonias O.; Nguyen, Steven M.; Wohlschlegel, James A.; Hill, Kent L.

    2011-01-01

    The flagellum of African trypanosomes is an essential and multifunctional organelle that functions in motility, cell morphogenesis, and host-parasite interaction. Previous studies of the trypanosome flagellum have been limited by the inability to purify flagella without first removing the flagellar membrane. This limitation is particularly relevant in the context of studying flagellum signaling, as signaling requires surface-exposed proteins in the flagellar membrane and soluble signaling proteins in the flagellar matrix. Here we employ a combination of genetic and mechanical approaches to purify intact flagella from the African trypanosome, Trypanosoma brucei, in its mammalian-infectious stage. We combined flagellum purification with affinity-purification of surface-exposed proteins to conduct independent proteomic analyses of the flagellum surface and matrix fractions. The proteins identified encompass a broad range of molecular functionalities, including many predicted to function in signaling. Immunofluorescence and RNA interference studies demonstrate flagellum localization and function for proteins identified and provide insight into mechanisms of flagellum attachment and motility. The flagellum surface proteome includes many T. brucei-specific proteins and is enriched for proteins up-regulated in the mammalian-infectious stage of the parasite life-cycle. The combined results indicate that the flagellum surface presents a diverse and dynamic host-parasite interface that is well-suited for host-parasite signaling. PMID:21685506

  15. TbPIF5 is a Trypanosoma brucei mitochondrial DNA helicase involved in processing of minicircle Okazaki fragments.

    Directory of Open Access Journals (Sweden)

    Beiyu Liu

    2009-09-01

    Full Text Available Trypanosoma brucei's mitochondrial genome, kinetoplast DNA (kDNA, is a giant network of catenated DNA rings. The network consists of a few thousand 1 kb minicircles and several dozen 23 kb maxicircles. Here we report that TbPIF5, one of T. brucei's six mitochondrial proteins related to Saccharomyces cerevisiae mitochondrial DNA helicase ScPIF1, is involved in minicircle lagging strand synthesis. Like its yeast homolog, TbPIF5 is a 5' to 3' DNA helicase. Together with other enzymes thought to be involved in Okazaki fragment processing, TbPIF5 localizes in vivo to the antipodal sites flanking the kDNA. Minicircles in wild type cells replicate unidirectionally as theta-structures and are unusual in that Okazaki fragments are not joined until after the progeny minicircles have segregated. We now report that overexpression of TbPIF5 causes premature removal of RNA primers and joining of Okazaki fragments on theta structures. Further elongation of the lagging strand is blocked, but the leading strand is completed and the minicircle progeny, one with a truncated H strand (ranging from 0.1 to 1 kb, are segregated. The minicircles with a truncated H strand electrophorese on an agarose gel as a smear. This replication defect is associated with kinetoplast shrinkage and eventual slowing of cell growth. We propose that TbPIF5 unwinds RNA primers after lagging strand synthesis, thus facilitating processing of Okazaki fragments.

  16. Trypanosoma brucei TBRGG1, a mitochondrial oligo(U)-binding protein that co-localizes with an in vitro RNA editing activity

    NARCIS (Netherlands)

    Vanhamme, L.; Perez-Morga, D.; Marchal, C.; Speijer, D.; Lambert, L.; Geuskens, M.; Alexandre, S.; Ismaïli, N.; Göringer, U.; Benne, R.; Pays, E.

    1998-01-01

    We report the characterization of a Trypanosoma brucei 75-kDa protein of the RGG (Arg-Gly-Gly) type, termed TBRGG1. Dicistronic and monocistronic transcripts of the TBRGG1 gene were produced by both alternative splicing and polyadenylation. TBRGG1 was found in two or three forms that differ in their

  17. The 2’-O-ribose methyltransferase for cap 1 of spliced leader RNA and U1 small nuclear RNA in Trypanosoma brucei

    Czech Academy of Sciences Publication Activity Database

    Zamudio, J. R.; Mittra, B.; Foldynová-Trantírková, Silvie; Zeiner, G. M.; Lukeš, Julius; Bujnicki, J. M.; Sturm, N. R.; Campbell, D. A.

    2007-01-01

    Roč. 27, č. 17 (2007), s. 6084-6092 ISSN 0270-7306 R&D Projects: GA MŠk 2B06129; GA MŠk LC07032 Institutional research plan: CEZ:AV0Z60220518 Keywords : methylation * Trypanosoma brucei * methyltransferase * RNA interference Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.420, year: 2007

  18. Cumulative causation, market transition, and emigration from China.

    Science.gov (United States)

    Liang, Zai; Chunyu, Miao David; Zhuang, Guotu; Ye, Wenzhen

    2008-11-01

    This article reports findings from a recent survey of international migration from China's Fujian Province to the United States. Using the ethnosurvey approach developed in the Mexican Migration Project, the authors conducted surveys in migrant-sending communities in China as well as in destination communities in New York City. Hypotheses are derived from the international migration literature and the market transition debate. The results are generally consistent with hypotheses derived from cumulative causation of migration; however, geographical location creates some differences in migration patterns to the United States. In China as in Mexico, the existence of migration networks increases the propensity of migration for others in the community. In contrast to the Mexican case, among Chinese immigrants, having a previously migrated household member increases the propensity of other household members to migrate only after the debt for previous migration is paid off. In step with market transition theory, the authors also find that political power influences the migration experience from the coastal Fujian Province.

  19. Illness Causation and Interpretation in a Newar Town

    Directory of Open Access Journals (Sweden)

    Madhusudan Subedi

    2012-06-01

    Full Text Available One of the core concerns of medical anthropology is to explore how people in different cultures and social groups explain the causes of ill health, the type of treatment they believe in, and to whom they turn if they do become ill. This article focuses on the understanding of illness causation by the Newars in Kirtipur and their concern about biological and socio-cultural aspects of healthy behavior, and particularly with the ways in which they have been coping in everyday life. The basic method of data collection for this study was formal and informal discussions with the elderly Newar males and females, followed by discussions with youths to explore the variations in their perceptions. The findings show that the understanding of illness etiology is multi-causal. The individual, natural, social, and supernatural causes are not mutually exclusive but are usually linked together in a particular case. In any specific case of illness, moreover, people’s explanatory model varies in how they explain its etiology.DOI: http://dx.doi.org/10.3126/dsaj.v5i0.6358 Dhaulagiri Journal of Sociology and Anthropology Vol. 5, 2011: 101-120    

  20. Causative factors for formation of toxic islet amyloid polypeptide oligomer in type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Jeong HR

    2015-11-01

    Full Text Available Hye Rin Jeong, Seong Soo A AnDepartment of Bionano Technology, Gachon Medical Research Institute, Gachon University, Gyeonggi-do, Republic of KoreaAbstract: Human islet amyloid polypeptide (h-IAPP is a peptide hormone that is synthesized and cosecreted with insulin from insulin-secreting pancreatic β-cells. Recently, h-IAPP was proposed to be the main component responsible for the cytotoxic pancreatic amyloid deposits in patients with type 2 diabetes mellitus (T2DM. Since the causative factors of IAPP (or amylin oligomer aggregation are not fully understood, this review will discuss the various forms of h-IAPP aggregation. Not all forms of IAPP aggregates trigger the destruction of β-cell function and loss of β-cell mass; however, toxic oligomers do trigger these events. Once these toxic oligomers form under abnormal metabolic conditions in T2DM, they can lead to cell disruption by inducing cell membrane destabilization. In this review, the various factors that have been shown to induce toxic IAPP oligomer formation will be presented, as well as the potential mechanism of oligomer and fibril formation from pro-IAPPs. Initially, pro-IAPPs undergo enzymatic reactions to produce the IAPP monomers, which can then develop into oligomers and fibrils. By this mechanism, toxic oligomers could be generated by diverse pathway components. Thus, the interconnections between factors that influence amyloid aggregation (eg, absence of PC2 enzyme, deamidation, reduction of disulfide bonds, environmental factors in the cell, genetic mutations, copper metal ions, and heparin will be presented. Hence, this review will aid in understanding the fundamental causative factors contributing to IAPP oligomer formation and support studies for investigating novel T2DM therapeutic approaches, such as the development of inhibitory agents for preventing oligomerization at the early stages of diabetic pathology.Keywords: amyloid aggregation, causative factor, IAPP, islet

  1. When Russians Learn English: How the Semantics of Causation May Change

    Science.gov (United States)

    Wolff, Phillip; Ventura, Tatyana

    2009-01-01

    We examined how the semantics of causal expressions in Russian and English might differ and how these differences might lead to changes in the way second language learners understand causal expressions in their first language. According to the dynamics model of causation (Wolff, 2007), expressions of causation based on CAUSE verbs (make, force)…

  2. 76 FR 36891 - Guidelines for Determining Probability of Causation Under the Energy Employees Occupational...

    Science.gov (United States)

    2011-06-23

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES 42 CFR Part 81 [Docket Number NIOSH-0209] RIN 0920-AA39 Guidelines for Determining Probability of Causation Under the Energy Employees Occupational Illness...: HHS published a proposed rule entitled ``Guidelines for Determining Probability of Causation Under the...

  3. Dynamics of gamete production and mating in the parasitic protist Trypanosoma brucei.

    Science.gov (United States)

    Peacock, Lori; Bailey, Mick; Gibson, Wendy

    2016-07-20

    Sexual reproduction in Plasmodium falciparum and Trypanosoma brucei occurs in the insect vector and is important in generating hybrid strains with different combinations of parental characteristics. Production of hybrid parasite genotypes depends on the likelihood of co-infection of the vector with multiple strains. In mosquitoes, existing infection with Plasmodium facilitates the establishment of a second infection, although the asynchronicity of gamete production subsequently prevents mating. In the trypanosome/tsetse system, flies become increasingly refractory to infection as they age, so the likelihood of a fly acquiring a second infection also decreases. This effectively restricts opportunities for trypanosome mating to co-infections picked up by the fly on its first feed, unless an existing infection increases the chance of successful second infection as in the Plasmodium/mosquito system. Using green and red fluorescent trypanosomes, we compared the rates of trypanosome infection and hybrid production in flies co-infected on the first feed, co-infected on a subsequent feed 18 days after emergence, or fed sequentially with each trypanosome clone 18 days apart. Infection rates were highest in the midguts and salivary glands (SG) of flies that received both trypanosome clones in their first feed, and were halved when the infected feed was delayed to day 18. In flies fed the two trypanosome clones sequentially, the second clone often failed to establish a midgut infection and consequently was not present in the SG. Nevertheless, hybrids were recovered from all three groups of infected flies. Meiotic stages and gametes were produced continuously from day 11 to 42 after the infective feed, and in sequentially infected flies, the co-occurrence of gametes led to hybrid formation. We found that a second trypanosome strain can establish infection in the tsetse SG 18 days after the first infected feed, with co-mingling of gametes and production of trypanosome hybrids

  4. The use of yellow fluorescent hybrids to indicate mating in Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Ferris Vanessa

    2008-02-01

    Full Text Available Abstract Background Trypanosoma brucei undergoes genetic exchange in its insect vector, the tsetse fly, by an unknown mechanism. The difficulties of working with this experimental system of genetic exchange have hampered investigation, particularly because the trypanosome life cycle stages involved cannot be cultured in vitro and therefore must be examined in the insect. Searching for small numbers of hybrid trypanosomes directly in the fly has become possible through the incorporation of fluorescent reporter genes, and we have previously carried out a successful cross using a reporter-repressor strategy. However, we could not be certain that all fluorescent trypanosomes observed in that cross were hybrids, due to mutations of the repressor leading to spontaneous fluorescence, and we have therefore developed an alternative strategy. Results To visualize the production of hybrids in the fly, parental trypanosome clones were transfected with a gene encoding Green Fluorescent Protein (GFP or Red Fluorescent Protein (RFP. Co-infection of flies with red and green fluorescent parental trypanosomes produced yellow fluorescent hybrids, which were easily visualized in the fly salivary glands. Yellow trypanosomes were not seen in midgut or proventricular samples and first appeared in the glands as epimastigotes as early as 13 days after fly infection. Cloned progeny originating from individual salivary glands had yellow, red, green or no fluorescence and were confirmed as hybrids by microsatellite, molecular karyotype and kinetoplast (mitochondrial DNA analyses. Hybrid clones showed biparental inheritance of both nuclear and kinetoplast genomes. While segregation and reassortment of the reporter genes and microsatellite alleles were consistent with Mendelian inheritance, flow cytometry measurement of DNA content revealed both diploid and polyploid trypanosomes among the hybrid progeny clones. Conclusion The strategy of using production of yellow hybrids

  5. Single-subunit oligosaccharyltransferases of Trypanosoma brucei display different and predictable peptide acceptor specificities.

    Science.gov (United States)

    Jinnelov, Anders; Ali, Liaqat; Tinti, Michele; Güther, Maria Lucia S; Ferguson, Michael A J

    2017-12-08

    Trypanosoma brucei causes African trypanosomiasis and contains three full-length oligosaccharyltransferase (OST) genes; two of which, Tb STT3A and Tb STT3B, are expressed in the bloodstream form of the parasite. These OSTs have different peptide acceptor and lipid-linked oligosaccharide donor specificities, and trypanosomes do not follow many of the canonical rules developed for other eukaryotic N -glycosylation pathways, raising questions as to the basic architecture and detailed function of trypanosome OSTs. Here, we show by blue-native gel electrophoresis and stable isotope labeling in cell culture proteomics that the Tb STT3A and Tb STT3B proteins associate with each other in large complexes that contain no other detectable protein subunits. We probed the peptide acceptor specificities of the OSTs in vivo using a transgenic glycoprotein reporter system and performed glycoproteomics on endogenous parasite glycoproteins using sequential endoglycosidase H and peptide: N -glycosidase-F digestions. This allowed us to assess the relative occupancies of numerous N -glycosylation sites by endoglycosidase H-resistant N -glycans originating from Man 5 GlcNAc 2 -PP-dolichol transferred by Tb STT3A, and endoglycosidase H-sensitive N -glycans originating from Man 9 GlcNAc 2 -PP-dolichol transferred by Tb STT3B. Using machine learning, we assessed the features that best define Tb STT3A and Tb STT3B substrates in vivo and built an algorithm to predict the types of N -glycan most likely to predominate at all the putative N -glycosylation sites in the parasite proteome. Finally, molecular modeling was used to suggest why Tb STT3A has a distinct preference for sequons containing and/or flanked by acidic amino acid residues. Together, these studies provide insights into how a highly divergent eukaryote has re-wired protein N -glycosylation to provide protein sequence-specific N -glycan modifications. Data are available via ProteomeXchange with identifiers PXD007236, PXD007267

  6. The Born Rule and Free Will: why Libertarian Agent-Causal Free Will is not "antiscientific"

    Science.gov (United States)

    Kastner, Ruth E.

    In the libertarian "agent causation" view of free will, free choices are attributable only to the choosing agent, as opposed to a specific cause or causes outside the agent. An often-repeated claim in the philosophical literature on free will is that agent causation necessarily implies lawlessness, and is therefore "antiscientific." That claim is critiqued and it is argued, on the contrary, that the volitional powers of a free agent need not be viewed as anomic, specifically with regard to the quantum statistical law (the Born Rule). Assumptions about the role and nature of causation, taken as bearing on volitional agency, are examined and found inadequate to the task. Finally, it is suggested that quantum theory may constitute precisely the sort of theory required for a nomic grounding of libertarian free will.

  7. The Aurora Kinase in Trypanosoma brucei plays distinctive roles in metaphase-anaphase transition and cytokinetic initiation.

    Directory of Open Access Journals (Sweden)

    Ziyin Li

    2009-09-01

    Full Text Available Aurora B kinase is an essential regulator of chromosome segregation with the action well characterized in eukaryotes. It is also implicated in cytokinesis, but the detailed mechanism remains less clear, partly due to the difficulty in separating the latter from the former function in a growing cell. A chemical genetic approach with an inhibitor of the enzyme added to a synchronized cell population at different stages of the cell cycle would probably solve this problem. In the deeply branched parasitic protozoan Trypanosoma brucei, an Aurora B homolog, TbAUK1, was found to control both chromosome segregation and cytokinetic initiation by evidence from RNAi and dominant negative mutation. To clearly separate these two functions, VX-680, an inhibitor of TbAUK1, was added to a synchronized T. brucei procyclic cell population at different cell cycle stages. The unique trans-localization pattern of the chromosomal passenger complex (CPC, consisting of TbAUK1 and two novel proteins TbCPC1 and TbCPC2, was monitored during mitosis and cytokinesis by following the migration of the proteins tagged with enhanced yellow fluorescence protein in live cells with time-lapse video microscopy. Inhibition of TbAUK1 function in S-phase, prophase or metaphase invariably arrests the cells in the metaphase, suggesting an action of TbAUK1 in promoting metaphase-anaphase transition. TbAUK1 inhibition in anaphase does not affect mitotic exit, but prevents trans-localization of the CPC from the spindle midzone to the anterior tip of the new flagellum attachment zone for cytokinetic initiation. The CPC in the midzone is dispersed back to the two segregated nuclei, while cytokinesis is inhibited. In and beyond telophase, TbAUK1 inhibition has no effect on the progression of cytokinesis or the subsequent G1, S and G2 phases until a new metaphase is attained. There are thus two clearly distinct points of TbAUK1 action in T. brucei: the metaphase-anaphase transition and

  8. Daytime Thermal Anisotropy of Urban Neighbourhoods: Morphological Causation

    Directory of Open Access Journals (Sweden)

    E. Scott Krayenhoff

    2016-01-01

    results allow first order estimation of the minimum effective anisotropy magnitude of urban neighbourhoods as a function of building-height-to-spacing ratio, building plan area density, and shortwave irradiance. Finally, four “local climate zones” are simulated at two latitudes. Removal of neighbourhood street orientation regularity for these zones decreases maximum anisotropy by 3%–31%. Furthermore, thermal and radiative material properties are a weaker predictor of anisotropy than neighbourhood morphology. This study is the first systematic evaluation of effective anisotropy magnitude and causation for urban landscapes.

  9. Causation of cancer by ionizing radiation and genomic instability

    International Nuclear Information System (INIS)

    Streffer, Christian

    2013-01-01

    The causation of cancer by ionizing radiation has been shown in many epidemiological (with exposed humans) as well as experimental studies with mammals especially mice but also rats, dogs and monkeys. Risk values have been determined in medium radiation dose ranges (∼100 to 2,000 mSv). However, in the low dose range (<100 mSv) the situation is unclear and unsolved up to now. A better knowledge of the mechanisms for the development of cancer in humans over decades after low to medium radiation exposures is necessary for the understanding of the open questions. An increase of chromosomal aberrations and other genetic changes have been frequently observed directly after radiation exposures in many cell systems including human cells. However, in 1989 it was found that an increase of genomic instability occurred after irradiation of mouse zygotes in the fibroblasts of the neonates developing from the irradiated zygotes. That means genomic instability developed many cell generations later in cells which never had been exposed to various qualities of ionizing radiations in vivo and any treatment and secondary cancers developed in photon irradiated M.Hodgkin patients preferentially in those patients who showed a comparatively high genomic instability in their lymphocytes. Since several decades it has been experienced that certain cancer patients show an extremely high radio-sensitivity. This clinical observation has been confirmed by experimental investigations with cells of such patients. It has been proven that this increased radio-sensitivity is due to genetic mutations. A number of syndromes could be defined on such a genetic basis like ataxia telangiectasia, bloom's syndrome, fanconi anemia, retinoblasoma and others. In all these syndromes mutations occur in genes which are to regulation of the cell cycle or DNA repair (preferentially repair of DSBs). These patients with an increased radio-sensitivity frequently develop cancer - very often lymphoma - and they also

  10. A role for Sar1 and ARF1 GTPases during Golgi biogenesis in the protozoan parasite Trypanosoma brucei

    Science.gov (United States)

    Yavuz, Sevil; Warren, Graham

    2017-01-01

    A single Golgi stack is duplicated and partitioned into two daughter cells during the cell cycle of the protozoan parasite Trypanosoma brucei. The source of components required to generate the new Golgi and the mechanism by which it forms are poorly understood. Using photoactivatable GFP, we show that the existing Golgi supplies components directly to the newly forming Golgi in both intact and semipermeabilized cells. The movement of a putative glycosyltransferase, GntB, requires the Sar1 and ARF1 GTPases in intact cells. In addition, we show that transfer of GntB from the existing Golgi to the new Golgi can be recapitulated in semipermeabilized cells and is sensitive to the GTP analogue GTPγS. We suggest that the existing Golgi is a key source of components required to form the new Golgi and that this process is regulated by small GTPases. PMID:28495798

  11. Sleep and rhythm changes at the time of Trypanosoma brucei invasion of the brain parenchyma in the rat.

    Science.gov (United States)

    Seke Etet, Paul F; Palomba, Maria; Colavito, Valeria; Grassi-Zucconi, Gigliola; Bentivoglio, Marina; Bertini, Giuseppe

    2012-05-01

    Human African trypanosomiasis (HAT), or sleeping sickness, is a severe disease caused by Trypanosoma brucei (T.b.). The disease hallmark is sleep alterations. Brain involvement in HAT is a crucial pathogenetic step for disease diagnosis and therapy. In this study, a rat model of African trypanosomiasis was used to assess changes of sleep-wake, rest-activity, and body temperature rhythms in the time window previously shown as crucial for brain parenchyma invasion by T.b. to determine potential biomarkers of this event. Chronic radiotelemetric monitoring in Sprague-Dawley rats was used to continuously record electroencephalogram, electromyogram, rest-activity, and body temperature in the same animals before (baseline recording) and after infection. Rats were infected with T.b. brucei. Data were acquired from 1 to 20 d after infection (parasite neuroinvasion initiates at 11-13 d post-infection in this model), and were compared to baseline values. Sleep parameters were manually scored from electroencephalographic-electromyographic tracings. Circadian rhythms of sleep time, slow-wave activity, rest-activity, and body temperature were studied using cosinor rhythmometry. Results revealed alterations of most of the analyzed parameters. In particular, sleep pattern and sleep-wake organization plus rest-activity and body temperature rhythms exhibited early quantitative and qualitative alterations, which became marked around the time interval crucial for parasite neuroinvasion or shortly after. Data derived from actigrams showed close correspondence with those from hypnograms, suggesting that rest-activity could be useful to monitor sleep-wake alterations in African trypanosomiasis.

  12. Impact of the probability of causation on the radiation protection program

    International Nuclear Information System (INIS)

    Meinhold, C.B.

    1988-01-01

    Although the probability of causation approach is the only scientific basis on which a given cancer can be judged to be causally related to a given exposure, the impact of this concept on the radiation safety program could be counter-productive. As health physicists, the practices and the concepts we employ have been developed to protect the worker. Effective dose equivalent and committed dose equivalent are protective concepts but useless for probability of causation analysis. Perhaps extensive records will be the only way that good radiation protection and probability of causation analysis can coexist

  13. [Alkylating agents].

    Science.gov (United States)

    Pourquier, Philippe

    2011-11-01

    With the approval of mechlorethamine by the FDA in 1949 for the treatment of hematologic malignancies, alkylating agents are the oldest class of anticancer agents. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in specific indications and sometimes represent the unique option for the treatment of refractory diseases. Here, we are reviewing the major classes of alkylating agents and their mechanism of action, with a particular emphasis for the new generations of alkylating agents. As for most of the chemotherapeutic agents used in the clinic, these compounds are derived from natural sources. With a complex but original mechanism of action, they represent new interesting alternatives for the clinicians, especially for tumors that are resistant to conventional DNA damaging agents. We also briefly describe the different strategies that have been or are currently developed to potentiate the use of classical alkylating agents, especially the inhibition of pathways that are involved in the repair of DNA lesions induced by these agents. In this line, the development of PARP inhibitors is a striking example of the recent regain of interest towards the "old" alkylating agents.

  14. Human and animal Trypanosomes in Côte d'Ivoire form a single breeding population.

    Directory of Open Access Journals (Sweden)

    Paul Capewell

    Full Text Available Trypanosoma brucei is the causative agent of African Sleeping Sickness in humans and contributes to the related veterinary disease, Nagana. T. brucei is segregated into three subspecies based on host specificity, geography and pathology. T. b. brucei is limited to animals (excluding some primates throughout sub-Saharan Africa and is non-infective to humans due to trypanolytic factors found in human serum. T. b. gambiense and T. b. rhodesiense are human infective sub-species. T. b. gambiense is the more prevalent human, causing over 97% of human cases. Study of T. b. gambiense is complicated in that there are two distinct groups delineated by genetics and phenotype. The relationships between the two groups and local T. b. brucei are unclear and may have a bearing on the evolution of the human infectivity traits.A collection of sympatric T. brucei isolates from Côte d'Ivoire, consisting of T. b. brucei and both groups of T. b. gambiense have previously been categorized by isoenzymes, RFLPs and Blood Incubation Infectivity Tests. These samples were further characterized using the group 1 specific marker, TgSGP, and seven microsatellites. The relationships between the T. b. brucei and T. b. gambiense isolates were determined using principal components analysis, neighbor-joining phylogenetics, STRUCTURE, FST, Hardy-Weinberg equilibrium and linkage disequilibrium.Group 1 T. b. gambiense form a clonal genetic group, distinct from group 2 and T. b. brucei, whereas group 2 T. b. gambiense are genetically indistinguishable from local T. b. brucei. There is strong evidence for mating within and between group 2 T. b. gambiense and T. b. brucei. We found no evidence to support the hypothesis that group 2 T. b. gambiense are hybrids of group 1 and T. b. brucei, suggesting that human infectivity has evolved independently in groups 1 and 2 T. b. gambiense.

  15. NEURO-VASCULAR CONFLICT AS CAUSATIVE FACTOR IN IDI-OPATHIC TRIGEMINAL NEURALGIA

    Directory of Open Access Journals (Sweden)

    Mumtaz Ali

    2010-12-01

    Full Text Available Introduction Trigeminal neuralgia is one of the most unbearable pain syndromes in one or more branches of trigeminal nerve. The basic pathology is still poorly understood 1. Two divergent view points, central versus peripheral have been presented to explain the possible mechanism 2. In spite of numerous favorable reports, the neurovascular conflict theory remains contra-vertical 3. Nevertheless, whether or not, neurovascular compression is accessory or predominant in the mechanism of trigeminal neuralgia is not yet determined. Although neurovascular compression and global atrophy of the root, a focal arachnoid thickening and angulated root on crossing over the petrous ridge have been observed. Yet, neurovascular conflict has made responsible as the main cause of this neuralgia 4. This lead to focal demylination of the nerve due to its pulsatile compression. Demylination result in short circuiting of neuronal flow and hence trigeminal neuralgia 5.      Present study was therefore designed as to appreciate neurovascular conflict as causative agent in idiopathic trigeminal neuralgia. Material and Methods This prospective observational study was conducted in department of Neurosurgery Government Lady Reading Hospital Peshawar where microvascular decompression is performed as a primary procedure of choice for patients with trigeminal neuralgia. The duration of this study was from May 2003 – to June 2007. Total number of patients operated was 86. Drug resistant cases of trigeminal neuralgia that were   willing for operation was selected and proper clinical record was documented. MRI was done in all patients to exclude secondary causes of trigeminal Neuralgia. Under general Anesthesia in lateral position, small 2.5x2.5cm retro-mastoid craniotomy was performed. All these cases were operated by one surgeon with a team of associate’s doctors. Microscopic per-operative anatomical findings were recorded. Any possible per-operative complications

  16. National Motor Vehicle Crash Causation Survey (NMVCCS) - NMVCCS XML Case Viewer

    Data.gov (United States)

    Department of Transportation — The National Motor Vehicle Crash Causation Survey (NMVVCS) was a nationwide survey of crashes involving light passenger vehicles, with a focus on the factors related...

  17. Finding the best fit for direct and indirect causation: a typological study

    Directory of Open Access Journals (Sweden)

    Levshina Natalia

    2016-12-01

    Full Text Available The contrast between direct and indirect causation is the most widely discussed semantic distinction in the literature on causative constructions. This distinction has been claimed to correlate with a number of formal parameters, such as formal distance, productivity and length, which are linked to different functional and diachronic explanations based on the principles of iconicity and economy. The present study tests these claims on a typologically representative sample of languages from 46 diverse families, examining four formal variables and their association with (indirectness of causation. According to the data, formal length displays the most pervasive association with the semantic distinction in question, which supports the economy-based explanation. In addition, the relative prominence of the other formal parameters depends on the type of causatives and their stage of grammaticalization.

  18. Towards an Account of Causation in a Multilingual Text Generation System

    OpenAIRE

    Degand, Liesbeth; Seventh International Workshop on Natural Language Generation

    1994-01-01

    Causation is a very pervasive phenomenom in natural language which can be expressed by numerous linguistic alternatives. Any language user or natural language generation system is thus confronted with the problem of choosing one alternative over another. In this paper, I analyze the semantic constraints deterrnining the selection of analytic causatives in Dutch and how this can be accounted for in a systernic functional generation system.

  19. Trypanosoma brucei TbIF1 inhibits the essential Finf1/inf-ATPase in the infectious form of the parasite

    Czech Academy of Sciences Publication Activity Database

    Panicucci, Brian; Gahura, Ondřej; Zíková, Alena

    2017-01-01

    Roč. 11, č. 4 (2017), č. článku e0005552. ISSN 1935-2735 R&D Projects: GA MŠk(CZ) EE2.3.30.0032; GA ČR GA17-22248S; GA MŠk LL1205 Institutional support: RVO:60077344 Keywords : mt * TblF1 * Trypanosoma brucei Subject RIV: EE - Microbiology, Virology OBOR OECD: Infectious Diseases Impact factor: 3.834, year: 2016

  20. Trypanosoma brucei gambiense: HMI-9 medium containing methylcellulose and human serum supports the continuous axenic in vitro propagation of the bloodstream form.

    Science.gov (United States)

    Van Reet, N; Pyana, P P; Deborggraeve, S; Büscher, P; Claes, F

    2011-07-01

    Trypanosoma brucei (T.b.) gambiense causes the chronic form of human African trypanosomiasis or sleeping sickness. One of the major problems with studying T.b. gambiense is the difficulty to isolate it from its original host and the difficult adaptation to in vivo and in vitro mass propagation. The objective of this study was to evaluate if an established method for axenic culture of pleomorphic bloodstream form T.b. brucei strains, based on methylcellulose containing HMI-9 medium, also facilitated the continuous in vitro propagation of other bloodstream form Trypanozoon strains, in particular of T.b. gambiense. Bloodstream form trypanosomes from one T.b. brucei, two T.b. rhodesiense, one T. evansi and seven T.b. gambiense strains were isolated from mouse blood and each was concurrently cultivated in liquid and methylcellulose-containing HMI-9 based medium, either with or without additional human serum supplementation, for over 10 consecutive sub passages. Although HMI-9 based medium supplemented with 1.1% (w/v) methylcellulose supported the continuous cultivation of all non-gambiense strains better than liquid media could, the in vitro cultivation of all gambiense strains was only achieved in HMI-9 based medium containing 1.1% (w/v) methylcellulose, 15% (v/v) fetal calf serum and 5% (v/v) heat-inactivated human serum. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Incorporation of causative quantitative trait nucleotides in single-step GBLUP.

    Science.gov (United States)

    Fragomeni, Breno O; Lourenco, Daniela A L; Masuda, Yutaka; Legarra, Andres; Misztal, Ignacy

    2017-07-26

    Much effort is put into identifying causative quantitative trait nucleotides (QTN) in animal breeding, empowered by the availability of dense single nucleotide polymorphism (SNP) information. Genomic selection using traditional SNP information is easily implemented for any number of genotyped individuals using single-step genomic best linear unbiased predictor (ssGBLUP) with the algorithm for proven and young (APY). Our aim was to investigate whether ssGBLUP is useful for genomic prediction when some or all QTN are known. Simulations included 180,000 animals across 11 generations. Phenotypes were available for all animals in generations 6 to 10. Genotypes for 60,000 SNPs across 10 chromosomes were available for 29,000 individuals. The genetic variance was fully accounted for by 100 or 1000 biallelic QTN. Raw genomic relationship matrices (GRM) were computed from (a) unweighted SNPs, (b) unweighted SNPs and causative QTN, (c) SNPs and causative QTN weighted with results obtained with genome-wide association studies, (d) unweighted SNPs and causative QTN with simulated weights, (e) only unweighted causative QTN, (f-h) as in (b-d) but using only the top 10% causative QTN, and (i) using only causative QTN with simulated weight. Predictions were computed by pedigree-based BLUP (PBLUP) and ssGBLUP. Raw GRM were blended with 1 or 5% of the numerator relationship matrix, or 1% of the identity matrix. Inverses of GRM were obtained directly or with APY. Accuracy of breeding values for 5000 genotyped animals in the last generation with PBLUP was 0.32, and for ssGBLUP it increased to 0.49 with an unweighted GRM, 0.53 after adding unweighted QTN, 0.63 when QTN weights were estimated, and 0.89 when QTN weights were based on true effects known from the simulation. When the GRM was constructed from causative QTN only, accuracy was 0.95 and 0.99 with blending at 5 and 1%, respectively. Accuracies simulating 1000 QTN were generally lower, with a similar trend. Accuracies using the

  2. Chemical Agents

    Science.gov (United States)

    ... CR) see Riot Control Agents Digitalis Distilled mustard (HD) see Sulfur mustard E Ethylene glycol F Fentanyls and other opioids H Hydrazine Hydrofluoric acid (hydrogen fluoride) Hydrogen chloride Hydrogen cyanide (AC) Hydrogen ...

  3. Vitamin D in endometriosis: a causative or confounding factor?

    Science.gov (United States)

    Sayegh, Lamia; Fuleihan, Ghada El-Hajj; Nassar, Anwar H

    2014-01-01

    The aim of this paper is to review the evidence from studies that evaluated the relationship between vitamin D and endometriosis. Comprehensive review. Systematic literature search in Medline for relevant publications from 1946 until June 2013. Endometriosis risk may be influenced by dietary vitamin D intake and plasma hydroxyvitamin D concentration. Vitamin D receptor and vitamin D metabolizing enzymes, 24-hydroxylase and 1-α hydroxylase, are found in the normal cycling endometrium and also in the eutopic and ectopic endometrium of women with endometriosis. The endometrium is a target of 1, 25 dihydroxyvitamin D actions through regulation of specific genes and via immunomodulation. The endometrium in endometriosis expresses dysregulation of some vitamin D enzymes and receptors. If vitamin D and its metabolites are implicated in endometriosis-associated infertility, it is likely through interference with HOXA10 gene expression. The Gc2 phenotype of vitamin D binding protein is prevalent in women with endometriosis and may be implicated in its pathogenesis. In a mouse model, Elocalcitol, a VDR-agonist was shown to reduce the development of endometriotic lesions and recurrence. A biological plausibility for a role of vitamin D, as an immunomodulator and anti-inflammatory agent, in the pathogenesis and treatment of endometriosis is suggested in this article, but is difficult to illustrate due to sparse evidence from human studies limited primarily to case-control studies. A significant knowledge gap precludes the establishment of a clear cause-effect relationship. The intriguing leads presented herein need to be investigated further with placebo-controlled supplementation trials. © 2013.

  4. Comparative Genomics of Glossina palpalis gambiensis and G. morsitans morsitans to Reveal Gene Orthologs Involved in Infection by Trypanosoma brucei gambiense.

    Science.gov (United States)

    Hamidou Soumana, Illiassou; Tchicaya, Bernadette; Rialle, Stéphanie; Parrinello, Hugues; Geiger, Anne

    2017-01-01

    Blood-feeding Glossina palpalis gambiense (Gpg) fly transmits the single-celled eukaryotic parasite Trypanosoma brucei gambiense (Tbg), the second Glossina fly African trypanosome pair being Glossina morsitans / T .brucei rhodesiense. Whatever the T. brucei subspecies, whereas the onset of their developmental program in the zoo-anthropophilic blood feeding flies does unfold in the fly midgut, its completion is taking place in the fly salivary gland where does emerge a low size metacyclic trypomastigote population displaying features that account for its establishment in mammals-human individuals included. Considering that the two Glossina - T. brucei pairs introduced above share similarity with respect to the developmental program of this African parasite, we were curious to map on the Glossina morsitans morsitans (Gmm), the Differentially Expressed Genes (DEGs) we listed in a previous study. Briefly, using the gut samples collected at days 3, 10, and 20 from Gpg that were fed or not at day 0 on Tbg-hosting mice, these DGE lists were obtained from RNA seq-based approaches. Here, post the mapping on the quality controlled DEGs on the Gmm genome, the identified ortholog genes were further annotated, the resulting datasets being compared. Around 50% of the Gpg DEGs were shown to have orthologs in the Gmm genome. Under one of the three Glossina midgut sampling conditions, the number of DEGs was even higher when mapping on the Gmm genome than initially recorded. Many Gmm genes annotated as "Hypothetical" were mapped and annotated on many distinct databases allowing some of them to be properly identified. We identify Glossina fly candidate genes encoding (a) a broad panel of proteases as well as (b) chitin-binding proteins, (c) antimicrobial peptide production-Pro3 protein, transferrin, mucin, atttacin, cecropin, etc-to further select in functional studies, the objectives being to probe and validated fly genome manipulation that prevents the onset of the developmental

  5. Antitrypanosomal compounds from the essential oil and extracts of Keetia leucantha leaves with inhibitor activity on Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase.

    Science.gov (United States)

    Bero, J; Beaufay, C; Hannaert, V; Hérent, M-F; Michels, P A; Quetin-Leclercq, J

    2013-02-15

    Keetia leucantha is a West African tree used in traditional medicine to treat several diseases among which parasitic infections. The dichloromethane extract of leaves was previously shown to possess growth-inhibitory activities on Plasmodium falciparum, Trypanosoma brucei brucei and Leishmania mexicana mexicana with low or no cytotoxicity (>100 μg/ml on human normal fibroblasts) (Bero et al. 2009, 2011). In continuation of our investigations on the antitrypanosomal compounds from this dichloromethane extract, we analyzed by GC-FID and GC-MS the essential oil of its leaves obtained by hydrodistillation and the major triterpenic acids in this extract by LC-MS. Twenty-seven compounds were identified in the oil whose percentages were calculated using the normalization method. The essential oil, seven of its constituents and the three triterpenic acids were evaluated for their antitrypanosomal activity on Trypanosoma brucei brucei bloodstream forms (Tbb BSF) and procyclic forms (Tbb PF) to identify an activity on the glycolytic process of trypanosomes. The oil showed an IC(50) of 20.9 μg/ml on Tbb BSF and no activity was observed on Tbb PF. The best antitrypanosomal activity was observed for ursolic acid with IC(50) of 2.5 and 6.5 μg/ml respectively on Tbb BSF and Tbb PF. The inhibitory activity on a glycolytic enzyme of T. brucei, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was also evaluated for betulinic acid, olenaolic acid, ursolic acid, phytol, α-ionone and β-ionone. The three triterpenic acids and β-ionone showed inhibitory activities on GAPDH with oleanolic acid being the most active with an inhibition of 72.63% at 20 μg/ml. This paper reports for the first time the composition and antitrypanosomal activity of the essential oil of Keetia leucantha. Several of its constituents and three triterpenic acids present in the dichloromethane leaves extract showed a higher antitrypanosomal activity on bloodstream forms of Tbb as compared to procyclic forms

  6. Alba-domain proteins of Trypanosoma brucei are cytoplasmic RNA-binding proteins that interact with the translation machinery.

    Directory of Open Access Journals (Sweden)

    Jan Mani

    Full Text Available Trypanosoma brucei and related pathogens transcribe most genes as polycistronic arrays that are subsequently processed into monocistronic mRNAs. Expression is frequently regulated post-transcriptionally by cis-acting elements in the untranslated regions (UTRs. GPEET and EP procyclins are the major surface proteins of procyclic (insect midgut forms of T. brucei. Three regulatory elements common to the 3' UTRs of both mRNAs regulate mRNA turnover and translation. The glycerol-responsive element (GRE is unique to the GPEET 3' UTR and regulates its expression independently from EP. A synthetic RNA encompassing the GRE showed robust sequence-specific interactions with cytoplasmic proteins in electromobility shift assays. This, combined with column chromatography, led to the identification of 3 Alba-domain proteins. RNAi against Alba3 caused a growth phenotype and reduced the levels of Alba1 and Alba2 proteins, indicative of interactions between family members. Tandem-affinity purification and co-immunoprecipitation verified these interactions and also identified Alba4 in sub-stoichiometric amounts. Alba proteins are cytoplasmic and are recruited to starvation granules together with poly(A RNA. Concomitant depletion of all four Alba proteins by RNAi specifically reduced translation of a reporter transcript flanked by the GPEET 3' UTR. Pulldown of tagged Alba proteins confirmed interactions with poly(A binding proteins, ribosomal protein P0 and, in the case of Alba3, the cap-binding protein eIF4E4. In addition, Alba2 and Alba3 partially cosediment with polyribosomes in sucrose gradients. Alba-domain proteins seem to have exhibited great functional plasticity in the course of evolution. First identified as DNA-binding proteins in Archaea, then in association with nuclear RNase MRP/P in yeast and mammalian cells, they were recently described as components of a translationally silent complex containing stage-regulated mRNAs in Plasmodium. Our results are

  7. Trends in peptic ulcer disease and the identification of Helicobacter Pylori as a causative organism: Population-based estimates from the US nationwide inpatient sample

    Directory of Open Access Journals (Sweden)

    Bronislava Bashinskaya

    2011-01-01

    Full Text Available Background: Peptic ulcer disease can lead to serious complications including massive hemorrhage or bowel perforation. The modern treatment of peptic ulcer disease has transitioned from the control of gastric acid secretion to include antibiotic therapy in light of the identification of Helicobacter pylori as a causative infectious organism. We sought to determine trends related to this discovery by using a national database. Materials and Methods: Patient discharges with peptic ulcer disease and associated sequelae were queried from the Nationwide Inpatient Sample, 1993 to 2007, under the auspices of a data user agreement. To account for the Nationwide Inpatient Sample weighting schema, design-adjusted analyses were used. Standard error was calculated using SUDAAN software (Research Triangle International, NC, USA. Results: Decreases in the incidences of gastrointestinal perforation, gastrointestinal hemorrhage, and surgical procedures most specific to peptic ulcer disease were statistically significant over the study period [range of P value (two tailed = 0.000 - 0.00353; significant at P < 0.001 to < 0.01]. The incidence of H. pylori rose dramatically, peaking at an estimated 97,823 cases in 1998 [SE = 3155; 95% CI = 6,184]. Since that time it has decreased and then stabilized. Conclusions: The identification of H. pylori as the causative agent in the majority of peptic ulcer disease has revolutionized the understanding and management of the disease. Medical conditions and surgical procedures associated with end-stage peptic ulcer disease have significantly decreased according to analysis of selected index categories. Resident physician education objectives may need to be modified in light of these trends. Review Criteria: We reviewed patients with peptic ulcer disease. The database used was the Nationwide Inpatient Sample, 1993 to 2007. Message for the Clinic: Medical therapy has resulted in decreased morbidity from H. pylori infection as it

  8. Heterogenity of Echinococcus canadensis genotype 6 - the main causative agent of cystic echinococcosis in Birjand, Eastern Iran.

    Science.gov (United States)

    Karamian, Mehdi; Haghighi, Fatemeh; Hemmati, Mina; Taylor, Walter Robert; Salehabadi, Alireza; Ghatee, Mohammad Amin

    2017-10-15

    Little is known about the genotypes of Echinococcus spp. and their life cycles in eastern Iran. We analysed the partial sequences of the nad1 and cox1 genes from 17 isolates from hydatid cyst-infected patients (n=9), camels (n=5) and sheep (n=3) in Birjand, eastern Iran. A new primer pair was also used to amplify the long fragment (1180bp) of the cox1 gene. All camel and eight human isolates were G6 strains of Echinococcus canadensis while one human isolate and the three sheep isolates were G1 genotypes (sheep strain) of E. granulosus sensu stricto (s.s.). Nad1 and cox1 sequence analyses showed high G6 genetic homogeneity, similar to previously reported G6 strains from southeast and central Iran, Sudan and Mauritania. Low nucleotide and haplotype diversity similar to G6 strains from Russia (Altai republic) and Kazakhstan was also found, consistent with a bottleneck effect. In this study, G6 was the most common Echinococcus genotype. Genetic homogeneity of east, southeast and central Iranian G6 and its low genetic diversity may be due limited mobility and contact between humans and camels from other regions because of large, inhospitable deserts. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. [Drinking water regulations in Ukraine and infectious morbidity rate with water pathway of transmission of causative agents].

    Science.gov (United States)

    Surmasheva, E V; Korchak, G I; Mikhienkova, A I; Nikonova, N A; Rosada, M A

    2013-01-01

    These are presented drinking water regulations in Ukraine on microbiological indices in the new state document "Hygienic Drinking water regulations intended for human consumption" (State sanitary regulations and standards (GsanPiN) 2.2.4-171-10). There is reported an analysis of both the open waterbodies water quality and water for centralized water supply in 2007-2011 and 1992-1996 also on sanitary-bacteriological indices for performance of comparative retrospective analysis. There has been shown water quality degradation for open waterbodies, the main sources of water supply for population. Against this background, a marked improvement of drinking water quality has been noted, the number of non-standard samples decreased to 3.6 % compared with 8.8% in the preceding 15 years. This index correlates with a decrease in the number of outbreaks of infections transmitted by water. There was noted unsatisfactory registration of viral infections with water pathway of transmission and the increase in morbidity rate of gastroenterocolitides of unknown etiology that may include acute viral intestinal infections. Expediency to keep "fermentation of glucose" test in bacteriological examination of water in the identification scheme of general coliforms has been substantiated.

  10. Screening, cloning and expression analysis of a cellulase derived from the causative agent of hypertrophy sorosis scleroteniosis, Ciboria shiraiana.

    Science.gov (United States)

    Lü, Ruihua; Zhao, Aichun; Li, Jun; Liu, Changying; Wang, Chuanhong; Wang, Xiling; Wang, Xiaohong; Pei, Ruichao; Lu, Cheng; Yu, Maode

    2015-07-10

    A cellulase gene (KJ700939, CsCelA) from Ciboria shiraiana that is highly expressed during the infection of mulberry fruit was screened by quantitative real-time PCR (qRT-PCR). Using cDNA isolated from infected mulberry fruits as template, the full-length 1170-bp sequence of CsCelA was obtained, which encodes a 390-amino acid protein with a putative signal peptide of 24 amino acids. The 998-bp fragment encoding the mature peptide of CsCelA was cloned into the multiple cloning site of the pPIC9K vector and overexpressed as an active protein of 55.3kDa in the methylotrophic yeast Pichia pastoris. The specific activity of induced supernatants of the recombinant cellulase (CsCelA) was 17.44U/ml and 135U/g for freeze-dried powder. The Kmax and Vmax of CsCelA for sodium carboxymethylcellulose (CMC) were 4.6mg/ml and 107.2U/mg, respectively. The supernatant and freeze-dried powder of the recombinant cellulase exhibited stable activity from pH4.0 to 9.0, and at temperatures ranging from 30°C to 55°C. Finally, the activity of the recombinant cellulase was assessed by enzymatic hydrolysis of the cell walls of mulberry leaves. CsCelA showed an endo-cellulase mode of cleavage, as assessed by thin layer chromatography (TLC). Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Identification of functional candidates amongst hypothetical proteins of Mycobacterium leprae Br4923, a causative agent of leprosy.

    Science.gov (United States)

    Naqvi, Ahmad Abu Turab; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2015-01-01

    Mycobacterium leprae is an intracellular obligate parasite that causes leprosy in humans, and it leads to the destruction of peripheral nerves and skin deformation. Here, we report an extensive analysis of the hypothetical proteins (HPs) from M. leprae strain Br4923, assigning their functions to better understand the mechanism of pathogenesis and to search for potential therapeutic interventions. The genome of M. leprae encodes 1604 proteins, of which the functions of 632 are not known (HPs). In this paper, we predicted the probable functions of 312 HPs. First, we classified all HPs into families and subfamilies on the basis of sequence similarity, followed by domain assignment, which provides many clues for their possible function. However, the functions of 320 proteins were not predicted because of low sequence similarity with proteins of known function. Annotated HPs were categorized into enzymes, binding proteins, transporters, and proteins involved in cellular processes. We found several novel proteins whose functions were unknown for M. leprae. These proteins have a requisite association with bacterial virulence and pathogenicity. Finally, our sequence-based analysis will be helpful for further validation and the search for potential drug targets while developing effective drugs to cure leprosy.

  12. Geomyces and Pseudogymnoascus: Emergence of a primary pathogen, the causative agent of bat white-nose syndrome: Chapter 28

    Science.gov (United States)

    Verant, Michelle L.; Minnis, Andrew M.; Lindner, Daniel L.; Blehert, David

    2017-01-01

    Geomyces and Pseudogymnoascus (Fungi, Ascomycota, Leotiomycetes, aff. Thelebolales) are closely related groups of globally occurring soil-associated fungi. Recently, these genera of fungi have received attention because a newly identified species, Pseudogymnoascus (initially classified as Geomyces) destructans, was discovered in association with significant and unusual mortality of hibernating bats in North America (Blehert et al. 2009; Gargas et al. 2009; Minnis and Linder 2013). This emergent disease called bat white-nose syndrome (WNS), has since caused drastic declines in populations of hibernating bats in the United States and Canada (Turner, Reeder, and Coleman 2011; Thogmartin et al. 2012) and threatens some species with regional extinction (Frick et al. 2010; Langwig et al. 2012; Thogmartin et al. 2013). As primary predators of insects and keystone species for cave ecosystems, the loss of bats due to WNS has important economic and ecological implications.

  13. Long-Term Persistence of Pseudogymnoascus destructans, the Causative Agent of White-Nose Syndrome, in the Absence of Bats.

    Science.gov (United States)

    Hoyt, Joseph R; Langwig, Kate E; Okoniewski, Joseph; Frick, Winifred F; Stone, Ward B; Kilpatrick, A Marm

    2015-06-01

    Wildlife diseases have been implicated in the declines and extinctions of several species. The ability of a pathogen to persist outside its host, existing as an "environmental reservoir", can exacerbate the impact of a disease and increase the likelihood of host extinction. Pseudogymnoascus destructans, the fungal pathogen that causes white-nose syndrome in bats, has been found in cave soil during the summer when hibernating bats had likely been absent for several months. However, whether the pathogen can persist over multiple years in the absence of bats is unknown, and long-term persistence of the pathogen can influence whether hibernacula where bats have been locally extirpated due to disease can be subsequently recolonized. Here, we show that P. destructans is capable of long-term persistence in the laboratory in the absence of bats. We cultured P. destructans from dried agar plates that had been kept at 5°C and low humidity conditions (30-40% RH) for more than 5 years. This suggests that P. destructans can persist in the absence of bats for long periods which may prevent the recolonization of hibernation, sites where bat populations were extirpated. This increases the extinction risk of bats affected by this disease.

  14. Pseudogymnoascus destructans: Causative Agent of White-Nose Syndrome in Bats Is Inhibited by Safe Volatile Organic Compounds.

    Science.gov (United States)

    Padhi, Sally; Dias, Itamar; Korn, Victoria L; Bennett, Joan W

    2018-04-10

    White-nose syndrome (WNS) is caused by Pseudogymnoascus destructans , a psychrophilic fungus that infects hibernating bats and has caused a serious decline in some species. Natural aroma compounds have been used to control growth of fungal food storage pathogens, so we hypothesized that a similar strategy could work for control of P. destructans . The effectiveness of exposure to low concentrations of the vapor phase of four of these compounds was tested on mycelial plugs and conidiospores at temperatures of 5, 10 and 15 °C. Here we report the efficacy of vapor phase mushroom alcohol (1-octen-3-ol) for inhibiting mycelial and conidiospore growth of P. destructans at 0.4 and 0.8 µmol/mL and demonstrate that the R enantiomer of this compound is more effective than the S enantiomer, supporting the finding that biological systems can be sensitive to stereochemistry. Further, we report that vapor phase leaf aldehyde ( trans -2-hexenal), a common aroma compound associated with cut grass odors and also the major volatile compound in extra virgin olive oil, is more effective than mushroom alcohol. At 0.05 µmol/mL, trans -2-hexenal is fungicidal to both conidiospores and mycelia of P. destructans .

  15. Bacteria isolated from bats inhibit the growth of Pseudogymnoascus destructans, the causative agent of white-nose syndrome.

    Science.gov (United States)

    Hoyt, Joseph R; Cheng, Tina L; Langwig, Kate E; Hee, Mallory M; Frick, Winifred F; Kilpatrick, A Marm

    2015-01-01

    Emerging infectious diseases are a key threat to wildlife. Several fungal skin pathogens have recently emerged and caused widespread mortality in several vertebrate groups, including amphibians, bats, rattlesnakes and humans. White-nose syndrome, caused by the fungal skin pathogen Pseudogymnoascus destructans, threatens several hibernating bat species with extinction and there are few effective treatment strategies. The skin microbiome is increasingly understood to play a large role in determining disease outcome. We isolated bacteria from the skin of four bat species, and co-cultured these isolates with P. destructans to identify bacteria that might inhibit or kill P. destructans. We then conducted two reciprocal challenge experiments in vitro with six bacterial isolates (all in the genus Pseudomonas) to quantify the effect of these bacteria on the growth of P. destructans. All six Pseudomonas isolates significantly inhibited growth of P. destructans compared to non-inhibitory control bacteria, and two isolates performed significantly better than others in suppressing P. destructans growth for at least 35 days. In both challenge experiments, the extent of suppression of P. destructans growth was dependent on the initial concentration of P. destructans and the initial concentration of the bacterial isolate. These results show that bacteria found naturally occurring on bats can inhibit the growth of P. destructans in vitro and should be studied further as a possible probiotic to protect bats from white-nose syndrome. In addition, the presence of these bacteria may influence disease outcomes among individuals, populations, and species.

  16. Spitting Image: Tick Saliva Assists the Causative Agent of Lyme Disease in Evading Host Skin's Innate Immune Response

    NARCIS (Netherlands)

    Hovius, Joppe W. R.

    2009-01-01

    Lyme disease is caused by the spirochete Borrelia burgdorferi and is transmitted through ticks. Inhibition of host skin's innate immune response might be instrumental to both tick feeding and B. burgdorferi transmission. The article by Marchal et al. describes how tick saliva suppresses B.

  17. Pseudogymnoascus destructans: Causative Agent of White-Nose Syndrome in Bats Is Inhibited by Safe Volatile Organic Compounds

    OpenAIRE

    Sally Padhi; Itamar Dias; Victoria L. Korn; Joan W. Bennett

    2018-01-01

    White-nose syndrome (WNS) is caused by Pseudogymnoascus destructans, a psychrophilic fungus that infects hibernating bats and has caused a serious decline in some species. Natural aroma compounds have been used to control growth of fungal food storage pathogens, so we hypothesized that a similar strategy could work for control of P. destructans. The effectiveness of exposure to low concentrations of the vapor phase of four of these compounds was tested on mycelial plugs and conidiospores at t...

  18. Bacteria isolated from bats inhibit the growth of Pseudogymnoascus destructans, the causative agent of white-nose syndrome.

    Directory of Open Access Journals (Sweden)

    Joseph R Hoyt

    Full Text Available Emerging infectious diseases are a key threat to wildlife. Several fungal skin pathogens have recently emerged and caused widespread mortality in several vertebrate groups, including amphibians, bats, rattlesnakes and humans. White-nose syndrome, caused by the fungal skin pathogen Pseudogymnoascus destructans, threatens several hibernating bat species with extinction and there are few effective treatment strategies. The skin microbiome is increasingly understood to play a large role in determining disease outcome. We isolated bacteria from the skin of four bat species, and co-cultured these isolates with P. destructans to identify bacteria that might inhibit or kill P. destructans. We then conducted two reciprocal challenge experiments in vitro with six bacterial isolates (all in the genus Pseudomonas to quantify the effect of these bacteria on the growth of P. destructans. All six Pseudomonas isolates significantly inhibited growth of P. destructans compared to non-inhibitory control bacteria, and two isolates performed significantly better than others in suppressing P. destructans growth for at least 35 days. In both challenge experiments, the extent of suppression of P. destructans growth was dependent on the initial concentration of P. destructans and the initial concentration of the bacterial isolate. These results show that bacteria found naturally occurring on bats can inhibit the growth of P. destructans in vitro and should be studied further as a possible probiotic to protect bats from white-nose syndrome. In addition, the presence of these bacteria may influence disease outcomes among individuals, populations, and species.

  19. Pseudogymnoascus destructans: Causative Agent of White-Nose Syndrome in Bats Is Inhibited by Safe Volatile Organic Compounds

    Directory of Open Access Journals (Sweden)

    Sally Padhi

    2018-04-01

    Full Text Available White-nose syndrome (WNS is caused by Pseudogymnoascus destructans, a psychrophilic fungus that infects hibernating bats and has caused a serious decline in some species. Natural aroma compounds have been used to control growth of fungal food storage pathogens, so we hypothesized that a similar strategy could work for control of P. destructans. The effectiveness of exposure to low concentrations of the vapor phase of four of these compounds was tested on mycelial plugs and conidiospores at temperatures of 5, 10 and 15 °C. Here we report the efficacy of vapor phase mushroom alcohol (1-octen-3-ol for inhibiting mycelial and conidiospore growth of P. destructans at 0.4 and 0.8 µmol/mL and demonstrate that the R enantiomer of this compound is more effective than the S enantiomer, supporting the finding that biological systems can be sensitive to stereochemistry. Further, we report that vapor phase leaf aldehyde (trans-2-hexenal, a common aroma compound associated with cut grass odors and also the major volatile compound in extra virgin olive oil, is more effective than mushroom alcohol. At 0.05 µmol/mL, trans-2-hexenal is fungicidal to both conidiospores and mycelia of P. destructans.

  20. Triphenylmethane derivatives have high in vitro and in vivo activity against the main causative agents of cutaneous leishmaniasis.

    Directory of Open Access Journals (Sweden)

    Renata Celi Carvalho de Souza Pietra

    Full Text Available The current standard of care for cutaneous leishmaniasis (CL is organic antimonial compounds, but the administration of these compounds is complicated by a low therapeutic - toxic index, as well as parenteral administration. Thus, there is an urgent need for the development of new and inexpensive therapies for the treatment of CL. In this study, we evaluate the activity of the triphenylmethane (TPM class of compounds against three species of Leishmania which are pathogenic in humans. The TPM have a history of safe use in humans, dating back to the use of the original member of this class, gentian violet (GV, from the early 20(th century. Initially, the in vitro efficacy against Leishmania (Viannia braziliensis, L. (Leishmania amazonensis and L. (L. major of 9 newly synthesized TPM, in addition to GV, was tested. Inhibitory concentrations (IC IC(50 of 0.025 to 0.84 µM had been found in promastigotes in vitro assays. The four most effective compounds were then tested in amastigote intracellular assays, resulting in IC(50 of 0.10 to 1.59 µM. A high degree of selectivity of antiparasitic activity over toxicity to mammalian cells was observed. Afterwards, GV and TPM 6 were tested in a topical formulation in mice infected with L. (L. amazonensis leading to elimination of parasite burdens at the site of lesion/infection. These results demonstrated that TPM present significant anti-leishmanial activities and provide a rationale for human clinical trials of GV and other TPM. TPM are inexpensive and safe, thus using them for treatment of CL may have a major impact on public health.

  1. Immunomodulation and disease resistance in postyearling rainbow trout infected with Myxobolus cerebralis, the causative agent of whirling disease

    Science.gov (United States)

    Densmore, Christine L.; Ottinger, C.A.; Blazer, V.S.; Iwanowicz, L.R.; Smith, D.R.

    2004-01-01

    Myxobolus cerebralis, the myxosporean parasite that causes whirling disease, has a number of deleterious effects on its salmonid host. Although it is well established that juvenile salmonids in the active stages of whirling disease mount an immune response to the pathogen, the occurrence and longevity of any related immunomodulatory effects are unknown. In this study, postyearling rainbow trout Oncorhynchus mykiss infected with M. cerebralis were examined for leukocyte functions and for resistance to Yersinia ruckeri, a bacterial pathogen of salmonids. Compared with uninfected controls, M. cerebralis-infected fish showed lower proliferative lymphocyte responses to four mitogens (concanavalin A, pokeweed mitogen, phytohemagglutinin, and lipopolysaccharide). Conversely, M. cerebralis-infected fish displayed greater bactericidal activity of anterior kidney macrophages than did uninfected fish. After bath challenges with K. ruckeri, M. cerebralis-infected fish had slightly lower survival and a more rapid onset of mortality than did the control fish. Renal tissue and fecal samples from M. cerebralis-infected and uninfected survivors were cultured for the presence of K. ruckeri, and no difference in prevalence was noted between the two groups. Because immunomodulatory changes in the M. cerebralis-infected fish involved functional enhancement and suppression of different leukocyte populations, disease resistance among M. cerebralis-infected fish in the later stages of whirling disease will probably vary with the secondary pathogen and the nature of immune response the pathogen evokes.

  2. New microbes as causative agents of Ibuprofen degradation capabilities in the hyporheic zone of a lowland stream

    Science.gov (United States)

    Njeru, Cyrus; Posselt, Malte; Horn, Marcus A.

    2017-04-01

    Ibuprofen is a non-steroidal anti-inflammatory pain reliever and among pharmaceutical residues detected in aquatic environments. Widespread use of the drug and incomplete removal during waste water treatment results in its persistence in effluents and receiving waters. Potential total removal by microbial activity in the hyporheic zone (HZ) of rivers downstream of wastewater treatment plant discharge sites has been hypothesized. Ibuprofen degradation associated microbial communities in are essentially unknown. To address this hypothesis, two sets of oxic HZ sediment microcosms spiked with ibuprofen only (5, 40, 200 and 400 µM), or ibuprofen and 1 mM acetate were set up under laboratory conditions. Ibuprofen degradation in non-sterile relative to autoclaved sediments indicated removal by microbial degradation. Ibuprofen was completely consumed in the absence and presence of supplemental acetate after approximately 11 and 16 days, respectively. Refeeding of ibuprofen and acetate after the first depletion resulted in complete degradation within 24 hours in all treatments. Metabolites of ibuprofen included 1-, 2-, 3-hydroxy- and carboxyibuprofen. Quantitative real-time PCR revealed no pronounced differences in copy numbers of 16S rRNA gene or transcripts between non-spiked controls and treatments. Time resolved triplicate amplicon Illumina MiSeq sequencing targeting the 16S rRNA genes and transcripts revealed increased relative abundances of Proteobacteria, Acidobacteria, Actinobacteria and Firmicutes in treatments with compared to those without ibuprofen. Alpha-, Beta- and Deltaproteobacteria were most active as indicated by RNA based analyses. Enrichment and isolation yielded new Alphaproteobacteria utilizing ibuprofen as sole carbon and energy source. The collective results indicated that (i) HZ sediments sustain efficient biotic (micro-)pollutant removal and (ii) are a reservoir of hitherto unknown microbial diversity associated with such ecosystem services, including the genera Fodinicola, Hyphobacterium, and subgroup 6 Acidobacteria.

  3. Viruses as the causative agent related to 'dampness' and the missing link between allergen exposure and onset of allergic disease

    DEFF Research Database (Denmark)

    Hersoug, Lars-Georg

    2005-01-01

    concentration and symptoms indicate a missing link between allergen exposure and onset of asthma. Respiratory viruses have been identified in up to 85% cases of asthma or exacerbations of asthma. The missing link between respiratory diseases and humid indoor climates could therefore be attributed to viruses....... The infectious effectiveness of respiratory viruses depends strongly on the environment where the viruses are spread. For respiratory viruses, survival and infectivity are dependent on temperature and relative humidity. A direct link between virus-induced inflammation and the asthmatogenic process has been...... subjects. Therefore, a humid indoor climate could also represent a higher risk for persons already sensitized to one or more allergens. PRACTICAL IMPLICATIONS: In epidemiological studies where the relationship between moisture in the indoor climate, respiratory symptoms and exposure to allergens...

  4. Acute suppurative appendicitis associated with Enterobius vermicularis: an incidental finding or a causative agent? A case report.

    Science.gov (United States)

    Efared, Boubacar; Atsame-Ebang, Gabrielle; Soumana, Boubacar Marou; Tahiri, Layla; Hammas, Nawal; El Fatemi, Hinde; Chbani, Laila

    2017-10-06

    Histological acute appendicitis patterns associated with Enterobius vermicularis is an extremely rare finding. The exact role of this parasite in acute appendicitis is controversial as usually resected specimens show no evidence of histological inflammation. We present herein a case of a 21-year-old male Arabic patient who presented with clinical syndrome of acute appendicitis. Emergency appendectomy was performed and the histopathological examination of the resected specimen showed the presence of E. vermicularis as well as intense acute inflammatory patterns such as mucosal ulceration and suppurative necrosis. The post-operative course was uneventful and the patient was discharged with appropriate anti-helmintic drug prescription. Acute appendicitis due to E. vermicularis is a very rare occurrence. The histopathological analysis of resected specimens should pay special attention to search for this parasite for adequate post-operative treatment of patients.

  5. Testing of inhibition activity of essential oils against Paenibacillus larvae – the causative agent of American foulbrood

    Directory of Open Access Journals (Sweden)

    Katarína Kuzyšinová

    2014-01-01

    Full Text Available American foulbrood is a dangerous world-wide spread disease of honey bees caused by the Paenibacillus larvae bacterium. Antibiotic treatments are less effective and leave residues in bee products. It is therefore necessary to find an alternative, especially using natural ingredients such as plant essential oils, probiotics, fatty or organic acids. Two strains of P. larvae were used for this study: CCM 4488, a strain from the Czech collection of micro-organisms and a Slovak field strain which was isolated from infected bee combs and characterized on the basis of biochemical properties. Plant essential oils of sage (Salvia officinalis, anise (Pimpinella anisum, oregano (Origanum vulgare, caraway (Carum carvi, thyme (Thymus vulgaris, rosemary (Rosmarinum officinalis, clove (Syzygium aromaticum, camomile (Chamomilla recutita and fennel (Foeniculum vulgare were used for the testing of the inhibitory activity against P. larvae. Essential oils at amounts of 5 µl and 10 µl were applied to sterile discs on MYPGP agar; inhibition zone diameters were measured after 24-h incubation at 37 °C. The strongest inhibitory activity against both P. larvae strains was noted in case of the essential oils from oregano, thyme and clove; essential oils from camomile, rosemary and fennel showed no or weak antibacterial activity. Medium strong inhibition activity was recorded in case of previously untested essential oil from Carum carvi. There was a difference in sensitivity of both tested strains to essential oils. Our study confirmed that some essential oils can be used in the prevention of American foulbrood but further experiments aimed at their influence on physiological intestinal microflora of honey bees must be performed.

  6. Cell-cycle synchronisation of bloodstream forms of Trypanosoma brucei using Vybrant DyeCycle Violet-based sorting.

    Science.gov (United States)

    Kabani, Sarah; Waterfall, Martin; Matthews, Keith R

    2010-01-01

    Studies on the cell-cycle of Trypanosoma brucei have revealed several unusual characteristics that differ from the model eukaryotic organisms. However, the inability to isolate homogenous populations of parasites in distinct cell-cycle stages has limited the analysis of trypanosome cell division and complicated the understanding of mutant phenotypes with possible impact on cell-cycle related events. Although hydroxyurea-induced cell-cycle arrest in procyclic and bloodstream forms has been applied recently with success, such block-release protocols can complicate the analysis of cell-cycle regulated events and have the potential to disrupt important cell-cycle checkpoints. An alternative approach based on flow cytometry of parasites stained with Vybrant DyeCycle Orange circumvents this problem, but is restricted to procyclic form parasites. Here, we apply Vybrant Dyecycle Violet staining coupled with flow cytometry to effectively select different cell-cycle stages of bloodstream form trypanosomes. Moreover, the sorted parasites remain viable, although synchrony is rapidly lost. This method enables cell-cycle enrichment of populations of trypanosomes in their mammal infective stage, particularly at the G1 phase.

  7. A global comparison of the human and T. brucei degradomes gives insights about possible parasite drug targets.

    Directory of Open Access Journals (Sweden)

    Susan T Mashiyama

    Full Text Available We performed a genome-level computational study of sequence and structure similarity, the latter using crystal structures and models, of the proteases of Homo sapiens and the human parasite Trypanosoma brucei. Using sequence and structure similarity networks to summarize the results, we constructed global views that show visually the relative abundance and variety of proteases in the degradome landscapes of these two species, and provide insights into evolutionary relationships between proteases. The results also indicate how broadly these sequence sets are covered by three-dimensional structures. These views facilitate cross-species comparisons and offer clues for drug design from knowledge about the sequences and structures of potential drug targets and their homologs. Two protease groups ("M32" and "C51" that are very different in sequence from human proteases are examined in structural detail, illustrating the application of this global approach in mining new pathogen genomes for potential drug targets. Based on our analyses, a human ACE2 inhibitor was selected for experimental testing on one of these parasite proteases, TbM32, and was shown to inhibit it. These sequence and structure data, along with interactive versions of the protein similarity networks generated in this study, are available at http://babbittlab.ucsf.edu/resources.html.

  8. Immunospecific immunoglobulins and IL-10 as markers for Trypanosoma brucei rhodesiense late stage disease in experimentally infected vervet monkeys

    DEFF Research Database (Denmark)

    Ngotho, Maina; Kagira, J.M.; Jensen, Henrik Michael Elvang

    2009-01-01

    and 140 days post-infection (dpi) respectively. Matched serum and CSF samples were obtained at regular intervals and immunospecific IgM, immunoglobulin G (IgG) and IL-10 were quantified by ELISA. RESULTS: There was no detectable immunospecific IgM and IgG in the CSF before 49 dpi. CSF IgM and Ig......OBJECTIVE: To determine the usefulness of IL-10 and immunoglobulin M (IgM) as biomarkers for staging HAT in vervet monkeys, a useful pathogenesis model for humans. METHODS: Vervet monkeys were infected with Trypanosoma brucei rhodesiense and subsequently given sub-curative and curative treatment 28...... curative treatment was given. After curative treatment, there was rapid and significant drop in serum IgM and IL-10 concentration as well as CSF WCC. However, the CSF IgM and IgG remained detectable to the end of the study. CONCLUSIONS: Serum and CSF concentrations of immunospecific IgM and CSF IgG changes...

  9. A global comparison of the human and T. brucei degradomes gives insights about possible parasite drug targets.

    Science.gov (United States)

    Mashiyama, Susan T; Koupparis, Kyriacos; Caffrey, Conor R; McKerrow, James H; Babbitt, Patricia C

    2012-01-01

    We performed a genome-level computational study of sequence and structure similarity, the latter using crystal structures and models, of the proteases of Homo sapiens and the human parasite Trypanosoma brucei. Using sequence and structure similarity networks to summarize the results, we constructed global views that show visually the relative abundance and variety of proteases in the degradome landscapes of these two species, and provide insights into evolutionary relationships between proteases. The results also indicate how broadly these sequence sets are covered by three-dimensional structures. These views facilitate cross-species comparisons and offer clues for drug design from knowledge about the sequences and structures of potential drug targets and their homologs. Two protease groups ("M32" and "C51") that are very different in sequence from human proteases are examined in structural detail, illustrating the application of this global approach in mining new pathogen genomes for potential drug targets. Based on our analyses, a human ACE2 inhibitor was selected for experimental testing on one of these parasite proteases, TbM32, and was shown to inhibit it. These sequence and structure data, along with interactive versions of the protein similarity networks generated in this study, are available at http://babbittlab.ucsf.edu/resources.html.

  10. IL-6 is Upregulated in Late-Stage Disease in Monkeys Experimentally Infected with Trypanosoma brucei rhodesiense

    Directory of Open Access Journals (Sweden)

    Dawn Nyawira Maranga

    2013-01-01

    Full Text Available The management of human African trypanosomiasis (HAT is constrained by lack of simple-to-use diagnostic, staging, and treatment tools. The search for novel biomarkers is, therefore, essential in the fight against HAT. The current study aimed at investigating the potential of IL-6 as an adjunct parameter for HAT stage determination in vervet monkey model. Four adult vervet monkeys (Chlorocebus aethiops were experimentally infected with Trypanosoma brucei rhodesiense and treated subcuratively at 28 days after infection (dpi to induce late stage disease. Three noninfected monkeys formed the control group. Cerebrospinal fluid (CSF and blood samples were obtained at weekly intervals and assessed for various biological parameters. A typical HAT-like infection was observed. The late stage was characterized by significant (P<0.05 elevation of CSF IL-6, white blood cell count, and total protein starting 35 dpi with peak levels of these parameters coinciding with relapse parasitaemia. Brain immunohistochemical staining revealed an increase in brain glial fibrillary acidic protein expression indicative of reactive astrogliosis in infected animals which were euthanized in late-stage disease. The elevation of IL-6 in CSF which accompanied other HAT biomarkers indicates onset of parasite neuroinvasion and show potential for use as an adjunct late-stage disease biomarker in the Rhodesian sleeping sickness.

  11. Molecular Evidence of a Trypanosoma brucei gambiense Sylvatic Cycle in the Human African Trypanosomiasis Foci of Equatorial Guinea

    Directory of Open Access Journals (Sweden)

    Carlos eCordon-Obras

    2015-07-01

    Full Text Available Gambiense trypanosomiasis is considered an anthroponotic disease. Consequently, control programs are generally aimed at stopping transmission of Trypanosoma brucei gambiense (T. b. gambiense by detecting and treating human cases. However, the persistence of numerous foci despite efforts to eliminate this disease questions this strategy as unique tool to pursue the eradication. The role of animals as a reservoir of T. b. gambiense is still controversial, but could partly explain maintenance of the infection at hypo-endemic levels. In the present study, we evaluated the presence of T. b. gambiense in wild animals in Equatorial Guinea. The infection rate ranged from 0.8% in the insular focus of Luba to more than 12% in Mbini, a focus with a constant trickle of human cases. The parasite was detected in a wide range of animal species including four species never described previously as putative reservoirs. Our study comes to reinforce the hypothesis that animals may play a role in the persistence of T. b. gambiense transmission, being particularly relevant in low transmission settings. Under these conditions the integration of sustained vector control and medical interventions should be considered to achieve the elimination of Gambiense trypanosomiasis.

  12. Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose.

    Directory of Open Access Journals (Sweden)

    Darren J Creek

    2015-03-01

    Full Text Available Metabolomics coupled with heavy-atom isotope-labelled glucose has been used to probe the metabolic pathways active in cultured bloodstream form trypomastigotes of Trypanosoma brucei, a parasite responsible for human African trypanosomiasis. Glucose enters many branches of metabolism beyond glycolysis, which has been widely held to be the sole route of glucose metabolism. Whilst pyruvate is the major end-product of glucose catabolism, its transamination product, alanine, is also produced in significant quantities. The oxidative branch of the pentose phosphate pathway is operative, although the non-oxidative branch is not. Ribose 5-phosphate generated through this pathway distributes widely into nucleotide synthesis and other branches of metabolism. Acetate, derived from glucose, is found associated with a range of acetylated amino acids and, to a lesser extent, fatty acids; while labelled glycerol is found in many glycerophospholipids. Glucose also enters inositol and several sugar nucleotides that serve as precursors to macromolecule biosynthesis. Although a Krebs cycle is not operative, malate, fumarate and succinate, primarily labelled in three carbons, were present, indicating an origin from phosphoenolpyruvate via oxaloacetate. Interestingly, the enzyme responsible for conversion of phosphoenolpyruvate to oxaloacetate, phosphoenolpyruvate carboxykinase, was shown to be essential to the bloodstream form trypanosomes, as demonstrated by the lethal phenotype induced by RNAi-mediated downregulation of its expression. In addition, glucose derivatives enter pyrimidine biosynthesis via oxaloacetate as a precursor to aspartate and orotate.

  13. Migraine and the social selection vs causation hypotheses: a question larger than either/or?

    Science.gov (United States)

    Peterlin, B Lee; Scher, Ann I

    2013-09-10

    For decades, the question of social selection vs social causation has been raised by public health researchers and social scientists to explain the association between socioeconomic factors and mood disorders.(1,2) The social selection or "downward drift" theory postulates that the disease itself limits an individual's educational and occupational achievements, leading to a lower socioeconomic status (SES). In contrast, the social causation hypothesis suggests that factors associated with low SES (e.g., stressful life events, poor health care access) increase the likelihood of disease onset or prolonged disease duration.(3,4) Simply stated, the end result of each hypothesis is as follows:

  14. Text-analytic Measurement of Effectuation and Causation Orientations among Small and Global Business Managers

    DEFF Research Database (Denmark)

    Mattsson, Jan; Helmersson, Helge

    2012-01-01

    We demonstrate how one can measure overall quality in texts gathered from interviews by means of PERTEX text analytic method. We compare text analytic measures and content for locally active Scandinavian small business managers and globally operating Indian IT managers when recapitulating......-components we are also able to display the degree of fragmentation, focus and integration in the text. We show how AFFI measures differ between managers with a causation or effectuation orientation irrespective of their role as small business manager or as an established global manager. Hence, we posit...... that effectuation and causation orientations may be generic characteristic of managers in general....

  15. Causative Chain Difference for each Type of Accidents in Japanese Maritime Traffic Systems (MTS)

    OpenAIRE

    Wanginingastuti Mutmainnah; Ludfi Pratiwi Bowo; Achmadi Bambang Sulistiyono; Masao Furusho

    2017-01-01

    Causative chain (CC) is a failure chain that cause accident as an outcome product of the second step of MOP model, namely line relation analysis (LRA). This CC is a connection of several causative factors (CF), an outcome product of first step of MOP model, namely corner analysis (CA). MOP Model is an abbreviation from 4M Overturned Pyramid, created by authors by combining 2 accident analysis models. There are two steps in this model, namely CA and LRA. Utilizing this model can know what is C...

  16. How can physics underlie the mind? top-down causation in the human context

    CERN Document Server

    Ellis, George

    2016-01-01

    Physics underlies all complexity, including our own existence: how is this possible? How can our own lives emerge from interactions of electrons, protons, and neutrons? This book considers the interaction of physical and non-physical causation in complex systems such as living beings, and in particular in the human brain, relating this to the emergence of higher levels of complexity with real causal powers. In particular it explores the idea of top-down causation, which is the key effect allowing the emergence of true complexity and also enables the causal efficacy of non-physical entities, including the value of money, social conventions, and ethical choices.

  17. Proof of causation through expert opinion evidence in low-level radiation cases

    International Nuclear Information System (INIS)

    Heideck, R.E.

    1985-01-01

    Tort law requires that the injured person prove that the injury was caused by a particular exposure to radiation for which the defendant is responsible. Heideck shows how expert evidence helps the court or jury resolve this question. The author analyzes a recent effort to bridge the gap between the legal requirement of proof of causation in individual cases and the conclusions that derive from group statistics. Some scientists argue that this approach is more technically sound than traditional tort law because it attempts to develop a probability of causation in individual cases

  18. The complete linkage disequilibrium test: a test that points to causative mutations underlying quantitative traits

    Directory of Open Access Journals (Sweden)

    Uleberg Eivind

    2011-05-01

    Full Text Available Abstract Background Genetically, SNP that are in complete linkage disequilibrium with the causative SNP cannot be distinguished from the causative SNP. The Complete Linkage Disequilibrium (CLD test presented here tests whether a SNP is in complete LD with the causative mutation or not. The performance of the CLD test is evaluated in 1000 simulated datasets. Methods The CLD test consists of two steps i.e. analysis I and analysis II. Analysis I consists of an association analysis of the investigated region. The log-likelihood values from analysis I are next ranked in descending order and in analysis II the CLD test evaluates differences in log-likelihood ratios between the best and second best markers. Under the null-hypothesis distribution, the best SNP is in greater LD with the QTL than the second best, while under the alternative-CLD-hypothesis, the best SNP is alike-in-state with the QTL. To find a significance threshold, the test was also performed on data excluding the causative SNP. The 5th, 10th and 50th highest TCLD value from 1000 replicated analyses were used to control the type-I-error rate of the test at p = 0.005, p = 0.01 and p = 0.05, respectively. Results In a situation where the QTL explained 48% of the phenotypic variance analysis I detected a QTL in 994 replicates (p = 0.001, where 972 were positioned in the correct QTL position. When the causative SNP was excluded from the analysis, 714 replicates detected evidence of a QTL (p = 0.001. In analysis II, the CLD test confirmed 280 causative SNP from 1000 simulations (p = 0.05, i.e. power was 28%. When the effect of the QTL was reduced by doubling the error variance, the power of the test reduced relatively little to 23%. When sequence data were used, the power of the test reduced to 16%. All SNP that were confirmed by the CLD test were positioned in the correct QTL position. Conclusions The CLD test can provide evidence for a causative SNP, but its power may be low in situations

  19. [Biological agents].

    Science.gov (United States)

    Amano, Koichi

    2009-03-01

    There are two types of biological agents for the treatment of rheumatoid arthritis (RA); monoclonal antibodies and recombinant proteins. Among the latter, etanercept, a recombinant fusion protein of soluble TNF receptor and IgG was approved in 2005 in Japan. The post-marketing surveillance of 13,894 RA patients revealed the efficacy and safety profiles of etanercept in the Japanese population, as well as overseas studies. Abatacept, a recombinant fusion protein of CTLA4 and IgG, is another biological agent for RA. Two clinical trials disclosed the efficacy of abatacept for difficult-to-treat patients: the AIM for MTX-resistant cases and the ATTAIN for patients who are resistant to anti-TNF. The ATTEST trial suggested abatacept might have more acceptable safety profile than infliximab. These biologics are also promising for the treatment of RA for not only relieving clinical symptoms and signs but retarding structural damage.

  20. RNA-Seq analysis validates the use of culture-derived Trypanosoma brucei and provides new markers for mammalian and insect life-cycle stages.

    Science.gov (United States)

    Naguleswaran, Arunasalam; Doiron, Nicholas; Roditi, Isabel

    2018-04-02

    Trypanosoma brucei brucei, the parasite causing Nagana in domestic animals, is closely related to the parasites causing sleeping sickness, but does not infect humans. In addition to its importance as a pathogen, the relative ease of genetic manipulation and an innate capacity for RNAi extend its use as a model organism in cell and infection biology. During its development in its mammalian and insect (tsetse fly) hosts, T. b. brucei passes through several different life-cycle stages. There are currently four life-cycle stages that can be cultured: slender forms and stumpy forms, which are equivalent to forms found in the mammal, and early and late procyclic forms, which are equivalent to forms in the tsetse midgut. Early procyclic forms show coordinated group movement (social motility) on semi-solid surfaces, whereas late procyclic forms do not. RNA-Seq was performed on biological replicates of each life-cycle stage. These constitute the first datasets for culture-derived slender and stumpy bloodstream forms and early and late procyclic forms. Expression profiles confirmed that genes known to be stage-regulated in the animal and insect hosts were also regulated in culture. Sequence reads of 100-125 bases provided sufficient precision to uncover differential expression of closely related genes. More than 100 transcripts showed peak expression in stumpy forms, including adenylate cyclases and several components of inositol metabolism. Early and late procyclic forms showed differential expression of 73 transcripts, a number of which encoded proteins that were previously shown to be stage-regulated. Moreover, two adenylate cyclases previously shown to reduce social motility are up-regulated in late procyclic forms. This study validates the use of cultured bloodstream forms as alternatives to animal-derived parasites and yields new markers for all four stages. In addition to underpinning recent findings that early and late procyclic forms are distinct life-cycle stages

  1. Peptide-targeted delivery of a pH sensor for quantitative measurements of intraglycosomal pH in live Trypanosoma brucei.

    Science.gov (United States)

    Lin, Sheng; Morris, Meredith T; Ackroyd, P Christine; Morris, James C; Christensen, Kenneth A

    2013-05-28

    Studies of dynamic changes in organelles of protozoan parasite Trypanosoma brucei have been limited, in part because of the difficulty of targeting analytical probes to specific subcellular compartments. Here we demonstrate application of a ratiometric probe for pH quantification in T. brucei glycosomes. The probe consists of a peptide encoding the peroxisomal targeting sequence (F-PTS1, acetyl-CKGGAKL) coupled to fluorescein, which responds to pH. When incubated with living parasites, the probe is internalized within vesicular structures that colocalize with a glycosomal marker. Inhibition of uptake of F-PTS1 at 4 °C and pulse-chase colocalization with fluorescent dextran suggested that the probe is initially taken up by non-receptor-mediated endocytosis but is subsequently transported separately from dextran and localized within glycosomes, prior to the final fusion of labeled glycosomes and lysosomes as part of glycosomal turnover. Intraorganellar measurements and pH calibration with F-PTS1 in T. brucei glycosomes indicate that the resting glycosomal pH under physiological conditions is 7.4 ± 0.2. However, incubation in glucose-depleted buffer triggered mild acidification of the glycosome over a period of 20 min, with a final observed pH of 6.8 ± 0.3. This glycosomal acidification was reversed by reintroduction of glucose. Coupling of ratiometric fluorescent sensors and reporters to PTS peptides offers an invaluable tool for monitoring in situ glycosomal response(s) to changing environmental conditions and could be applied to additional kinetoplastid parasites.

  2. Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes.

    Directory of Open Access Journals (Sweden)

    Claudia Laperchia

    2016-12-01

    Full Text Available The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications.Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses.Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion.These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging.

  3. Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes.

    Science.gov (United States)

    Laperchia, Claudia; Palomba, Maria; Seke Etet, Paul F; Rodgers, Jean; Bradley, Barbara; Montague, Paul; Grassi-Zucconi, Gigliola; Kennedy, Peter G E; Bentivoglio, Marina

    2016-12-01

    The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications. Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses. Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion. These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging.

  4. Are All Children Equal? Causative Factors of Child Labour in Selected Districts of South Punjab, Pakistan

    Science.gov (United States)

    Haider, Syed Zubair; Qureshi, Ayesha

    2016-01-01

    The present study investigates the causative factors of child labour in selected districts of South Punjab, Pakistan. As a member of the International Labour Organization (ILO) Pakistan has a responsibility to stamp out child labour from its regions. Our sample was selected from seven working environments (workshops, hotels, tea stalls,…

  5. Proof of Causation in Medical Malpractice Cases in the Czech Republic

    Czech Academy of Sciences Publication Activity Database

    Doležal, Adam; Doležal, Tomáš

    2015-01-01

    Roč. 5, č. 3 (2015), s. 195-205 ISSN 1805-8396 R&D Projects: GA ČR GAP408/12/2574 Institutional support: RVO:68378122 Keywords : causation * liability * medical malpractice cases Subject RIV: AG - Legal Sciences

  6. Contemporary Thinking about Causation in Evaluation: A Dialogue with Tom Cook and Michael Scriven

    Science.gov (United States)

    Cook, Thomas D.; Scriven, Michael; Coryn, Chris L. S.; Evergreen, Stephanie D. H.

    2010-01-01

    Legitimate knowledge claims about causation have been a central concern among evaluators and applied researchers for several decades and often have been the subject of heated debates. In recent years these debates have resurfaced with a renewed intensity, due in part to the priority currently being given to randomized experiments by many funders…

  7. Effect of experimental single Ancylostoma caninum and mixed infections of Trypanosoma brucei and Trypanosoma congolense on the humoural immune response to anti-rabies vaccination in dogs

    Directory of Open Access Journals (Sweden)

    Nwoha Rosemary Ijeoma Ogechi

    2015-06-01

    Full Text Available Objective: To determine the effect of Ancylostoma caninum (A. caninum and trypanosome parasites on the immune response to vaccination in dogs in endemic environments. Methods: Sixteen dogs for the experiment were grouped into 4 of 4 members each. Group I was the uninfected control one, and GPII was infected with A. caninum; GPIII was infected with A. caninum/Trypanosoma congolense (T. congolense, and GPIV was infected with Trypanosoma brucei (T. brucei/A. caninum. The dogs were first vaccinated with antirabies vaccine before infecting GPII, GPIII and GPIV with A. caninum which were done 4 weeks after vaccination. By 2-week post-vaccination, trypanosome parasites were superimposed on both GPIII and GPIV. A secondary vaccination was given to GPI, GPII, GPIII, and GPIV by Week 12 of the experiment (4 weeks post treatment. Results: The prepatent period was (3.00 ± 1.40 days, in the conjunct infection of T. brucei/ A. caninum. It was (9.00 ± 1.10 days, in conjunct T. congolense/A. caninum. The prepatent period of A. caninum was (14.0 ± 2.0 days in the single A. caninum group and (13.0 ± 1.0 days in the conjunct trypanosome/A. caninum. At the 1st week after vaccination, the antibody titer in all the vaccinated groups (GPI, GPII, GPIII, and GPIV significantly increased (P < 0.05 and peaked at the 3rd week after vaccination. Following infections, there were marked significant decreases (P < 0.05 in the antibody production against rabies in GPII, GPIII and GPIV. The significant decrease (P < 0.05 in antibody titer was highest in the conjunct groups (GPIII and GPIV compared to the single infection (GPII. Treatment with diminazene aceturate and mebendazole did not significantly improve antibody response in the dogs. A secondary vaccination administered at the 12th week after the primary vaccination significantly increased (P < 0.05 the antibody titer with a peak at the 3rd week after the secondary vaccination. Conclusions: It was therefore concluded

  8. Interaction between the flagellar pocket collar and the hook complex via a novel microtubule-binding protein in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Anna Albisetti

    2017-11-01

    Full Text Available Trypanosoma brucei belongs to a group of unicellular, flagellated parasites that are responsible for human African trypanosomiasis. An essential aspect of parasite pathogenicity is cytoskeleton remodelling, which occurs during the life cycle of the parasite and is accompanied by major changes in morphology and organelle positioning. The flagellum originates from the basal bodies and exits the cell body through the flagellar pocket (FP but remains attached to the cell body via the flagellum attachment zone (FAZ. The FP is an invagination of the pellicular membrane and is the sole site for endo- and exocytosis. The FAZ is a large complex of cytoskeletal proteins, plus an intracellular set of four specialised microtubules (MtQ that elongate from the basal bodies to the anterior end of the cell. At the distal end of the FP, an essential, intracellular, cytoskeletal structure called the flagellar pocket collar (FPC circumvents the flagellum. Overlapping the FPC is the hook complex (HC (a sub-structure of the previously named bilobe that is also essential and is thought to be involved in protein FP entry. BILBO1 is the only functionally characterised FPC protein and is necessary for FPC and FP biogenesis. Here, we used a combination of in vitro and in vivo approaches to identify and characterize a new BILBO1 partner protein-FPC4. We demonstrate that FPC4 localises to the FPC, the HC, and possibly to a proximal portion of the MtQ. We found that the C-terminal domain of FPC4 interacts with the BILBO1 N-terminal domain, and we identified the key amino acids required for this interaction. Interestingly, the FPC4 N-terminal domain was found to bind microtubules. Over-expression studies highlight the role of FPC4 in its association with the FPC, HC and FPC segregation. Our data suggest a tripartite association between the FPC, the HC and the MtQ.

  9. The miRNA and mRNA Signatures of Peripheral Blood Cells in Humans Infected with Trypanosoma brucei gambiense.

    Directory of Open Access Journals (Sweden)

    Smiths Lueong

    Full Text Available Simple, reliable tools for diagnosis of human African Trypanosomiases could ease field surveillance and enhance patient care. In particular, current methods to distinguish patients with (stage II and without (stage I brain involvement require samples of cerebrospinal fluid. We describe here an exploratory study to find out whether miRNAs from peripheral blood leukocytes might be useful in diagnosis of human trypanosomiasis, or for determining the stage of the disease. Using microarrays, we measured miRNAs in samples from Trypanosoma brucei gambiense-infected patients (9 stage I, 10 stage II, 8 seronegative parasite-negative controls and 12 seropositive, but parasite-negative subjects. 8 miRNAs (out of 1205 tested showed significantly lower expression in patients than in seronegative, parasite-negative controls, and 1 showed increased expression. There were no clear differences in miRNAs between patients in different disease stages. The miRNA profiles could not distinguish seropositive, but parasitologically negative samples from controls and results within this group did not correlate with those from the trypanolysis test. Some of the regulated miRNAs, or their predicted mRNA targets, were previously reported changed during other infectious diseases or cancer. We conclude that the changes in miRNA profiles of peripheral blood lymphocytes in human African trypanosomiasis are related to immune activation or inflammation, are probably disease-non-specific, and cannot be used to determine the disease stage. The approach has little promise for diagnostics but might yield information about disease pathology.

  10. Functional and structural insights revealed by molecular dynamics simulations of an essential RNA editing ligase in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Rommie E Amaro

    2007-11-01

    Full Text Available RNA editing ligase 1 (TbREL1 is required for the survival of both the insect and bloodstream forms of Trypanosoma brucei, the parasite responsible for the devastating tropical disease African sleeping sickness. The type of RNA editing that TbREL1 is involved in is unique to the trypanosomes, and no close human homolog is known to exist. In addition, the high-resolution crystal structure revealed several unique features of the active site, making this enzyme a promising target for structure-based drug design. In this work, two 20 ns atomistic molecular dynamics (MD simulations are employed to investigate the dynamics of TbREL1, both with and without the ATP substrate present. The flexibility of the active site, dynamics of conserved residues and crystallized water molecules, and the interactions between TbREL1 and the ATP substrate are investigated and discussed in the context of TbREL1's function. Differences in local and global motion upon ATP binding suggest that two peripheral loops, unique to the trypanosomes, may be involved in interdomain signaling events. Notably, a significant structural rearrangement of the enzyme's active site occurs during the apo simulations, opening an additional cavity adjacent to the ATP binding site that could be exploited in the development of effective inhibitors directed against this protozoan parasite. Finally, ensemble averaged electrostatics calculations over the MD simulations reveal a novel putative RNA binding site, a discovery that has previously eluded scientists. Ultimately, we use the insights gained through the MD simulations to make several predictions and recommendations, which we anticipate will help direct future experimental studies and structure-based drug discovery efforts against this vital enzyme.

  11. Isolation of Trypanosoma brucei gambiense from cured and relapsed sleeping sickness patients and adaptation to laboratory mice.

    Directory of Open Access Journals (Sweden)

    Patient Pati Pyana

    Full Text Available BACKGROUND: Sleeping sickness due to Trypanosoma brucei (T.b. gambiense is still a major public health problem in some central African countries. Historically, relapse rates around 5% have been observed for treatment with melarsoprol, widely used to treat second stage patients. Later, relapse rates of up to 50% have been recorded in some isolated foci in Angola, Sudan, Uganda and Democratic Republic of the Congo (DRC. Previous investigations are not conclusive on whether decreased sensitivity to melarsoprol is responsible for these high relapse rates. Therefore we aimed to establish a parasite collection isolated from cured as well as from relapsed patients for downstream comparative drug sensitivity profiling. A major constraint for this type of investigation is that T.b. gambiense is particularly difficult to isolate and adapt to classical laboratory rodents. METHODOLOGY/PRINCIPAL FINDINGS: From 360 patients treated in Dipumba hospital, Mbuji-Mayi, D.R. Congo, blood and cerebrospinal fluid (CSF was collected before treatment. From patients relapsing during the 24 months follow-up, the same specimens were collected. Specimens with confirmed parasite presence were frozen in liquid nitrogen in a mixture of Triladyl, egg yolk and phosphate buffered glucose solution. Isolation was achieved by inoculation of the cryopreserved specimens in Grammomys surdaster, Mastomys natalensis and SCID mice. Thus, 85 strains were isolated from blood and CSF of 55 patients. Isolation success was highest in Grammomys surdaster. Forty strains were adapted to mice. From 12 patients, matched strains were isolated before treatment and after relapse. All strains belong to T.b. gambiense type I. CONCLUSIONS AND SIGNIFICANCE: We established a unique collection of T.b. gambiense from cured and relapsed patients, isolated in the same disease focus and within a limited period. This collection is available for genotypic and phenotypic characterisation to investigate the

  12. Trading Agents

    CERN Document Server

    Wellman, Michael

    2011-01-01

    Automated trading in electronic markets is one of the most common and consequential applications of autonomous software agents. Design of effective trading strategies requires thorough understanding of how market mechanisms operate, and appreciation of strategic issues that commonly manifest in trading scenarios. Drawing on research in auction theory and artificial intelligence, this book presents core principles of strategic reasoning that apply to market situations. The author illustrates trading strategy choices through examples of concrete market environments, such as eBay, as well as abst

  13. Trypanosoma brucei Inhibition by Essential Oils from Medicinal and Aromatic Plants Traditionally Used in Cameroon (Azadirachta indica, Aframomum melegueta, Aframomum daniellii, Clausena anisata, Dichrostachys cinerea and Echinops giganteus).

    Science.gov (United States)

    Kamte, Stephane L Ngahang; Ranjbarian, Farahnaz; Campagnaro, Gustavo Daniel; Nya, Prosper C Biapa; Mbuntcha, Hélène; Woguem, Verlaine; Womeni, Hilaire Macaire; Ta, Léon Azefack; Giordani, Cristiano; Barboni, Luciano; Benelli, Giovanni; Cappellacci, Loredana; Hofer, Anders; Petrelli, Riccardo; Maggi, Filippo

    2017-07-06

    Essential oils are complex mixtures of volatile components produced by the plant secondary metabolism and consist mainly of monoterpenes and sesquiterpenes and, to a minor extent, of aromatic and aliphatic compounds. They are exploited in several fields such as perfumery, food, pharmaceutics, and cosmetics. Essential oils have long-standing uses in the treatment of infectious diseases and parasitosis in humans and animals. In this regard, their therapeutic potential against human African trypanosomiasis (HAT) has not been fully explored. In the present work, we have selected six medicinal and aromatic plants ( Azadirachta indica , Aframomum melegueta , Aframomum daniellii , Clausena anisata , Dichrostachys cinerea , and Echinops giganteus ) traditionally used in Cameroon to treat several disorders, including infections and parasitic diseases, and evaluated the activity of their essential oils against Trypanosma brucei TC221. Their selectivity was also determined with Balb/3T3 (mouse embryonic fibroblast cell line) cells as a reference. The results showed that the essential oils from A. indica , A . daniellii , and E. giganteus were the most active ones, with half maximal inhibitory concentration (IC 50 ) values of 15.21, 7.65, and 10.50 µg/mL, respectively. These essential oils were characterized by different chemical compounds such as sesquiterpene hydrocarbons, monoterpene hydrocarbons, and oxygenated sesquiterpenes. Some of their main components were assayed as well on T. brucei TC221, and their effects were linked to those of essential oils.

  14. RNA interference analyses suggest a transcript-specific regulatory role for mitochondrial RNA-binding proteins MRP1 and MRP2 in RNA editing and other RNA processing in Trypanosoma brucei

    NARCIS (Netherlands)

    Vondrusková, Eva; van den Burg, Janny; Zíková, Alena; Ernst, Nancy Lewis; Stuart, Kenneth; Benne, Rob; Lukes, Julius

    2005-01-01

    Mitochondrial RNA-binding proteins MRP1 and MRP2 occur in a heteromeric complex that appears to play a role in U-insertion/deletion editing in trypanosomes. Reduction in the levels of MRP1 (gBP21) and/or MRP2 (gBP25) mRNA by RNA interference in procyclic Trypanosoma brucei resulted in severe growth

  15. Radioprotective Agents

    Directory of Open Access Journals (Sweden)

    Ilker Kelle

    2008-01-01

    Full Text Available Since1949, a great deal of research has been carried out on the radioprotective activity of various chemical substances. Thiol compounds, compounds which contain –SH radical, different classes of pharmacological agents and other compounds such as vitamine C and WR-2721 have been shown to reduce mortality when administered prior to exposure to a lethal dose of radiation. Recently, honey bee venom as well as that of its components melittin and histamine have shown to be valuable in reduction of radiation-induced damage and also provide prophylactic alternative treatment for serious side effects related with radiotherapy. It has been suggested that the radioprotective activity of bee venom components is related with the stimulation of the hematopoetic system.

  16. Multiple evolutionary origins of Trypanosoma evansi in Kenya.

    Directory of Open Access Journals (Sweden)

    Christine M Kamidi

    2017-09-01

    Full Text Available Trypanosoma evansi is the parasite causing surra, a form of trypanosomiasis in camels and other livestock, and a serious economic burden in Kenya and many other parts of the world. Trypanosoma evansi transmission can be sustained mechanically by tabanid and Stomoxys biting flies, whereas the closely related African trypanosomes T. brucei brucei and T. b. rhodesiense require cyclical development in tsetse flies (genus Glossina for transmission. In this study, we investigated the evolutionary origins of T. evansi. We used 15 polymorphic microsatellites to quantify levels and patterns of genetic diversity among 41 T. evansi isolates and 66 isolates of T. b. brucei (n = 51 and T. b. rhodesiense (n = 15, including many from Kenya, a region where T. evansi may have evolved from T. brucei. We found that T. evansi strains belong to at least two distinct T. brucei genetic units and contain genetic diversity that is similar to that in T. brucei strains. Results indicated that the 41 T. evansi isolates originated from multiple T. brucei strains from different genetic backgrounds, implying independent origins of T. evansi from T. brucei strains. This surprising finding further suggested that the acquisition of the ability of T. evansi to be transmitted mechanically, and thus the ability to escape the obligate link with the African tsetse fly vector, has occurred repeatedly. These findings, if confirmed, have epidemiological implications, as T. brucei strains from different genetic backgrounds can become either causative agents of a dangerous, cosmopolitan livestock disease or of a lethal human disease, like for T. b. rhodesiense.

  17. Are All Children Equal? Causative Factors of Child Labour in Selected Districts of South Punjab, Pakistan

    Directory of Open Access Journals (Sweden)

    Syed Zubair Haider

    2016-01-01

    Full Text Available The present study investigates the causative factors of child labour in selected districts of South Punjab, Pakistan. As member of the International Labour Organization (ILO Pakistan has a responsibility to stamp out child labour from its regions. Our sample was selected from seven working environments (workshops, hotels, tea stalls, households, etc. through purposive sampling. The data were collected via a questionnaire which was completed by a sample of 547 working children. The findings of the exploratory factor analysis (EFA explored four factors from the research. Multilevel analyses were calculated to pinpoint the causative factors of child labour. The study results revealed that, due to family responsibilities, a lack of educational opportunities for children from low-income families, and increasing poverty, children develop an interest in working to earn their livelihood at the cost of their education. The children are involved in labour because their parents cannot meet their personal and educational requirements.

  18. Stress fractures of the ribs and upper extremities: causation, evaluation, and management.

    Science.gov (United States)

    Miller, Timothy L; Harris, Joshua D; Kaeding, Christopher C

    2013-08-01

    Stress fractures are common troublesome injuries in athletes and non-athletes. Historically, stress fractures have been thought to predominate in the lower extremities secondary to the repetitive stresses of impact loading. Stress injuries of the ribs and upper extremities are much less common and often unrecognized. Consequently, these injuries are often omitted from the differential diagnosis of rib or upper extremity pain. Given the infrequency of this diagnosis, few case reports or case series have reported on their precipitating activities and common locations. Appropriate evaluation for these injuries requires a thorough history and physical examination. Radiographs may be negative early, requiring bone scintigraphy or MRI to confirm the diagnosis. Nonoperative and operative treatment recommendations are made based on location, injury classification, and causative activity. An understanding of the most common locations of upper extremity stress fractures and their associated causative activities is essential for prompt diagnosis and optimal treatment.

  19. Analyzing the causation of a railway accident based on a complex network

    Science.gov (United States)

    Ma, Xin; Li, Ke-Ping; Luo, Zi-Yan; Zhou, Jin

    2014-02-01

    In this paper, a new model is constructed for the causation analysis of railway accident based on the complex network theory. In the model, the nodes are defined as various manifest or latent accident causal factors. By employing the complex network theory, especially its statistical indicators, the railway accident as well as its key causations can be analyzed from the overall perspective. As a case, the “7.23” China—Yongwen railway accident is illustrated based on this model. The results show that the inspection of signals and the checking of line conditions before trains run played an important role in this railway accident. In conclusion, the constructed model gives a theoretical clue for railway accident prediction and, hence, greatly reduces the occurrence of railway accidents.

  20. How emotion shapes behavior: feedback, anticipation, and reflection, rather than direct causation.

    Science.gov (United States)

    Baumeister, Roy F; Vohs, Kathleen D; DeWall, C Nathan; Zhang, Liqing

    2007-05-01

    Fear causes fleeing and thereby saves lives: this exemplifies a popular and common sense but increasingly untenable view that the direct causation of behavior is the primary function of emotion. Instead, the authors develop a theory of emotion as a feedback system whose influence on behavior is typically indirect. By providing feedback and stimulating retrospective appraisal of actions, conscious emotional states can promote learning and alter guidelines for future behavior. Behavior may also be chosen to pursue (or avoid) anticipated emotional outcomes. Rapid, automatic affective responses, in contrast to the full-blown conscious emotions, may inform cognition and behavioral choice and thereby help guide current behavior. The automatic affective responses may also remind the person of past emotional outcomes and provide useful guides as to what emotional outcomes may be anticipated in the present. To justify replacing the direct causation model with the feedback model, the authors review a large body of empirical findings.

  1. DeepPVP: phenotype-based prioritization of causative variants using deep learning

    KAUST Repository

    Boudellioua, Imene

    2018-05-02

    Background: Prioritization of variants in personal genomic data is a major challenge. Recently, computational methods that rely on comparing phenotype similarity have shown to be useful to identify causative variants. In these methods, pathogenicity prediction is combined with a semantic similarity measure to prioritize not only variants that are likely to be dysfunctional but those that are likely involved in the pathogenesis of a patient\\'s phenotype. Results: We have developed DeepPVP, a variant prioritization method that combined automated inference with deep neural networks to identify the likely causative variants in whole exome or whole genome sequence data. We demonstrate that DeepPVP performs significantly better than existing methods, including phenotype-based methods that use similar features. DeepPVP is freely available at https://github.com/bio-ontology-research-group/phenomenet-vp Conclusions: DeepPVP further improves on existing variant prioritization methods both in terms of speed as well as accuracy.

  2. Analyzing the causation of a railway accident based on a complex network

    International Nuclear Information System (INIS)

    Ma Xin; Li Ke-Ping; Luo Zi-Yan; Zhou Jin

    2014-01-01

    In this paper, a new model is constructed for the causation analysis of railway accident based on the complex network theory. In the model, the nodes are defined as various manifest or latent accident causal factors. By employing the complex network theory, especially its statistical indicators, the railway accident as well as its key causations can be analyzed from the overall perspective. As a case, the “7.23” China—Yongwen railway accident is illustrated based on this model. The results show that the inspection of signals and the checking of line conditions before trains run played an important role in this railway accident. In conclusion, the constructed model gives a theoretical clue for railway accident prediction and, hence, greatly reduces the occurrence of railway accidents. (interdisciplinary physics and related areas of science and technology)

  3. Multiple Statistical Models Based Analysis of Causative Factors and Loess Landslides in Tianshui City, China

    Science.gov (United States)

    Su, Xing; Meng, Xingmin; Ye, Weilin; Wu, Weijiang; Liu, Xingrong; Wei, Wanhong

    2018-03-01

    Tianshui City is one of the mountainous cities that are threatened by severe geo-hazards in Gansu Province, China. Statistical probability models have been widely used in analyzing and evaluating geo-hazards such as landslide. In this research, three approaches (Certainty Factor Method, Weight of Evidence Method and Information Quantity Method) were adopted to quantitively analyze the relationship between the causative factors and the landslides, respectively. The source data used in this study are including the SRTM DEM and local geological maps in the scale of 1:200,000. 12 causative factors (i.e., altitude, slope, aspect, curvature, plan curvature, profile curvature, roughness, relief amplitude, and distance to rivers, distance to faults, distance to roads, and the stratum lithology) were selected to do correlation analysis after thorough investigation of geological conditions and historical landslides. The results indicate that the outcomes of the three models are fairly consistent.

  4. Causation and Effectuation Processes: Opportunity Discovery and Exploitation Logics of Habitual Entrepreneurs

    DEFF Research Database (Denmark)

    Müller, Sabine

    2010-01-01

    This study investigates how habitual entrepreneurs (i.e. serial and portfolio entrepreneurs) discover and exploit opportunities, deal with risk and uncertainty, predict or control the future, and plan their businesses based on a causation and effectuation perspective. This study thereby uncovered...... the causation and effectuation logics applied by habitual entrepreneurs with regard to four dimensions of the venture creation: View of the future (VF), Opportunity Discovery (OD), Opportunity Exploitation (OE), and Dealing with Risk (DR). Six habitual entrepreneurs, who had to meet three strictly defined...... criteria, where sampled and case studies performed. The findings clearly indicate that habitual entrepreneurs mainly apply an effectual logic with regards to the four dimensions examined. Some of the more inexperienced habitual entrepreneurs tend to apply both logics, but almost exclusively become...

  5. Ventilator-Associated Pneumonia and Causative Microorganisms in Intensive Care Unit: A Two Year Retrospective Analysis

    OpenAIRE

    Onur Palabıyık; Yaşar Toptaş; Aziz Öğütlü

    2016-01-01

    Objective: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in the intensive care units (ICUs). It causes prolonged hospital stay and increases mortality. In this study, we aimed to investigate the rate of VAP, causative microorganisms, and their antibiotic susceptibilities in anaesthesiology and reanimation ICU (ARICU). Material and Method: This retrospective study included patients who were admitted to 12-bed ARICU between January 2013 and December 2014. The ...

  6. New Levels of Language Processing Complexity and Organization Revealed by Granger Causation

    OpenAIRE

    Gow, David W.; Caplan, David N.

    2012-01-01

    Granger causation analysis of high spatiotemporal resolution reconstructions of brain activation offers a new window on the dynamic interactions between brain areas that support language processing. Premised on the observation that causes both precede and uniquely predict their effects, this approach provides an intuitive, model-free means of identifying directed causal interactions in the brain. It requires the analysis of all non-redundant potentially interacting signals, and has shown that...

  7. UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production

    OpenAIRE

    Wood, Simon R.; Berwick, Marianne; Ley, Ronald D.; Walter, Ronald B.; Setlow, Richard B.; Timmins, Graham S.

    2006-01-01

    Controversy continues both as to which wavelengths of sunlight cause melanoma and the mechanisms by which these different wavelengths act. Direct absorption of UVB by DNA is central in albino animal models, but melanin-pigmented models have shown major contributions by wavelengths longer than UVB that are thought to be mediated by photosensitized oxidant production. The only model for which the action spectrum of melanoma causation is known is a genetically melanoma-susceptible specific cross...

  8. Moxifloxacin susceptibility mediates the relationship between causative organism and clinical outcome in bacterial keratitis.

    Science.gov (United States)

    Oldenburg, Catherine E; Lalitha, Prajna; Srinivasan, Muthiah; Manikandan, Palanisamy; Bharathi, M Jayahar; Rajaraman, Revathi; Ravindran, Meenakshi; Mascarenhas, Jeena; Nardone, Natalie; Ray, Kathryn J; Glidden, David V; Acharya, Nisha R; Lietman, Thomas M

    2013-02-28

    Bacterial keratitis is a sight-threatening infection of the cornea that is one of the leading causes of blindness globally. In this report, we analyze the role of moxifloxacin susceptibility in the relationship between causative organisms and clinical outcome in bacteria keratitis. A mediation analysis is used to assess the role of moxifloxacin susceptibility in the relationship between causative organisms and clinical outcome in bacterial keratitis using data collected in a randomized, controlled trial. In the Steroids for Corneal Ulcers Trial (SCUT), 500 corneal infections were treated with topical moxifloxacin. The outcome of 3-week best spectacle-corrected visual acuity was significantly associated with an organism (Streptococcus pneumoniae, Pseudomonas aeruginosa, etc., P = 0.008). An indirect effects mediation model suggests that MIC accounted for approximately 13% (95% confidence interval, 3%-24%, P = 0.015) of the effect of the organism on 3-week visual acuity. Moxifloxacin mediates the relationship between causative organisms and clinical outcome in bacterial keratitis, and is likely on the causal pathway between the organism and outcome. (ClinicalTrials.gov number, NCT00324168.).

  9. Decadal trends in beach morphology on the east coast of South Africa and likely causative factors

    Directory of Open Access Journals (Sweden)

    S. Corbella

    2012-08-01

    Full Text Available Sandy shorelines are dynamic with constant changes that can cause hazards in developed areas. The causes of change may be either natural or anthropogenic. This paper evaluates evidence for shoreline changes and their causative factors using a case study on the east coast of South Africa. Beach morphology trends were found to be location-specific, but overall the beaches show a receding trend. It was hypothesized that wave, tide, sea level and wind trends as well as anthropogenic influences are causative factors, and their contributions to shoreline changes were evaluated. Maximum significant wave heights, average wave direction, peak period and storm event frequencies all show weak increasing trends, but only the increases in peak period and wave direction are statistically significant. The chronic beach erosion cannot be attributed to wave climate changes since they are still too small to explain the observations. Instead, the impacts of sea level rise and reductions in the supply of beach sediments are suggested as the main causative factors. The analysis also identifies a trend in the frequency of severe erosion events due to storms that coincide with a 4.5-yr extreme tide cycle, which demonstrates the potential impact of future sea level rise.

  10. UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production

    Science.gov (United States)

    Wood, Simon R.; Berwick, Marianne; Ley, Ronald D.; Walter, Ronald B.; Setlow, Richard B.; Timmins, Graham S.

    2006-01-01

    Controversy continues both as to which wavelengths of sunlight cause melanoma and the mechanisms by which these different wavelengths act. Direct absorption of UVB by DNA is central in albino animal models, but melanin-pigmented models have shown major contributions by wavelengths longer than UVB that are thought to be mediated by photosensitized oxidant production. The only model for which the action spectrum of melanoma causation is known is a genetically melanoma-susceptible specific cross of Xiphophorus fish. We used electron paramagnetic resonance to quantitatively detect the UV induction of reactive melanin radicals in situ in the melanin-containing cells in the skin of this model and derived the action spectrum for melanin-photosensitized oxidant production (Φox). This action spectrum was identical to that for melanoma induction (Φmel). These results confirm the hypothesis that melanin-photosensitized radical production is the major causative step of melanoma in this model and demonstrate that the wavelengths and mechanisms of melanoma causation in different models are dependent on the presence of melanin. This approach should be applicable to humans, thus providing an accurate surrogate for Φmel for prevention studies. PMID:16537493

  11. Fungal Agents as a Cause of Nasal Polyposis

    Directory of Open Access Journals (Sweden)

    Mohammad Nejadkazem

    2015-01-01

    Full Text Available Introduction: Sinonasal polyposis is the most common tumor of nasal cavity and sinuses. Its complications are but not limited to sinusitis, breathing difficulties, hyposmia, anosmia and bone erosion. Methods and materials: A total of 98 patients with sinonasal polyposis were examined for suspicious causative fungal agent. Results: Direct microscopy and culture confirmed fungal agent in 8 patients (8.1% from which 3 cases had Alternaria spp, 1 patient Aspergillus spp, 1 patient Bipolaris spp, and 3 patients yeast. Conclusion: Fungi may be considered as a potential cause of sinonasal polyposis.   Keywords: Sinonasal Polyposis, Rhinosinusitis, Fungi

  12. Head injury causation scenarios for belted, rear-seated children in frontal impacts.

    Science.gov (United States)

    Bohman, Katarina; Arbogast, Kristy B; Bostrom, Ola

    2011-02-01

    Head injuries are the most common serious injuries sustained by children in motor vehicle crashes and are of critical importance with regard to long-term disability. There is a lack of understanding of how seat belt-restrained children sustain head injuries in frontal impacts. The aim of the study was to identify the AIS2+ head injury causation scenarios for rear-seated, belt-restrained children in frontal impacts, including the set of parameters contributing to the injury. In-depth crash investigations from two National Highway Traffic Safety Administration (NHTSA) databases, the National Automotive Sampling System-Crashworthiness Data System (NASS-CDS; 1997-2008) and the Crash Injury Research and Engineering Network (CIREN; 1996-2009), were collected and analyzed in detail. Selection criteria were all frontal impacts with principal direction of force (PDOF) of 11, 12, and 1 o'clock involving rear-seated, three-point belt-restrained, with or without booster cushion, children from 3 to 13 years with an AIS2+ head injury. Cases were analyzed using the BioTab method of injury causation assessment in order to systematically analyze the injury causation scenario for each case. There were 27 cases meeting the inclusion criteria, 19 cases with MAIS2 head injuries and 8 cases with MAIS3+ head injuries, including 2 fatalities. Three major injury causation scenarios were identified, including head contact with seatback (10 cases), head contact with side interior (7 cases,) and no evidence of head contact (9 cases). Head injuries with seatback or side interior contact typically included a PDOF greater than 10 degree (similar to the Insurance Institute for Highway Safety [IIHS] and EuroNCAP offset frontal testing) and vehicle maneuvers. For seatback contact, the vehicle's movements contributed to occupant kinematics inboard the vehicle, causing a less than optimal restraint of the torso and/or torso roll out of the shoulder belt. For side interior contact, the PDOF and

  13. A core MRB1 complex component is indispensable for RNA editing in insect and human infective stages of Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Michelle L Ammerman

    Full Text Available Uridine insertion/deletion RNA editing is a unique and vital process in kinetoplastids, required for creation of translatable open reading frames in most mitochondrially-encoded RNAs. Emerging as a key player in this process is the mitochondrial RNA binding 1 (MRB1 complex. MRB1 comprises an RNA-independent core complex of at least six proteins, including the GAP1/2 guide RNA (gRNA binding proteins. The core interacts in an RNA-enhanced or -dependent manner with imprecisely defined TbRGG2 subcomplexes, Armadillo protein MRB10130, and additional factors that comprise the dynamic MRB1 complex. Towards understanding MRB1 complex function in RNA editing, we present here functional characterization of the pentein domain-containing MRB1 core protein, MRB11870. Inducible RNAi studies demonstrate that MRB11870 is essential for proliferation of both insect vector and human infective stage T. brucei. MRB11870 ablation causes a massive defect in RNA editing, affecting both pan-edited and minimally edited mRNAs, but does not substantially affect mitochondrial RNA stability or processing of precursor transcripts. The editing defect in MRB1-depleted cells occurs at the initiation stage of editing, as pre-edited mRNAs accumulate. However, the gRNAs that direct editing remain abundant in the knockdown cells. To examine the contribution of MRB11870 to MRB1 macromolecular interactions, we tagged core complexes and analyzed their composition and associated proteins in the presence and absence of MRB11870. These studies demonstrated that MRB11870 is essential for association of GAP1/2 with the core, as well as for interaction of the core with other proteins and subcomplexes. Together, these data support a model in which the MRB1 core mediates functional interaction of gRNAs with the editing machinery, having GAP1/2 as its gRNA binding constituents. MRB11870 is a critical component of the core, essential for its structure and function.

  14. Causation in negligence: from anti-jurisprudence to principle--individual responsibility as the cornerstone for the attribution of liability.

    Science.gov (United States)

    Bagaric, Mirko; Erbacher, Sharon

    2011-06-01

    Causation is one of the most esoteric and poorly defined legal principles. The common law standards of the "but for" test and common sense are, in reality, code for unconstrained judicial choice. This leads to a high degree of unpredictability in negligence cases. Changes to the causation standard following the torts reforms have done nothing to inject principle into this area of law: the concept of "appropriateness" is no more illuminating than common sense. Despite this, the trend of recent High Court decisions offers some prospect of clarifying the test for causation. Key themes to emerge are an increased emphasis on individual responsibility and the associated concept of coherency with other legal standards. This article examines the doctrinal reasons underpinning the increasingly important role of these ideals and suggests how they can be accommodated into the test for causation to inject greater coherence and predictability into this area of law.

  15. Clinical characteristics of biopsy-proven allergic bronchopulmonary mycosis: variety in causative fungi and laboratory findings.

    Science.gov (United States)

    Ishiguro, Takashi; Takayanagi, Noboru; Kagiyama, Naho; Shimizu, Yoshihiko; Yanagisawa, Tsutomu; Sugita, Yutaka

    2014-01-01

    The diagnosis of allergic bronchopulmonary mycosis (ABPM) has traditionally relied widely on Rosenberg's criteria, which emphasize immunologic responses while overlooking the investigation of mucous plugs as a primary criterion. Therefore, the characteristics of biopsy-proven ABPM require further elucidation. The aim of this study was to analyze the clinical characteristics of biopsy-proven ABPM and address whether full compliance with clinical criteria, such as the presence of asthma, and certain laboratory findings is necessary to establish a diagnosis of ABPM. We retrospectively analyzed 17 patients with biopsy-proven ABPM focusing on causative fungi and laboratory findings. Causative fungi included Aspergillus sp. in seven patients, Schizophyllum commune in four patients, Penicillium sp. in two patients and unknown in five patients. Bronchial asthma was observed in 10 patients, eosinophilia was observed in 10 patients and an increased serum immunoglobulin (Ig) E level was observed in 14 of the 17 patients. IgG for Aspergillus sp. was positive in six of the seven patients with ABPM due to Aspergillus and turned positive in the remaining patient during follow-up. Technological limitations prevented the measurement of specific IgE for S. commune and IgG for S. commune and Penicillium sp. in most patients. Computed tomography revealed central bronchiectasis, pulmonary infiltration and mucous plugs in all patients. Causative fungi other than Aspergillus sp. are not uncommon, and immunological tests for other fungi should be popularized. Asthma and characteristic laboratory findings, such as peripheral blood eosinophilia, increased serum IgE and precipitating antibodies, may not always be required to diagnose ABPM. The importance of typical pathologic findings of mucous plugs for diagnosing ABPM requires reevaluation. Further studies are needed to establish more elaborate diagnostic criteria for ABPM.

  16. Severe Enterovirus Infections in Hospitalized Children in the South of England: Clinical Phenotypes and Causative Genotypes.

    Science.gov (United States)

    de Graaf, Hans; Pelosi, Emanuela; Cooper, Andrea; Pappachan, John; Sykes, Kim; MacIntosh, Iain; Gbesemete, Diane; Clark, Tristan W; Patel, Sanjay V; Faust, Saul N; Tebruegge, Marc

    2016-07-01

    Most enterovirus surveillance studies lack detailed clinical data, which limits their clinical usefulness. This study aimed to describe the clinical spectrum and outcome of severe enterovirus infections in children, and to determine whether there are associations between causative enterovirus genotypes and clinical phenotypes. Retrospective analysis of microbiological and clinical data from a tertiary children's hospital in the South of England over a 17-month period (2012-2013). In total, 30 patients were identified, comprising sepsis (n = 9), myocarditis (n = 8), meningitis (n = 8) and encephalitis (n = 5). Cases with sepsis or myocarditis were significantly younger than those with central nervous system disease (median age 21 and 15 days vs. 79 days; P = 0.0244 and P = 0.0310, respectively). There was considerable diversity in the causative genotypes in each of the clinical phenotypes, with some predominance of echoviruses in the meningitis group, and coxsackie B viruses in the myocarditis group. Thirteen cases required mechanical ventilation, 11 cases inotropic support, 3 cases dialysis and 3 cases extracorporal membrane oxygenation. The overall mortality was 10% (sepsis group, n = 1; myocarditis group, n = 2). Of the survivors, 5 (19%) had long-term sequelae (myocardial dysfunction, n = 2; neurological sequelae, n = 3). Patients with encephalitis had the longest hospital stay (median: 16 days), compared with 9, 6 and 3 days in patients with myocarditis, sepsis and meningitis, respectively (P = 0.005). Enterovirus infections, particularly enteroviral myocarditis and encephalitis, can cause significant morbidity and mortality. The results show that there are currently no strong associations between clinical phenotypes and particular causative enterovirus genotypes in the South of England.

  17. Probability of causation tables and their possible implications for the practice of diagnostic radiology

    International Nuclear Information System (INIS)

    Gur, D.; Wald, N.

    1986-01-01

    In compliance with requirements in the Orphan Drug Act (97-414) of 1983, tables were recently constructed by an ad hoc committee of the National Institutes of Health (NIH) in which the probabilities that certain specific cancers are caused by previous radiation exposure are estimated. The reports of the NIH committee and a National Academy of Science oversight committee may have broad implications for the future practice of diagnostic radiology. The basis on which the probability of causation tables were established and some of the possible implications for diagnostic radiology are discussed

  18. Scandinavian object shift, remnant VP-topicalisation, verb particles and causatives

    DEFF Research Database (Denmark)

    Engels, Eva; Vikner, Sten

    2013-01-01

    constructions in Danish and Swedish, namely particle verb constructions and causative constructions with Danish "lade" and Swedish "låta" ‘let’. It is shown how differences in the VP-internal object position give rise to mirror image sequences concerning Object Shift in connection with verb second (Vº......On the basis of an examination of remnant VP-topicalisation constructions, this paper argues for an order preservation analysis of Scandinavian Object Shift. Extending the empirical database, we account for the phenomena in an Optimality Theoretic framework. The paper focusses on two particular...

  19. Limit of probability of causation in the compensation of radiation induced malignant diseases

    International Nuclear Information System (INIS)

    Sun Shiquan

    1989-01-01

    Etiological relationship between previous radiation exposure and malignant diseases concerned could be estimated from NIH Epidemiological Tables expressed as Probability of Causation (PC). But the limit of PC in the compensation of radiation induced malignant diseases has not been decided definitely. In this paper PC calculations were made for populations of occupational exposure with typical distribution of individual doses and levels of exposure. The results show that it is feasible to choice PC ≥ 50% as a limit of compensation for leukemia and radon induced lung cancer. Some lenient limits may be taken for other radiation related solid carcinomas

  20. Feline immunodeficiency virus: disease association versus causation in domestic and nondomestic felids.

    Science.gov (United States)

    White, Joanna; Stickney, Alison; Norris, Jacqueline M

    2011-11-01

    Feline immunodeficiency virus (FIV) is an important infection in both domestic and nondomestic cats. Although many studies have provided insight into FIV pathophysiology and immunologic responses to infection in cats, questions remain regarding the association of FIV with specific disease syndromes. For many diseases, both association and causation of disease with FIV remain to be confirmed and clarified. The use of experimental infection models is unlikely to yield answers about naturally infected domestic cats and is not feasible in nondomestic felids, many of which are endangered species. Researches might consider further study of naturally occurring disease with an emphasis on confirming which diseases have a likely association with FIV.

  1. "Are we there yet?": Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits.

    Science.gov (United States)

    Page, Grier P; George, Varghese; Go, Rodney C; Page, Patricia Z; Allison, David B

    2003-10-01

    Although mathematical relationships can be proven by deductive logic, biological relationships can only be inferred from empirical observations. This is a distinct disadvantage for those of us who strive to identify the genes involved in complex diseases and quantitative traits. If causation cannot be proven, however, what does constitute sufficient evidence for causation? The philosopher Karl Popper said, "Our belief in a hypothesis can have no stronger basis than our repeated unsuccessful critical attempts to refute it." We believe that to establish causation, as scientists, we must make a serious attempt to refute our own hypotheses and to eliminate all known sources of bias before association becomes causation. In addition, we suggest that investigators must provide sufficient data and evidence of their unsuccessful efforts to find any confounding biases. In this editorial, we discuss what "causation" means in the context of complex diseases and quantitative traits, and we suggest guidelines for steps that may be taken to address possible confounders of association before polymorphisms may be called "causative."

  2. Characterization of a Novel Class I Transcription Factor A (CITFA) Subunit That Is Indispensable for Transcription by the Multifunctional RNA Polymerase I of Trypanosoma brucei

    KAUST Repository

    Nguyen, T. N.

    2012-10-26

    Trypanosoma brucei is the only organism known to have evolved a multifunctional RNA polymerase I (pol I) system that is used to express the parasite\\'s ribosomal RNAs, as well as its major cell surface antigens, namely, the variant surface glycoprotein (VSG) and procyclin, which are vital for establishing successful infections in the mammalian host and the tsetse vector, respectively. Thus far, biochemical analyses of the T. brucei RNA pol I transcription machinery have elucidated the subunit structure of the enzyme and identified the class I transcription factor A (CITFA). CITFA binds to RNA pol I promoters, and its CITFA-2 subunit was shown to be absolutely essential for RNA pol I transcription in the parasite. Tandem affinity purification (TAP) of CITFA revealed the subunits CITFA-1 to -6, which are conserved only among kinetoplastid organisms, plus the dynein light chain DYNLL1. Here, by tagging CITFA-6 instead of CITFA-2, a complex was purified that contained all known CITFA subunits, as well as a novel proline-rich protein. Functional studies carried out in vivo and in vitro, as well as a colocalization study, unequivocally demonstrated that this protein is a bona fide CITFA subunit, essential for parasite viability and indispensable for RNA pol I transcription of ribosomal gene units and the active VSG expression site in the mammalian-infective life cycle stage of the parasite. Interestingly, CITFA-7 function appears to be species specific, because expression of an RNA interference (RNAi)-resistant CITFA-7 transgene from Trypanosoma cruzi could not rescue the lethal phenotype of silencing endogenous CITFA-7.

  3. Structures of Trypanosoma brucei methionyl-tRNA synthetase with urea-based inhibitors provide guidance for drug design against sleeping sickness.

    Directory of Open Access Journals (Sweden)

    Cho Yeow Koh

    2014-04-01

    Full Text Available Methionyl-tRNA synthetase of Trypanosoma brucei (TbMetRS is an important target in the development of new antitrypanosomal drugs. The enzyme is essential, highly flexible and displaying a large degree of changes in protein domains and binding pockets in the presence of substrate, product and inhibitors. Targeting this protein will benefit from a profound understanding of how its structure adapts to ligand binding. A series of urea-based inhibitors (UBIs has been developed with IC50 values as low as 19 nM against the enzyme. The UBIs were shown to be orally available and permeable through the blood-brain barrier, and are therefore candidates for development of drugs for the treatment of late stage human African trypanosomiasis. Here, we expand the structural diversity of inhibitors from the previously reported collection and tested for their inhibitory effect on TbMetRS and on the growth of T. brucei cells. The binding modes and binding pockets of 14 UBIs are revealed by determination of their crystal structures in complex with TbMetRS at resolutions between 2.2 Å to 2.9 Å. The structures show binding of the UBIs through conformational selection, including occupancy of the enlarged methionine pocket and the auxiliary pocket. General principles underlying the affinity of UBIs for TbMetRS are derived from these structures, in particular the optimum way to fill the two binding pockets. The conserved auxiliary pocket might play a role in binding tRNA. In addition, a crystal structure of a ternary TbMetRS•inhibitor•AMPPCP complex indicates that the UBIs are not competing with ATP for binding, instead are interacting with ATP through hydrogen bond. This suggests a possibility that a general 'ATP-engaging' binding mode can be utilized for the design and development of inhibitors targeting tRNA synthetases of other disease-causing pathogen.

  4. The orthologue of Sjögren's syndrome nuclear autoantigen 1 (SSNA1 in Trypanosoma brucei is an immunogenic self-assembling molecule.

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    Helen P Price

    Full Text Available Primary Sjögren's Syndrome (PSS is a highly prevalent autoimmune disease, typically manifesting as lymphocytic infiltration of the exocrine glands leading to chronically impaired lacrimal and salivary secretion. Sjögren's Syndrome nuclear autoantigen 1 (SSNA1 or NA14 is a major specific target for autoantibodies in PSS but the precise function and clinical relevance of this protein are largely unknown. Orthologues of the gene are absent from many of the commonly used model organisms but are present in Chlamyodomonas reinhardtii (in which it has been termed DIP13 and most protozoa. We report the functional characterisation of the orthologue of SSNA1 in the kinetoplastid parasite, Trypanosoma brucei. Both TbDIP13 and human SSNA1 are small coiled-coil proteins which are predicted to be remote homologues of the actin-binding protein tropomyosin. We use comparative proteomic methods to identify potential interacting partners of TbDIP13. We also show evidence that TbDIP13 is able to self-assemble into fibril-like structures both in vitro and in vivo, a property which may contribute to its immunogenicity. Endogenous TbDIP13 partially co-localises with acetylated α-tubulin in the insect procyclic stage of the parasite. However, deletion of the DIP13 gene in cultured bloodstream and procyclic stages of T. brucei has little effect on parasite growth or morphology, indicating either a degree of functional redundancy or a function in an alternative stage of the parasite life cycle.

  5. Septic Pulmonary Embolism Requiring Critical Care: Clinicoradiological Spectrum, Causative Pathogens and Outcomes

    Science.gov (United States)

    Chou, Deng-Wei; Wu, Shu-Ling; Chung, Kuo-Mou; Han, Shu-Chen; Cheung, Bruno Man-Hon

    2016-01-01

    OBJECTIVES: Septic pulmonary embolism is an uncommon but life-threatening disorder. However, data on patients with septic pulmonary embolism who require critical care have not been well reported. This study elucidated the clinicoradiological spectrum, causative pathogens and outcomes of septic pulmonary embolism in patients requiring critical care. METHODS: The electronic medical records of 20 patients with septic pulmonary embolism who required intensive care unit admission between January 2005 and December 2013 were reviewed. RESULTS: Multiple organ dysfunction syndrome developed in 85% of the patients, and acute respiratory failure was the most common organ failure (75%). The most common computed tomographic findings included a feeding vessel sign (90%), peripheral nodules without cavities (80%) or with cavities (65%), and peripheral wedge-shaped opacities (75%). The most common primary source of infection was liver abscess (40%), followed by pneumonia (25%). The two most frequent causative pathogens were Klebsiella pneumoniae (50%) and Staphylococcus aureus (35%). Compared with survivors, nonsurvivors had significantly higher serum creatinine, arterial partial pressure of carbon dioxide, and Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores, and they were significantly more likely to have acute kidney injury, disseminated intravascular coagulation and lung abscesses. The in-hospital mortality rate was 30%. Pneumonia was the most common cause of death, followed by liver abscess. CONCLUSIONS: Patients with septic pulmonary embolism who require critical care, especially those with pneumonia and liver abscess, are associated with high mortality. Early diagnosis, appropriate antibiotic therapy, surgical intervention and respiratory support are essential. PMID:27759843

  6. Septic Pulmonary Embolism Requiring Critical Care: Clinicoradiological Spectrum, Causative Pathogens and Outcomes

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    Deng-Wei Chou

    Full Text Available OBJECTIVES: Septic pulmonary embolism is an uncommon but life-threatening disorder. However, data on patients with septic pulmonary embolism who require critical care have not been well reported. This study elucidated the clinicoradiological spectrum, causative pathogens and outcomes of septic pulmonary embolism in patients requiring critical care. METHODS: The electronic medical records of 20 patients with septic pulmonary embolism who required intensive care unit admission between January 2005 and December 2013 were reviewed. RESULTS: Multiple organ dysfunction syndrome developed in 85% of the patients, and acute respiratory failure was the most common organ failure (75%. The most common computed tomographic findings included a feeding vessel sign (90%, peripheral nodules without cavities (80% or with cavities (65%, and peripheral wedge-shaped opacities (75%. The most common primary source of infection was liver abscess (40%, followed by pneumonia (25%. The two most frequent causative pathogens were Klebsiella pneumoniae (50% and Staphylococcus aureus (35%. Compared with survivors, nonsurvivors had significantly higher serum creatinine, arterial partial pressure of carbon dioxide, and Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores, and they were significantly more likely to have acute kidney injury, disseminated intravascular coagulation and lung abscesses. The in-hospital mortality rate was 30%. Pneumonia was the most common cause of death, followed by liver abscess. CONCLUSIONS: Patients with septic pulmonary embolism who require critical care, especially those with pneumonia and liver abscess, are associated with high mortality. Early diagnosis, appropriate antibiotic therapy, surgical intervention and respiratory support are essential.

  7. Beliefs about causation of schizophrenia: do Indian families believe in supernatural causes?

    Science.gov (United States)

    Srinivasan, T N; Thara, R

    2001-03-01

    Beliefs about the causation of schizophrenia could influence the attitudes patients' families adopt towards the patient and may also influence their help-seeking behaviour. Indian families have been typically described as often believing in causes like supernatural forces and therefore seeking help from magico-religious healers. In the changing mental health scenario in India, this impression needs verification. Key relatives living with 254 chronic schizophrenia patients were interviewed and asked to name the causes they believed were behind the illness. A list of possible causes was provided for the families to select from, and relatives were also encouraged to mention other possible causes, not featured in the list. The possible causes identified and the factors related to attributions made were analysed. A supernatural cause was named by only 12% of the families and as the only cause by 5%. Psychosocial stress was most commonly cited cause, followed by personality defect and heredity. A small number of families (14%) could not name any cause and 39% named more than one cause. Patient gender and education, duration of illness and the key relative's education and the nature of relationship were related to the type of causal attributions made. Families living with patients suffering chronic schizophrenia receiving treatment in urban India rarely subscribe to the idea of supernatural causation of the illness. The causal attributions made by them are fairly rational and understandable, given the relative lack of exposure to proper information about the illness.

  8. Attribution of intentional causation influences the perception of observed movements: Behavioural evidence and neural correlates

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    James W Moore

    2013-01-01

    Full Text Available Recent research on human agency suggests that intentional causation is associated with a subjective compression in the temporal interval between actions and their effects. That is, intentional movements and their causal effects are perceived as closer together in time than equivalent unintentional movements and their causal effects. This so-called intentional binding effect is consistently found for one’s own self-generated actions. It has also been suggested that intentional binding occurs when observing intentional movements of others. However, this evidence is undermined by limitations of the paradigm used. In the current study we aimed to overcome these limitations using a more rigorous design in combination with functional Magnetic Resonance Imaging (fMRI to explore the neural underpinnings of intentional binding of observed movements. In particular, we aimed to identify brain areas sensitive to the interaction between intentionality and causality attributed to the observed action. Our behavioural results confirmed the occurrence of intentional binding for observed movements using this more rigorous paradigm. Our fMRI results highlighted a collection of brain regions whose activity was sensitive to the interaction between intentionality and causation. Intriguingly, these brain regions have previously been implicated in the sense of agency over one’s own movements. We discuss the implications of these results for intentional binding specifically, and the sense of agency more generally.

  9. Causative Chain Difference for each Type of Accidents in Japanese Maritime Traffic Systems (MTS

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    Wanginingastuti Mutmainnah

    2017-09-01

    Full Text Available Causative chain (CC is a failure chain that cause accident as an outcome product of the second step of MOP model, namely line relation analysis (LRA. This CC is a connection of several causative factors (CF, an outcome product of first step of MOP model, namely corner analysis (CA. MOP Model is an abbreviation from 4M Overturned Pyramid, created by authors by combining 2 accident analysis models. There are two steps in this model, namely CA and LRA. Utilizing this model can know what is CF that happen dominantly to the accidents and what is a danger CC that characterize accidents in a certain place and certain period. By knowing the characteristics, the preventive action can be decided to decrease the number of accident in the next period. The aim of this paper is providing the development of MOP Model that has been upgraded and understanding the characteristics of each type accident. The data that is analyzed in this paper is Japanese accidents from 2008 until 2013, which is available on Japan Transportation Safety Board (JTSB’s website. The analysis shows that every type of accidents has a unique characteristic, shown by their CFs and CCs. However, Man Factor is still playing role to the system dominantly.

  10. Negative life events and symptoms of depression and anxiety: stress causation and/or stress generation.

    Science.gov (United States)

    Phillips, Anna C; Carroll, Douglas; Der, Geoff

    2015-01-01

    Stressful life events are known to contribute to development of depression; however, it is possible this link is bidirectional. The present study examined whether such stress generation effects are greater than the effects of stressful life events on depression, and whether stress generation is also evident with anxiety. Participants were two large age cohorts (N = 732 aged 44 years; N = 705 aged 63 years) from the West of Scotland Twenty-07 study. Stressful life events, depression, and anxiety symptoms were measured twice five years apart. Cross-lagged panel analysis examined the mutual influences of stressful life events on depression and on anxiety over time. Life events predicted later depressive symptomatology (p = .01), but the depression predicting life events relationship was less strong (p = .06), whereas earlier anxiety predicted life events five years later (p = .001). There was evidence of sex differences in the extent to which life events predicted later anxiety. This study provides evidence of stress causation for depression and weaker evidence for stress generation. In contrast, there was strong evidence of stress generation for anxiety but weaker evidence for stress causation, and that differed for men and women.

  11. Causative factors of cost overrun in highway projects of Sindh province of Pakistan

    Science.gov (United States)

    Sohu, S.; Halid, A.; Nagapan, S.; Fattah, A.; Latif, I.; Ullah, K.

    2017-11-01

    Cost overrun is an increase of cost of project from approved budget which was signed by parties at the time of tender. Cost overrun in construction of highway projects is a common problem worldwide and construction industry of Pakistan is also facing this crucial problem of cost overrun in highway projects of Pakistan. The main objective of this research is to identify the causative factors of cost overrun in highway projects of Sindh province of Pakistan. A well designed questionnaire was developed based on 64 common factors of cost overrun from literature review. Developed questionnaire was distributed among selected 30 experts from owner/client, designer/consultant and contractor who have experience more than 20 years’ experience in highway projects. The collected data was statistical analyzed. After analysis results showed that delay process in payment by client, inadequate planning, client interference, poor contract management, delay of decision making, change of scope of project and financial problems faced by client were most causative factors of cost overrun in highway projects. This research will provide alertness to stakeholders of highway projects of Sindh province to avoid cost overrun in projects.

  12. Frequency of causative factors for pleural effusions: a hospital based study

    International Nuclear Information System (INIS)

    Ibrahim, M.T.; Saeed, M.K.; Umar, M.

    2010-01-01

    To determine the frequency of various causative factors of pleural effusion in adults. Combined Military Hospital, Attock and PAF hospital Faisal Karachi. One hundred and fifty patients of clinical signs of pleural effusion, were selected and then, further classified in to transudative and exudative variety by carrying out pleural fluid routine testing and using Light's criteria . Later the final etiological diagnosis was made with the help of appropriate laboratory tests. Out of total 150 patients who were studied, 123 patients were found to have exudative effusions whereas 27 cases had transudative effusion. A total of five 5 patients (3.33%) were lost to follow up. Three patients were out of exudative variety and 02 were from transudative variety. Out of 120 patient of exudative pleural effusion, 70(58.2%) had tuberculosis, 28(23.2%) had malignancy, 12(10%) had pneumonia, 5(6%) were uraemic, 2(1.6%) had pulmonary embolism, and rheumatoid arthritis, Systemic lupus erythematosis and liver abscess were causative factors in 1(0.8%) each patient. Out of transudative effusions, 14(56%) had congestive cardiac failure, 5(20%) had cirrhosis liver, 4(16%) had nephrotic syndrome and 1(4%) each had cardiac tamponade and myxoedema. The most common cause of pleural effusion remains tuberculosis. (author)

  13. Interacting agents in finance

    NARCIS (Netherlands)

    Hommes, C.; Durlauf, S.N.; Blume, L.E.

    2008-01-01

    Interacting agents in finance represent a behavioural, agent-based approach in which financial markets are viewed as complex adaptive systems consisting of many boundedly rational agents interacting through simple heterogeneous investment strategies, constantly adapting their behaviour in response

  14. Riot Control Agents

    Science.gov (United States)

    ... Submit What's this? Submit Button Facts About Riot Control Agents Interim document Recommend on Facebook Tweet Share Compartir What riot control agents are Riot control agents (sometimes referred to ...

  15. Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme

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    Alcione Silva de Carvalho

    2014-06-01

    Full Text Available Megazol (7 is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8 in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7 for nitrogen (in the triazole in 8, the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7.

  16. Reasoning about emotional agents

    OpenAIRE

    Meyer, J.-J.

    2004-01-01

    In this paper we discuss the role of emotions in artificial agent design, and the use of logic in reasoning about the emotional or affective states an agent can reside in. We do so by extending the KARO framework for reasoning about rational agents appropriately. In particular we formalize in this framework how emotions are related to the action monitoring capabilities of an agent.

  17. The evolution of the causation concept and its relation with statistical methods in Epidemiology

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    Luis Fernando Lisboa

    2008-09-01

    Full Text Available A historical review places the first registers of Epidemiology in ancient Greece, with Hippocrates, who identified environmental causes of diseases. Along the centuries, the evolution of the causation concept started to be related to changes in scientific paradigms. In London, during the 17th century, the quantitative method was introduced in Epidemiology, but it was only by the end of the 19th century that the concept of the environment and a mathematical approach to understanding Public Health issues were well established. This was a very rich period to setting new concepts and systematizations in epidemiologic methodology. The beginning of the 20th century consolidated Epidemiology as a scientific discipline and the development of computers in the post-war years brought much advance in this field. Nowadays, Epidemiology plays an important role as it integrates scientific knowledge on the health/disease process to the professional area, participating in population healthcare efforts.

  18. Evidence, illness, and causation: an epidemiological perspective on the Russo-Williamson Thesis.

    Science.gov (United States)

    Fiorentino, Alexander R; Dammann, Olaf

    2015-12-01

    According to the Russo-Williamson Thesis, causal claims in the health sciences need to be supported by both difference-making and mechanistic evidence. In this article, we attempt to determine whether Evidence-based Medicine (EBM) can be improved through the consideration of mechanistic evidence. We discuss the practical composition and function of each RWT evidence type and propose that exposure-outcome evidence (previously known as difference-making evidence) provides associations that can be explained through a hypothesis of causation, while mechanistic evidence provides finer-grained associations and knowledge of entities that ultimately explains a causal hypothesis. We suggest that mechanistic evidence holds untapped potential to add value to the assessment of evidence quality in EBM and propose initial recommendations for the integration of mechanistic and exposure-outcome evidence to improve EBM by robustly leveraging available evidence in support of good medical decisions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Non-Reflective Thinkers Are Predisposed to Attribute Supernatural Causation to Uncanny Experiences.

    Science.gov (United States)

    Bouvet, Romain; Bonnefon, Jean-François

    2015-07-01

    For unknown reasons, individuals who are confident in their intuitions are more likely to hold supernatural beliefs. How does an intuitive cognitive style lead one to believe in faith healing, astrology, or extrasensory perception (ESP)? We hypothesize that cognitive style is critically important after one experiences an uncanny event that seems to invite a supernatural explanation. In three studies, we show that irrespective of their prior beliefs in the supernatural, non-reflective thinkers are more likely than reflective thinkers to accept supernatural causation after an uncanny encounter with astrology and ESP. This is the first time that controlled experiments demonstrate the negative dynamics of reflection and supernatural causality attribution. We consider the possible generalization of our findings to religious beliefs and their implications for the social vulnerability of non-reflective individuals. © 2015 by the Society for Personality and Social Psychology, Inc.

  20. Correlation not Causation: The Relationship between Personality Traits and Political Ideologies

    Science.gov (United States)

    Verhulst, Brad; Eaves, Lindon J.; Hatemi, Peter K.

    2013-01-01

    The assumption in the personality and politics literature is that a person's personality motivates them to develop certain political attitudes later in life. This assumption is founded on the simple correlation between the two constructs and the observation that personality traits are genetically influenced and develop in infancy, whereas political preferences develop later in life. Work in psychology, behavioral genetics, and recently political science, however, has demonstrated that political preferences also develop in childhood and are equally influenced by genetic factors. These findings cast doubt on the assumed causal relationship between personality and politics. Here we test the causal relationship between personality traits and political attitudes using a direction of causation structural model on a genetically informative sample. The results suggest that personality traits do not cause people to develop political attitudes; rather, the correlation between the two is a function of an innate common underlying genetic factor. PMID:22400142

  1. Correlation not causation: the relationship between personality traits and political ideologies.

    Science.gov (United States)

    Verhulst, Brad; Eaves, Lindon J; Hatemi, Peter K

    2012-01-01

    The assumption in the personality and politics literature is that a person's personality motivates them to develop certain political attitudes later in life. This assumption is founded on the simple correlation between the two constructs and the observation that personality traits are genetically influenced and develop in infancy, whereas political preferences develop later in life. Work in psychology, behavioral genetics, and recently political science, however, has demonstrated that political preferences also develop in childhood and are equally influenced by genetic factors. These findings cast doubt on the assumed causal relationship between personality and politics. Here we test the causal relationship between personality traits and political attitudes using a direction of causation structural model on a genetically informative sample. The results suggest that personality traits do not cause people to develop political attitudes; rather, the correlation between the two is a function of an innate common underlying genetic factor.

  2. THE ROLE OF ADVERSE LIFESTYLE CHANGES IN THE CAUSATION OF CORONARY ARTERY DISEASE

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    M. H. Lotfi

    2008-05-01

    Full Text Available Adverse lifestyle changes like rapid change in dietary habits coupled with decreased physical activity and increasing rates of alcohol and tobacco consumption can increase Coronary Artery Disease risk factors and its mortality even higher than the rates predicted. To evaluate the role of Adverse Lifestyle changes factors in the causation of CAD, a hospital based case-control study was conducted in an urban area of East Delhi from April 2002 to December 2003. A total of 500 subjects with age group 30-75 (250 cases and 250 controls, were included in this study. To obtain more validate comparisons, 250 controls also was selected from community of East Delhi. The tool of enquiry was a pre-tested and pre-coded questionnaire. A confidence level of 95% and study power of 80% were considered for the interpretation of possible significant findings. Sexwise stratified analysis was separately done for male and female subjects using Multiple Logistic Regression. Comparison of male cases with their counterparts in both control groups indicated that milk consumption, using saturated oils for cooking medium, and tobacco consumption could account for as CAD independent predictors (P < 0.001. The comparison of female cases with their counterparts in both control groups also showed that majority of those significantly were nuts consumer (P < 0.01. Male cases compared to males in hospital group and female cases compared with females in community control group significantly were nuts consumer and used saturated oils in their cookings respectively (P < 0.01. Our study showed that dietary factors such as consumption of milk, nuts, saturated oils and smoking, as misbehavior factor, could play an important role in the causation of Coronary Artery Diseases (CAD in urban area of East Delhi, India.

  3. Ventilator-Associated Pneumonia and Causative Microorganisms in Intensive Care Unit: A Two Year Retrospective Analysis

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    Onur Palabıyık

    2016-12-01

    Full Text Available Objective: Ventilator-associated pneumonia (VAP is the most common nosocomial infection in the intensive care units (ICUs. It causes prolonged hospital stay and increases mortality. In this study, we aimed to investigate the rate of VAP, causative microorganisms, and their antibiotic susceptibilities in anaesthesiology and reanimation ICU (ARICU. Material and Method: This retrospective study included patients who were admitted to 12-bed ARICU between January 2013 and December 2014. The detection of VAP was done according to Centers for Disease Control and Prevention criteria. The rate of VAP, VAP ratio, and ventilator utilization ratio (VUR were calculated according to guidelines of Turkish National Infection Surveillance Control Group. Endotracheal aspiration samples were collected and cultivated. The identification of the isolates was performed by using VITEK-2 automated system. Antibiotic susceptibilities were determined by the disc diffusion method according to the Clinical and Laboratory Standards Institute criteria. Results: VAP was determined in 16 of 359 patients who required invasive mechanic ventilation for longer than 48 hours and hospitalized in ARICU. VUR was 65%, VAP ratio was 4.5% and the rate of VAP was 3.3 per 1000 ventilator days. Seventeen microorganisms were isolated from endotracheal aspiration samples, including Acinetobacter baumannii (n=6, Pseudomonas aeruginosa (n=4, methicillin-resistant Staphylococcus aureus (n=4, Klebsiella pneumoniae, Enterobacter cloacae and Serratia marcescens. The most sensitive antibiotics for microorganisms are listed as follows; Acinetobacter baumannii: colistin, Pseudomonas aeruginosa: amikacin, carbapenems; Methicillin-resistant Staphylococcus aureus: linezolid, teicoplanin, vancomycin, trimethoprim sulfamethoxazole; Klebsiella and Enterobacteriaceae species: carbapenems, trimethoprim sulfamethoxazole, gentamicin. Conclusion: Intermittent analyses and antibiotic susceptibilities of VAP

  4. Prevalence of musculoskeletal disorders and related occupational causative factors among electricity linemen: A narrative review

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    Vinothini Padmanathan

    2016-10-01

    Full Text Available Occupational tasks of linemen are highly associated with the development of work related musculoskeletal disorders (WRMDs. Although linemen are prone to develop WRMDs, there is paucity of information on the prevalence of WRMDs and related occupational causative factors. Therefore, the present review was conducted to report on the prevalence of WRMDs and to outline causative risk factors within occupational tasks in the lineman profession. Literature search was conducted in various databases such as Scopus, PubMed and ScienceDirect for articles published between 1996–2013. The articles were analyzed, selected and retrieved based on predetermined objectives, inclusion criteria and Medical Subject Headings (MeSH. In the review process only articles published in English were considered. The review identified moderate to high prevalence of WRMDs among the linemen population. Back and shoulder regions were highly affected compared to the other body regions. The review also reported occupational tasks such as bar installation, insulator fixation and manual handling of tools as high risk tasks that lead to the development of WRMDs. In addition, occupational tools such as ladders, manual cutters and manual presses were also identified as a potential ergonomic hazard. In conclusion, the current review identified that WRMDs are common in the back and shoulder regions among linemen. Also, a number of occupational risk factors were identified to be associated with WRMDs among the linemen. Hence, future research on prevention and intervention studies concerning lineman profession population in order to develop a good job practice are recommended. Int J Occup Med Environ Health 2016;29(5:725–734

  5. Does marriage inhibit antisocial behavior?: An examination of selection vs causation via a longitudinal twin design.

    Science.gov (United States)

    Burt, S Alexandra; Donnellan, M Brent; Humbad, Mikhila N; Hicks, Brian M; McGue, Matt; Iacono, William G

    2010-12-01

    Previous studies have indicated that marriage is negatively associated with male antisocial behavior. Although often interpreted as a causal association, marriage is not a random event. As such, the association may stem from selection processes, whereby men less inclined toward antisocial behavior are more likely to marry. To evaluate selection vs causation explanations of the association between marriage and desistence from antisocial behavior. Co-twin control analyses in a prospective twin study provided an analogue of the idealized counterfactual model of causation. The co-twin control design uses the unmarried co-twin of a married twin to estimate what the married twin would have looked like had he remained unmarried. Discordant monozygotic (MZ) twins are particularly informative because they share a common genotype and rearing environment. General community study. Two hundred eighty-nine male-male twin pairs (65.1% MZ) from the Minnesota Twin Family Study underwent assessment at 17, 20, 24, and 29 years of age. None of the participants were married at 17 years of age, and 2.6% were married at 20 years of age. By 29 years of age, 58.8% of the participants were or had been married. A tally of criterion C symptoms of DSM-III-R antisocial personality disorder, as assessed via structured clinical interview. Mean differences in antisocial behavior across marital status at age 29 years were present even at 17 and 20 years of age, suggesting a selection process. However, the within-pair effect of marriage was significant for MZ twins, such that the married twin engaged in less antisocial behavior following marriage than his unmarried co-twin. Results were equivalent to those in dizygotic twins and persisted when controlling for prior antisocial behavior. Results indicate an initial selection effect, whereby men with lower levels of antisocial behavior are more likely to marry. However, this tendency to refrain from antisocial behavior appears to be accentuated by the

  6. Endophthalmitis caused by gram-positive bacteria resistant to vancomycin: Clinical settings, causative organisms, antimicrobial susceptibilities, and treatment outcomes

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    Hegde Sharat Shivaramaiah

    2018-06-01

    Full Text Available Purpose: To report the clinical settings, causative organisms, antimicrobial susceptibilities, and treatment outcomes of patients with endophthalmitis caused by gram-positive bacteria resistant to vancomycin. Methods: Retrospective case series of all patients with culture-proven endophthalmitis caused by gram-positive bacteria resistant to vancomycin between January 2010 and December 2016 in LV Prasad Eye Institute, Visakhapatnam, India. Results: The current study included 14 patients. The clinical settings were post-cataract surgery in 8/14 (57.1% and open globe injury in 6/14 (42.8%. Primary intervention for all patients included tap and intravitreal antibiotic injection. During subsequent follow-up, pars plana vitrectomy was performed in 6 patients and one patient underwent penetrating keratoplasty. Mean number of intravitreal antibiotic injections performed were 3.4 per patient. The most common organisms isolated were coagulase-negative Staphylococci in 6/14 (42.8%, Staphylococcus aureus in 5/14 (35.7%, Streptococcus sp in 2/14 (14.2% and Bacillus sp in 1/14 (7.14%. In addition to vancomycin, resistance to multiple drugs (three or more groups of antibiotics was found in all 14 cases. Antimicrobial susceptibility results showed susceptibility to amikacin in 7/14 (50.0%, gatifloxacin in 6/14 (42.8%, moxifloxacin in 3/13 (23.0%, cefazoline in 5/14 (35.7%, cefuroxime in 3/14 (21.4%, ciprofloxacin in 2/14 (14.2% and linezolid in 5/5 (100%. The mean duration of follow-up was 30.7 weeks (6 weeks–90 weeks. At last follow-up, visual acuity (VA of 20/200 or better was recorded in 7/14 (50% and VA < 5/200 occurred in 7/14 (50%. Conclusion and importance: Antimicrobial susceptibility testing may help in selection of suitable antimicrobial agents for repeat intravitreal injection. Inspite of retreatment with intravitreal antibiotics, these patients generally had poor VA outcomes. Keywords: Coagulase-negative Staphylococci, Endophthalmitis

  7. Chemical warfare agents.

    Science.gov (United States)

    Kuca, Kamil; Pohanka, Miroslav

    2010-01-01

    Chemical warfare agents are compounds of different chemical structures. Simple molecules such as chlorine as well as complex structures such as ricin belong to this group. Nerve agents, vesicants, incapacitating agents, blood agents, lung-damaging agents, riot-control agents and several toxins are among chemical warfare agents. Although the use of these compounds is strictly prohibited, the possible misuse by terrorist groups is a reality nowadays. Owing to this fact, knowledge of the basic properties of these substances is of a high importance. This chapter briefly introduces the separate groups of chemical warfare agents together with their members and the potential therapy that should be applied in case someone is intoxicated by these agents.

  8. Genotypic status of the TbAT1/P2 adenosine transporter of Trypanosoma brucei gambiense isolates from Northwestern Uganda following melarsoprol withdrawal.

    Directory of Open Access Journals (Sweden)

    Anne J N Kazibwe

    Full Text Available BACKGROUND: The development of arsenical and diamidine resistance in Trypanosoma brucei is associated with loss of drug uptake by the P2 purine transporter as a result of alterations in the corresponding T. brucei adenosine transporter 1 gene (TbAT1. Previously, specific TbAT1 mutant type alleles linked to melarsoprol treatment failure were significantly more prevalent in T. b. gambiense from relapse patients at Omugo health centre in Arua district. Relapse rates of up to 30% prompted a shift from melarsoprol to eflornithine (alpha-difluoromethylornithine, DFMO as first-line treatment at this centre. The aim of this study was to determine the status of TbAT1 in recent isolates collected from T. b. gambiense sleeping sickness patients from Arua and Moyo districts in Northwestern Uganda after this shift in first-line drug choice. METHODOLOGY AND RESULTS: Blood and cerebrospinal fluids of consenting patients were collected for DNA preparation and subsequent amplification. All of the 105 isolates from Omugo that we successfully analysed by PCR-RFLP possessed the TbAT1 wild type allele. In addition, PCR/RFLP analysis was performed for 74 samples from Moyo, where melarsoprol is still the first line drug; 61 samples displayed the wild genotype while six were mutant and seven had a mixed pattern of both mutant and wild-type TbAT1. The melarsoprol treatment failure rate at Moyo over the same period was nine out of 101 stage II cases that were followed up at least once. Five of the relapse cases harboured mutant TbAT1, one had the wild type, while no amplification was achieved from the remaining three samples. CONCLUSIONS/SIGNIFICANCE: The apparent disappearance of mutant alleles at Omugo may correlate with melarsoprol withdrawal as first-line treatment. Our results suggest that melarsoprol could successfully be reintroduced following a time lag subsequent to its replacement. A field-applicable test to predict melarsoprol treatment outcome and identify

  9. Radiopharmaceutical scanning agents

    International Nuclear Information System (INIS)

    1976-01-01

    This invention is directed to dispersions useful in preparing radiopharmaceutical scanning agents, to technetium labelled dispersions, to methods for preparing such dispersions and to their use as scanning agents

  10. Taskable Reactive Agent Communities

    National Research Council Canada - National Science Library

    Myers, Karen

    2002-01-01

    The focus of Taskable Reactive Agent Communities (TRAC) project was to develop mixed-initiative technology to enable humans to supervise and manage teams of agents as they perform tasks in dynamic environments...

  11. Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation

    DEFF Research Database (Denmark)

    Pedersen, O B; Svendsen, Anders Jørgen; Ejstrup, L

    2008-01-01

    genetic effects account for 94% (95% CI 0.56-0.99) of the variance in the causation of AS. CONCLUSION: Self-reported AS needs careful validation. The occurrence of AS in a Danish twin population was 0.1% and accords well with previous studies on singletons in hospital settings. The present study adds...

  12. Decision making for business model development : A process study of effectuation and causation in new technology-based ventures

    NARCIS (Netherlands)

    Reymen, Isabelle; Berends, Hans; Oudehand, Rob; Stultiëns, Rutger

    2017-01-01

    This study investigates the decision-making logics used by new ventures to develop their business models. In particular, they focussed on the logics of effectuation and causation and how their dynamics shape the development of business models over time. They found that the effectual decision-making

  13. Reply to Matt Mortellaro on ‘Block’s Paradox’: Causation, Responsibility, Libertarian Law, Entrapment, Threats and Blackmail

    Directory of Open Access Journals (Sweden)

    Walter Block

    2009-08-01

    Full Text Available Matt Mortellaro’s “Causation and Responsibility: A New Direction” is a brilliant Rothbardian analysis that makes numerous new and important points. It also critiques some of my own previous publications. In this piece I focus on Mortellaro’s rejoinders to me, and set forth a defense of my own positions.

  14. 20 CFR 718.204 - Total disability and disability causation defined; criteria for determining total disability and...

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Total disability and disability causation... Section 718.204 Employees' Benefits EMPLOYMENT STANDARDS ADMINISTRATION, DEPARTMENT OF LABOR FEDERAL COAL... than those listed in Table B1 (Males) or Table B2 (Females) in Appendix B to this part for an...

  15. Can a Microwave Heat up Coffee? How English- and Japanese-Speaking Children Choose Subjects in Lexical Causative Sentences

    Science.gov (United States)

    Kanero, Junko; Hirsh-Pasek, Kathy; Golinkoff, Roberta Michnick

    2016-01-01

    Languages differ greatly in how they express causal events. In languages like Japanese, the subjects of causative sentences, or "causers," are generally animate and intentional, whereas in other languages like English, causers range widely from animate beings to inanimate objects (e.g. Wolff, Jeon & Li, 2009). This paper explores…

  16. Understanding dynamics of strategic decision-making in venture creation: a process study of effectuation and causation

    NARCIS (Netherlands)

    Reymen, I.M.M.J.; Andries, P.; Berends, J.J.; Mauer, R.; Stephan, U.; van Burg, J.C.

    2015-01-01

    This study draws upon effectuation and causation as examples of planning-based and flexible decision-making logics and investigates dynamics in the use of both logics. The study applies a longitudinal process research approach to investigate strategic decision making in new venture creation over

  17. Highlights from the literature on accident causation and system safety: Review of major ideas, recent contributions, and challenges

    Energy Technology Data Exchange (ETDEWEB)

    Saleh, J.H., E-mail: jsaleh@gatech.ed [School of Aerospace Engineering, Georgia Institute of Technology (United States); Marais, K.B. [School of Aeronautics and Astronautics, Purdue University (United States); Bakolas, E.; Cowlagi, R.V. [School of Aerospace Engineering, Georgia Institute of Technology (United States)

    2010-11-15

    This work constitutes a short guide to the extensive but fragmented literature on accident causation and system safety. After briefly motivating the interest in accident causation and discussing the notion of a safety value chain, we delve into our multi-disciplinary review with discussions of Man Made Disasters, Normal Accident, and the High Reliability Organizations (HRO) paradigm. The HRO literature intersects an extensive literature on safety culture, a subject we then briefly touch upon. Following this discussion, we note that while these social and organizational contributions have significantly enriched our understanding of accident causation and system safety, they have important deficiencies and are lacking in their understanding of technical and design drivers of system safety and accident causation. These missing ingredients, we argue, were provided in part by the development of Probabilistic Risk Assessment (PRA). The idea of anticipating possible accident scenarios, based on the system design and configuration, as well as its technical and operational characteristics, constitutes an important contribution of PRA, which builds on and extends earlier contributions made by the development of Fault Tree and Event Tree Analysis. We follow the discussion of PRA with an exposition of the concept of safety barriers and the principle of defense-in-depth, both of which emphasize the functions and 'safety elements [that should be] deliberately inserted' along potential accident trajectories to prevent, contain, or mitigate accidents. Finally, we discuss two ideas that are emerging as foundational in the literature on system safety and accident causation, namely that system safety is a 'control problem', and that it requires a 'system theoretic' approach to be dealt with. We clarify these characterizations and indicate research opportunities to be pursued along these directions. We conclude this work with two general recommendations

  18. Highlights from the literature on accident causation and system safety: Review of major ideas, recent contributions, and challenges

    International Nuclear Information System (INIS)

    Saleh, J.H.; Marais, K.B.; Bakolas, E.; Cowlagi, R.V.

    2010-01-01

    This work constitutes a short guide to the extensive but fragmented literature on accident causation and system safety. After briefly motivating the interest in accident causation and discussing the notion of a safety value chain, we delve into our multi-disciplinary review with discussions of Man Made Disasters, Normal Accident, and the High Reliability Organizations (HRO) paradigm. The HRO literature intersects an extensive literature on safety culture, a subject we then briefly touch upon. Following this discussion, we note that while these social and organizational contributions have significantly enriched our understanding of accident causation and system safety, they have important deficiencies and are lacking in their understanding of technical and design drivers of system safety and accident causation. These missing ingredients, we argue, were provided in part by the development of Probabilistic Risk Assessment (PRA). The idea of anticipating possible accident scenarios, based on the system design and configuration, as well as its technical and operational characteristics, constitutes an important contribution of PRA, which builds on and extends earlier contributions made by the development of Fault Tree and Event Tree Analysis. We follow the discussion of PRA with an exposition of the concept of safety barriers and the principle of defense-in-depth, both of which emphasize the functions and 'safety elements [that should be] deliberately inserted' along potential accident trajectories to prevent, contain, or mitigate accidents. Finally, we discuss two ideas that are emerging as foundational in the literature on system safety and accident causation, namely that system safety is a 'control problem', and that it requires a 'system theoretic' approach to be dealt with. We clarify these characterizations and indicate research opportunities to be pursued along these directions. We conclude this work with two general recommendations: (1) that more fundamental

  19. RNA-seq de novo Assembly Reveals Differential Gene Expression in Glossina palpalis gambiensis Infected with Trypanosoma brucei gambiense vs. Non-Infected and Self-Cured Flies.

    Science.gov (United States)

    Hamidou Soumana, Illiassou; Klopp, Christophe; Ravel, Sophie; Nabihoudine, Ibouniyamine; Tchicaya, Bernadette; Parrinello, Hugues; Abate, Luc; Rialle, Stéphanie; Geiger, Anne

    2015-01-01

    Trypanosoma brucei gambiense (Tbg), causing the sleeping sickness chronic form, completes its developmental cycle within the tsetse fly vector Glossina palpalis gambiensis (Gpg) before its transmission to humans. Within the framework of an anti-vector disease control strategy, a global gene expression profiling of trypanosome infected (susceptible), non-infected, and self-cured (refractory) tsetse flies was performed, on their midguts, to determine differential genes expression resulting from in vivo trypanosomes, tsetse flies (and their microbiome) interactions. An RNAseq de novo assembly was achieved. The assembled transcripts were mapped to reference sequences for functional annotation. Twenty-four percent of the 16,936 contigs could not be annotated, possibly representing untranslated mRNA regions, or Gpg- or Tbg-specific ORFs. The remaining contigs were classified into 65 functional groups. Only a few transposable elements were present in the Gpg midgut transcriptome, which may represent active transpositions and play regulatory roles. One thousand three hundred and seventy three genes differentially expressed (DEGs) between stimulated and non-stimulated flies were identified at day-3 post-feeding; 52 and 1025 between infected and self-cured flies at 10 and 20 days post-feeding, respectively. The possible roles of several DEGs regarding fly susceptibility and refractoriness are discussed. The results provide new means to decipher fly infection mechanisms, crucial to develop anti-vector control strategies.

  20. Characterization of recombinant Trypanosoma brucei gambiense Translationally Controlled Tumor Protein (rTbgTCTP) and its interaction with Glossina midgut bacteria.

    Science.gov (United States)

    Bossard, Géraldine; Bartoli, Manon; Fardeau, Marie-Laure; Holzmuller, Philippe; Ollivier, Bernard; Geiger, Anne

    2017-09-03

    In humans, sleeping sickness (i.e. Human African Trypanosomiasis) is caused by the protozoan parasites Trypanosoma brucei gambiense (Tbg) in West and Central Africa, and T. b. rhodesiense in East Africa. We previously showed in vitro that Tbg is able to excrete/secrete a large number of proteins, including Translationally Controlled Tumor Protein (TCTP). Moreover, the tctp gene was described previously to be expressed in Tbg-infected flies. Aside from its involvement in diverse cellular processes, we have investigated a possible alternative role within the interactions occurring between the trypanosome parasite, its tsetse fly vector, and the associated midgut bacteria. In this context, the Tbg tctp gene was synthesized and cloned into the baculovirus vector pAcGHLT-A, and the corresponding protein was produced using the baculovirus Spodoptera frugicola (strain 9) / insect cell system. The purified recombinant protein rTbgTCTP was incubated together with bacteria isolated from the gut of tsetse flies, and was shown to bind to 24 out of the 39 tested bacteria strains belonging to several genera. Furthermore, it was shown to affect the growth of the majority of these bacteria, especially when cultivated under microaerobiosis and anaerobiosis. Finally, we discuss the potential for TCTP to modulate the fly microbiome composition toward favoring trypanosome survival.

  1. Transcriptome and proteome analyses and the role of atypical calpain protein and autophagy in the spliced leader silencing pathway in Trypanosoma brucei.

    Science.gov (United States)

    Hope, Ronen; Egarmina, Katarina; Voloshin, Konstantin; Waldman Ben-Asher, Hiba; Carmi, Shai; Eliaz, Dror; Drori, Yaron; Michaeli, Shulamit

    2016-10-01

    Under persistent ER stress, Trypanosoma brucei parasites induce the spliced leader silencing (SLS) pathway. In SLS, transcription of the SL RNA gene, the SL donor to all mRNAs, is extinguished, arresting trans-splicing and leading to programmed cell death (PCD). In this study, we investigated the transcriptome following silencing of SEC63, a factor essential for protein translocation across the ER membrane, and whose silencing induces SLS. The proteome of SEC63-silenced cells was analyzed with an emphasis on SLS-specific alterations in protein expression, and modifications that do not directly result from perturbations in trans-splicing. One such protein identified is an atypical calpain SKCRP7.1/7.2. Co-silencing of SKCRP7.1/7.2 and SEC63 eliminated SLS induction due its role in translocating the PK3 kinase. This kinase initiates SLS by migrating to the nucleus and phosphorylating TRF4 leading to shut-off of SL RNA transcription. Thus, SKCRP7.1 is involved in SLS signaling and the accompanying PCD. The role of autophagy in SLS was also investigated; eliminating autophagy through VPS34 or ATG7 silencing demonstrated that autophagy is not essential for SLS induction, but is associated with PCD. Thus, this study identified factors that are used by the parasite to cope with ER stress and to induce SLS and PCD. © 2016 John Wiley & Sons Ltd.

  2. Users, Bystanders and Agents

    DEFF Research Database (Denmark)

    Krummheuer, Antonia Lina

    2015-01-01

    Human-agent interaction (HAI), especially in the field of embodied conversational agents (ECA), is mainly construed as dyadic communication between a human user and a virtual agent. This is despite the fact that many application scenarios for future ECAs involve the presence of others. This paper...

  3. Asymptotically Optimal Agents

    OpenAIRE

    Lattimore, Tor; Hutter, Marcus

    2011-01-01

    Artificial general intelligence aims to create agents capable of learning to solve arbitrary interesting problems. We define two versions of asymptotic optimality and prove that no agent can satisfy the strong version while in some cases, depending on discounting, there does exist a non-computable weak asymptotically optimal agent.

  4. Reasoning about emotional agents

    NARCIS (Netherlands)

    Meyer, J.-J.

    In this paper we discuss the role of emotions in artificial agent design, and the use of logic in reasoning about the emotional or affective states an agent can reside in. We do so by extending the KARO framework for reasoning about rational agents appropriately. In particular we formalize in

  5. Changing pattern of causative factors in development of umbilical infections (omphalitis) in newborns

    International Nuclear Information System (INIS)

    Nadeem, A.Z.; Malik, R.

    2010-01-01

    Despite the drastic decrease in the incidence of neonatal tetanus due to better aseptic techniques in cutting and tying of umbilical cord at birth, an increase in the prevalence of umbilical infections has been noticed. Objectives The objectives were to assess the ongoing practices in umbilical care, detect the prevailing causative factors responsible for umbilical infections in newborns and suggest measures for minimizing these infections. Design setting This descriptive study was a collaborative effort at CMH Nowshera, Mardan and Lahore from January 2007 through 2009. Patients and Methods Three hundred consecutive cases of umbilical sepsis ( omphalitis), infants less than 20 days old were included irrespective of place of delivery and severity of infection. Those with congenital anomalies of umbilicus were excluded. A detailed questionnaire was filled for every patient covering related aspects. Results Antisepsis (mainly spirit) was used in 91 % cases irrespective of place of delivery. Major tool for cutting the cord was surgical or new common blade (277 cases). Clamp was used in 138 cases. Cord was intentionally attended in subsequent weeks after birth in only 48 cases. Hand washing practice was found in only 62 parents in subsequent weeks after birth. Diapers were used in 261 cases, majority of these were found covering the umbilicus or umbilical stump when initially examined (81 %). 48% of infected unshed cords were more than 3 inches long. Use of unwarranted substances applied on cord was found in only 16 cases. (author)

  6. Venous reflux on contrast-enhanced head and neck magnetic resonance angiography: Analysis of causative factors

    International Nuclear Information System (INIS)

    Shin, Dong Jae; Lee, Eun Ja; Bae, Jong Myon

    2016-01-01

    The purpose of this study was to analyze the causative factors of venous reflux on contrast-enhanced head and neck magnetic resonance angiography. We retrospectively reviewed 150 patients with right-arm injections and 150 patients with left-arm injections. We included the age, gender, body mass index, history of hypertension, and history of diabetes mellitus in the evaluation of all patients. We measured the shortest width of the left or right brachiocephalic vein (BCV), the diameter of the aortic arch, and the distance between the sternum and vertebral body. The relationship between these factors and the venous reflux was analyzed. In patients with venous reflux, we performed qualitative image scoring for suboptimal images. In patients with venous reflux, the image quality of the left-arm injection group was significantly inferior to the image quality of the right-arm injection group. The mean age and the male-to-female ratio of patients with venous reflux were significantly higher than those of patients without venous reflux. In patients receiving the left-arm injection, the mean shortest width of the left BCV was significantly narrower in patients with venous reflux than in patients without venous reflux. A left-arm injection should be avoided, especially in elderly patients, to acquire an optimal image

  7. Venous reflux on contrast-enhanced head and neck magnetic resonance angiography: Analysis of causative factors

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Dong Jae; Lee, Eun Ja [Dept. of Radiology, Dongguk University Ilsan Hospital, Goyang (Korea, Republic of); Bae, Jong Myon [Dept. of Preventive Medicine, Jeju National University School of Medicine, Jeju (Korea, Republic of)

    2016-12-15

    The purpose of this study was to analyze the causative factors of venous reflux on contrast-enhanced head and neck magnetic resonance angiography. We retrospectively reviewed 150 patients with right-arm injections and 150 patients with left-arm injections. We included the age, gender, body mass index, history of hypertension, and history of diabetes mellitus in the evaluation of all patients. We measured the shortest width of the left or right brachiocephalic vein (BCV), the diameter of the aortic arch, and the distance between the sternum and vertebral body. The relationship between these factors and the venous reflux was analyzed. In patients with venous reflux, we performed qualitative image scoring for suboptimal images. In patients with venous reflux, the image quality of the left-arm injection group was significantly inferior to the image quality of the right-arm injection group. The mean age and the male-to-female ratio of patients with venous reflux were significantly higher than those of patients without venous reflux. In patients receiving the left-arm injection, the mean shortest width of the left BCV was significantly narrower in patients with venous reflux than in patients without venous reflux. A left-arm injection should be avoided, especially in elderly patients, to acquire an optimal image.

  8. The Treatment of Uncertainty in Compensation Schemes for Cancer Based on the Probability of Causation Methodology

    International Nuclear Information System (INIS)

    Koch, J.

    2014-01-01

    Since it is commonly accepted that exposure to ionizing radiation, even at the low levels encountered in the workplace, can cause malignant diseases, radiation workers are at some risk, although much is done to optimize radiation protection and reduce occupational exposure to levels a s low as reasonably achievable . However, the causal relationship between exposure to radiation and malignant diseases is difficult to establish, since cancer is such a frequent disease and many other factors may contribute to its development. Ideally, those workers who developed cancer as a result of occupational exposure to radiation should be compensated. Guidance on procedures and methodology to assess attributability of cancer to occupational exposure to radiation and to assist decision-making in compensating workers is provided in a recent joint IAEA/ILO/WHO publication.This guide also reviews compensation schemes in place in several countries, with an emphasis on those based on the probability of causation (POC), also known as assigned share (AS) methodology. The POC method provides a scientifically based framework to assess cancer attributability to occupational exposure and was extensively reviewed by Wakeford et al. This paper presents a comparison of two well-known compensation schemes based on the POC approach with regard to their treatment of uncertainty

  9. Cholesterol as a Causative Factor in Alzheimer Disease: A Debatable Hypothesis

    Science.gov (United States)

    Wood, W. Gibson; Li, Ling; Müller, Walter E.; Eckert, Gunter P.

    2014-01-01

    High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Aβ) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD. Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only APP and Aβ. The purpose of this review, therefore, is to examine the above-mentioned issues and discuss the pros and cons of the cholesterol-AD hypothesis, and the involvement of other lipids in the mevalonate pathway, such as isoprenoids and oxysterols, in AD. PMID:24329875

  10. Evidence of Biomass Smoke Exposure as a Causative Factor for the Development of COPD

    Directory of Open Access Journals (Sweden)

    Sarah J. Capistrano

    2017-12-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is a progressive disease of the lungs characterised by chronic inflammation, obstruction of airways, and destruction of the parenchyma (emphysema. These changes gradually impair lung function and prevent normal breathing. In 2002, COPD was the fifth leading cause of death, and is estimated by the World Health Organisation (WHO to become the third by 2020. Cigarette smokers are thought to be the most at risk of developing COPD. However, recent studies have shown that people with life-long exposure to biomass smoke are also at high risk of developing COPD. Most common in developing countries, biomass fuels such as wood and coal are used for cooking and heating indoors on a daily basis. Women and children have the highest amounts of exposures and are therefore more likely to develop the disease. Despite epidemiological studies providing evidence of the causative relationship between biomass smoke and COPD, there are still limited mechanistic studies on how biomass smoke causes, and contributes to the progression of COPD. This review will focus upon why biomass fuels are used, and their relationship to COPD. It will also suggest methodological approaches to model biomass exposure in vitro and in vivo.

  11. New levels of language processing complexity and organization revealed by Granger causation

    Directory of Open Access Journals (Sweden)

    David W Gow

    2012-11-01

    Full Text Available Granger causation analysis of high spatiotemporal resolution reconstructions of brain activation offers a new window on the dynamic interactions between brain areas that support language processing. Premised on the observation that causes both precede and uniquely predict their effects, this approach provides an intuitive, model-free means of identifying directed causal interactions in the brain. It requires the analysis of all nonredundant potentially interacting signals, and has shown that even early processes such as speech perception involve interactions of many areas in a strikingly large network that extends well beyond traditional left hemisphere perisylvian cortex that play out over hundreds of milliseconds. In this paper we describe this technique and review several general findings that reframe the way we think about language processing and brain function in general. These include the extent and complexity of language processing networks, the central role of interactive processing dynamics, the role of processing hubs where the input from many distinct brain regions are integrated, and the degree to which task requirements and stimulus properties influence processing dynamics and inform our understanding of language-specific localized processes.

  12. Cumulative Causation of Rural Migration and Initial Peri-Urbanization in China.

    Science.gov (United States)

    Hao, Lingxin

    2012-01-01

    This paper posits that rural migration feeds the high demand for cheap labor in peri-urbanization, which is driven by globalization, flows of foreign capital, and entrepreneurial local governments. While the gravity model and push/pull perspective ignore the dynamics of migratory course, we use the cumulative causation of migration theory to conceptualize social expectations for outmigration and social resources from migrant networks in destinations. Four major findings are drawn from this demographic analysis based on micro data from China's 2000 Census. First, the expectation of outmigration significantly increases outmigration, and this effect is independent of push factors. Second, foreign direct investment (FDI) contributes to attracting rural labor migrants from other provinces to peri-urban areas as it does to cities. Third, social resources from migrant networks play an important role in attracting rural labor migrants to both city and noncity destinations. Fourth, the importance of wage differentials declines in gravitating rural labor migrants to peri-urban areas. These findings provide tentative evidence that rural labor migration is indispensable during initial peri-urbanization. Infused with flows of FDI and entrepreneurial local governments, rural migration has created a favorable initial condition for peri-urbanization.

  13. The Complex Relationship of Extracorporeal Membrane Oxygenation and Acute Kidney Injury: Causation or Association?

    Science.gov (United States)

    Kilburn, Daniel J; Shekar, Kiran; Fraser, John F

    2016-01-01

    Extracorporeal membrane oxygenation (ECMO) is a modified cardiopulmonary bypass (CPB) circuit capable of providing prolonged cardiorespiratory support. Recent advancement in ECMO technology has resulted in increased utilisation and clinical application. It can be used as a bridge-to-recovery, bridge-to-bridge, bridge-to-transplant, or bridge-to-decision. ECMO can restitute physiology in critically ill patients, which may minimise the risk of progressive multiorgan dysfunction. Alternatively, iatrogenic complications of ECMO clearly contribute to worse outcomes. These factors affect the risk : benefit ratio of ECMO which ultimately influence commencement/timing of ECMO. The complex interplay of pre-ECMO, ECMO, and post-ECMO pathophysiological processes are responsible for the substantial increased incidence of ECMO-associated acute kidney injury (EAKI). The development of EAKI significantly contributes to morbidity and mortality; however, there is a lack of evidence defining a potential benefit or causative link between ECMO and AKI. This area warrants investigation as further research will delineate the mechanisms involved and subsequent strategies to minimise the risk of EAKI. This review summarizes the current literature of ECMO and AKI, considers the possible benefits and risks of ECMO on renal function, outlines the related pathophysiology, highlights relevant investigative tools, and ultimately suggests an approach for future research into this under investigated area of critical care.

  14. The Complex Relationship of Extracorporeal Membrane Oxygenation and Acute Kidney Injury: Causation or Association?

    Directory of Open Access Journals (Sweden)

    Daniel J. Kilburn

    2016-01-01

    Full Text Available Extracorporeal membrane oxygenation (ECMO is a modified cardiopulmonary bypass (CPB circuit capable of providing prolonged cardiorespiratory support. Recent advancement in ECMO technology has resulted in increased utilisation and clinical application. It can be used as a bridge-to-recovery, bridge-to-bridge, bridge-to-transplant, or bridge-to-decision. ECMO can restitute physiology in critically ill patients, which may minimise the risk of progressive multiorgan dysfunction. Alternatively, iatrogenic complications of ECMO clearly contribute to worse outcomes. These factors affect the risk : benefit ratio of ECMO which ultimately influence commencement/timing of ECMO. The complex interplay of pre-ECMO, ECMO, and post-ECMO pathophysiological processes are responsible for the substantial increased incidence of ECMO-associated acute kidney injury (EAKI. The development of EAKI significantly contributes to morbidity and mortality; however, there is a lack of evidence defining a potential benefit or causative link between ECMO and AKI. This area warrants investigation as further research will delineate the mechanisms involved and subsequent strategies to minimise the risk of EAKI. This review summarizes the current literature of ECMO and AKI, considers the possible benefits and risks of ECMO on renal function, outlines the related pathophysiology, highlights relevant investigative tools, and ultimately suggests an approach for future research into this under investigated area of critical care.

  15. Causative pathogens and antibiotic resistance in children hospitalized for urinary tract infection.

    Science.gov (United States)

    Koçak, Mesut; Büyükkaragöz, Bahar; Çelebi Tayfur, Asli; Çaltik, Aysun; Köksoy, Adem Yasin; Çizmeci, Zeynep; Günbey, Sacit

    2016-06-01

    Urinary tract infections (UTI) are one of the most common bacterial infections in children and a major cause of hospitalization. In this study we investigated the clinical characteristics, causative uropathogens; their antibiotic susceptibility and resistance patterns, treatment modalities and efficacy in children hospitalized for UTI in a tertiary care setting. Patients hospitalized for an upper UTI between March 2009 and July 2014 were enrolled. The urine culture-antibiogram results and accompanying urinary tract abnormalities were recorded retrospectively. A total of 142 patients (104 girls, 73.2%; 38 boys, 26.8%) were enrolled. Mean patient age was 32.6 ± 4.1 months. History of recurrent UTI was present in 45.8% (n = 65), with prior hospitalization in 12.0% (n = 17). Frequency of vesicoureteral reflux was 18.3% (n = 26). Gram-negative enteric microorganisms yielded growth in all culture-positive UTI and the most common microorganism was Escherichia coli (n = 114, 80.3%). Extended spectrum beta-lactamase-producing (ESBL (+)) bacterial strains were detected in 49.3% (n = 70), with third-generation cephalosporin resistance in all and increased duration of hospitalization. The prevalence of UTI with ESBL (+) bacterial strains with multi-drug resistance is increasing in the hospitalized pediatric population, therefore rational use of antibiotics is essential. © 2015 Japan Pediatric Society.

  16. New levels of language processing complexity and organization revealed by granger causation.

    Science.gov (United States)

    Gow, David W; Caplan, David N

    2012-01-01

    Granger causation analysis of high spatiotemporal resolution reconstructions of brain activation offers a new window on the dynamic interactions between brain areas that support language processing. Premised on the observation that causes both precede and uniquely predict their effects, this approach provides an intuitive, model-free means of identifying directed causal interactions in the brain. It requires the analysis of all non-redundant potentially interacting signals, and has shown that even "early" processes such as speech perception involve interactions of many areas in a strikingly large network that extends well beyond traditional left hemisphere perisylvian cortex that play out over hundreds of milliseconds. In this paper we describe this technique and review several general findings that reframe the way we think about language processing and brain function in general. These include the extent and complexity of language processing networks, the central role of interactive processing dynamics, the role of processing hubs where the input from many distinct brain regions are integrated, and the degree to which task requirements and stimulus properties influence processing dynamics and inform our understanding of "language-specific" localized processes.

  17. Radiographic scanning agent

    International Nuclear Information System (INIS)

    Bevan, J.A.

    1983-01-01

    This invention relates to radiodiagnostic agents and more particularly to a composition and method for preparing a highly effective technetium-99m-based bone scanning agent. One deficiency of x-ray examination is the inability of that technique to detect skeletal metastases in their incipient stages. It has been discovered that the methanehydroxydiphosphonate bone mineral-seeking agent is unique in that it provides the dual benefits of sharp radiographic imaging and excellent lesion detection when used with technetium-99m. This agent can also be used with technetium-99m for detecting soft tissue calcification in the manner of the inorganic phosphate radiodiagnostic agents

  18. Agente adaptable y aprendizaje

    Directory of Open Access Journals (Sweden)

    Arturo Angel Lara Rivero

    2013-05-01

    Full Text Available En este trabajo se contrasta el concepto de agente programado con el de agente complejo adaptable, se presenta una nueva visión ligada al aprendizaje y la estructura del agente. La imagen del agente se analiza considerando los modelos internos, la práctica, el concepto de rutina y la influencia en su comportamiento, y la importancia del aprendizaje ex ante y ex post. Por último se muestra que la resolución de problemas está sujeta a restricciones del agente y se describen las formas de explorar el espacio de soluciones mediante tres tipos de exploración: exhaustiva, aleatoria y selectiva.

  19. A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency.

    Science.gov (United States)

    Liu, Hongli; Xu, Xiaofei; Han, Ting; Yan, Lei; Cheng, Lei; Qin, Yingying; Liu, Wen; Zhao, Shidou; Chen, Zi-Jiang

    2017-12-01

    To identify the potential FSHR mutation in a Chinese woman with primary ovarian insufficiency (POI). Genetic and functional studies. University-based reproductive medicine center. A POI patient, her family members, and another 192 control women with regular menstruation. Ovarian biopsy was performed in the patient. Sanger sequencing was carried out for the patient, her sister, and parents. The novel variant identified was further confirmed with the use of control subjects. Sanger sequencing and genotype analysis to identify the potential variant of the FSHR gene; hematoxylin and eosin staining of the ovarian section to observe the follicular development; Western blotting and immunofluorescence to detect FSH receptor (FSHR) expression; and cyclic adenosine monophosphate (cAMP) assay to monitor FSH-induced signaling. Histologic examination of the ovaries in the patient revealed follicular development up to the early antral stage. Mutational screening and genotype analysis of the FSHR gene identified a novel homozygous mutation c.175C>T (p.R59X) in exon 2, which was inherited in the autosomal recessive mode from her heterozygous parents but was absent in her sister and the 192 control women. Functional studies demonstrated that in vitro the nonsense mutation caused the loss of full-length FSHR expression and that p.R59X mutant showed no response to FSH stimulation in the cAMP level. The mutation p.R59X in FSHR is causative for POI by means of arresting folliculogenesis. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  20. GEOSTATISTICAL BASED SUSCEPTIBILITY MAPPING OF SOIL EROSION AND OPTIMIZATION OF ITS CAUSATIVE FACTORS: A CONCEPTUAL FRAMEWORK

    Directory of Open Access Journals (Sweden)

    ABDULKADIR T. SHOLAGBERU

    2017-11-01

    Full Text Available Soil erosion hazard is the second biggest environmental challenges after population growth causing land degradation, desertification and water deterioration. Its impacts on watersheds include loss of soil nutrients, reduced reservoir capacity through siltation which may lead to flood risk, landslide, high water turbidity, etc. These problems become more pronounced in human altered mountainous areas through intensive agricultural activities, deforestation and increased urbanization among others. However, due to challenging nature of soil erosion management, there is great interest in assessing its spatial distribution and susceptibility levels. This study is thus intend to review the recent literatures and develop a novel framework for soil erosion susceptibility mapping using geostatistical based support vector machine (SVM, remote sensing and GIS techniques. The conceptual framework is to bridge the identified knowledge gaps in the area of causative factors’ (CFs selection. In this research, RUSLE model, field studies and the existing soil erosion maps for the study area will be integrated for the development of inventory map. Spatial data such as Landsat 8, digital soil and geological maps, digital elevation model and hydrological data shall be processed for the extraction of erosion CFs. GISbased SVM techniques will be adopted for the establishment of spatial relationships between soil erosion and its CFs, and subsequently for the development of erosion susceptibility maps. The results of this study include evaluation of predictive capability of GIS-based SVM in soil erosion mapping and identification of the most influential CFs for erosion susceptibility assessment. This study will serve as a guide to watershed planners and to alleviate soil erosion challenges and its related hazards.

  1. Estimating the time and temperature relationship for causation of deep-partial thickness skin burns.

    Science.gov (United States)

    Abraham, John P; Plourde, Brian; Vallez, Lauren; Stark, John; Diller, Kenneth R

    2015-12-01

    The objective of this study is to develop and present a simple procedure for evaluating the temperature and exposure-time conditions that lead to causation of a deep-partial thickness burn and the effect that the immediate post-burn thermal environment can have on the process. A computational model has been designed and applied to predict the time required for skin burns to reach a deep-partial thickness level of injury. The model includes multiple tissue layers including the epidermis, dermis, hypodermis, and subcutaneous tissue. Simulated exposure temperatures ranged from 62.8 to 87.8°C (145-190°F). Two scenarios were investigated. The first and worst case scenario was a direct exposure to water (characterized by a large convection coefficient) with the clothing left on the skin following the exposure. A second case consisted of a scald insult followed immediately by the skin being washed with cool water (20°C). For both cases, an Arrhenius injury model was applied whereby the extent and depth of injury were calculated and compared for the different post-burn treatments. In addition, injury values were compared with experiment data from the literature to assess verification of the numerical methodology. It was found that the clinical observations of injury extent agreed with the calculated values. Furthermore, inundation with cool water decreased skin temperatures more quickly than the clothing insulating case and led to a modest decrease in the burn extent. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

  2. Najar or Bhut-Evil eye or ghost affliction: Gujarati views about illness causation.

    Science.gov (United States)

    Spiro, Alison M

    2005-04-01

    This paper examines the supernatural beliefs of najar (evil eye) and bhut (ghost) and their roles in illness causation in Gujarati families in Britain today. The data arose unexpectedly in an ethnography of child rearing patterns carried out in Harrow, North West London and a short period of observation in Ahmedabad, India. I used anthropological methods of participant observation and unstructured interviews, which were transcribed using pseudonyms. The study group involved 70 Hindu and Jain Gujarati households with children and the fieldwork was conducted over a period of four years. Many of the individuals studied had migrated from India to East Africa before coming to the UK in the 1970s, but maintain links with both countries through kinship ties, marriage and rituals. I set out to study the continuity of women's roles in the transmission of religious and moral values, the rituals of childhood, views about infant feeding, and parenting relationships within joint families. The beliefs of najar and bhut in poor, rural settings in India have been described, but these Gujarati beliefs in Britain have not been well documented. This study indicates that najar and bhut continue to be a concern of women in most Gujarati families in Britain today and across all socio-economic groups, not confined to those on the 'bread-line', as have been previously suggested. These beliefs align themselves with Hindu ideas of the soul and reincarnation: powerful forces residing outside the body. An understanding of these beliefs could be informative to health professionals working with Gujarati communities in the UK.

  3. Moral actor, selfish agent.

    Science.gov (United States)

    Frimer, Jeremy A; Schaefer, Nicola K; Oakes, Harrison

    2014-05-01

    People are motivated to behave selfishly while appearing moral. This tension gives rise to 2 divergently motivated selves. The actor-the watched self-tends to be moral; the agent-the self as executor-tends to be selfish. Three studies present direct evidence of the actor's and agent's distinct motives. To recruit the self-as-actor, we asked people to rate the importance of various goals. To recruit the self-as-agent, we asked people to describe their goals verbally. In Study 1, actors claimed their goals were equally about helping the self and others (viz., moral); agents claimed their goals were primarily about helping the self (viz., selfish). This disparity was evident in both individualist and collectivist cultures, attesting to the universality of the selfish agent. Study 2 compared actors' and agents' motives to those of people role-playing highly prosocial or selfish exemplars. In content (Study 2a) and in the impressions they made on an outside observer (Study 2b), actors' motives were similar to those of the prosocial role-players, whereas agents' motives were similar to those of the selfish role-players. Study 3 accounted for the difference between the actor and agent: Participants claimed that their agent's motives were the more realistic and that their actor's motives were the more idealistic. The selfish agent/moral actor duality may account for why implicit and explicit measures of the same construct diverge, and why feeling watched brings out the better angels of human nature.

  4. Agent Architectures for Compliance

    Science.gov (United States)

    Burgemeestre, Brigitte; Hulstijn, Joris; Tan, Yao-Hua

    A Normative Multi-Agent System consists of autonomous agents who must comply with social norms. Different kinds of norms make different assumptions about the cognitive architecture of the agents. For example, a principle-based norm assumes that agents can reflect upon the consequences of their actions; a rule-based formulation only assumes that agents can avoid violations. In this paper we present several cognitive agent architectures for self-monitoring and compliance. We show how different assumptions about the cognitive architecture lead to different information needs when assessing compliance. The approach is validated with a case study of horizontal monitoring, an approach to corporate tax auditing recently introduced by the Dutch Customs and Tax Authority.

  5. Stabilized radiographic scanning agents

    International Nuclear Information System (INIS)

    Fawzi, M.B.

    1982-01-01

    Stable compositions useful as technetium 99m-based scintigraphic agents comprise gentisic acid or a pharmaceutically-acceptable salt or ester thereof in combination with a pertechnetate reducing agent or dissolved in pertechnetate-99m (sup(99m)TcOsub(4)sup(-)) solution. The compositions are especially useful in combination with a phosphate or phosphonate material that carries the radionuclide to bone, thus providing a skeletal imaging agent

  6. Consistent Treatment of Variables and Causation Poses a Challenge for Behavioral Research Methods: A Commentary on Nesselroade and Molenaar (2016).

    Science.gov (United States)

    Markus, Keith A

    2016-01-01

    Nesselroade and Molenaar presented the ideographic filter as a proposal for analyzing lawful regularities in behavioral research. The proposal highlights an inconsistency that poses a challenge for behavioral research more generally. One can distinguish a broadly Humean approach from a broadly non-Humean approach as they relate to variables and to causation. Nesselroade and Molenaar rejected a Humean approach to latent variables that characterizes them as nothing more than summaries of their manifest indicators. By contrast, they tacitly accepted a Humean approach to causes characterized as nothing more than summaries of their manifest causal effects. A non-Humean treatment of variables coupled with a Humean treatment of causation creates a theoretical tension within their proposal. For example, one can interpret the same model elements as simultaneously representing both variables and causes. Future refinement of the ideographic filter proposal to address this tension could follow any of a number of strategies.

  7. Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Diabetes and health". Challenges in the study of causation of obesity

    DEFF Research Database (Denmark)

    Sørensen, Thorkild I A

    2009-01-01

    Use of the energy balance equation for understanding the causation of obesity is discussed. Its basis on the thermodynamic laws is expressed in mathematical models for body-weight changes. Only a very small net energy surplus per time unit constitutes the energy deposition during weight gain......, making measurements of its components difficult. The physical laws provide exact quantitative relationships between energy intake, energy expenditure and deposition of energy, but cannot disentangle the initiating and driving forces of the energy imbalance, which may also be an active storage of fat...... in adipose tissue. These and various other limitations of the energy balance model warrant cautiousness in using the model in studies of obesity causation. Weight gain may be self-promoting and mathematical feedback models allowing estimation of such effects show that they are realistic. Predisposition...

  8. Contrast agents for MRI

    International Nuclear Information System (INIS)

    Bonnemain, B.

    1994-01-01

    Contrast agents MRI (Magnetic Resonance Imaging) have been developed to improve the diagnostic information obtained by this technic. They mainly interact on T1 and T2 parameters and increase consequently normal to abnormal tissues contrast. The paramagnetic agents which mainly act on longitudinal relaxation rate (T1) are gadolinium complexes for which stability is the main parameter to avoid any release of free gadolinium. The superparamagnetic agents that decrease signal intensity by an effect on transversal relaxation rate (T2) are developed for liver, digestive and lymph node imaging. Many area of research are now opened for optimal use of present and future contrast agents in MRI. (author). 28 refs., 4 tabs

  9. Decontamination Data - Blister Agents

    Data.gov (United States)

    U.S. Environmental Protection Agency — Decontamination efficacy data for blister agents on various building materials using various decontamination solutions. This dataset is associated with the following...

  10. Development of inhibitors of the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway enzymes as potential anti-infective agents

    NARCIS (Netherlands)

    Masini, Tiziana; Hirsch, Anna K H

    2014-01-01

    Important pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum, the causative agents of tuberculosis and malaria, respectively, and plants, utilize the 2C-methyl-D-erythritol 4-phosphate (MEP, 5) pathway for the biosynthesis of isopentenyl diphosphate (1) and dimethylallyl

  11. Joint analysis of quantitative trait loci and majoreffect causative mutations affecting meat quality and carcass composition traits in pigs

    OpenAIRE

    Cherel, Pierre; Pires, José; Glénisson, Jérôme; Milan, Denis; Iannuccelli, Nathalie; Herault, Frédéric; Damon, Marie; Le Roy, Pascale

    2011-01-01

    Abstract Background Detection of quantitative trait loci (QTLs) affecting meat quality traits in pigs is crucial for the design of efficient marker-assisted selection programs and to initiate efforts toward the identification of underlying polymorphisms. The RYR1 and PRKAG3 causative mutations, originally identified from major effects on meat characteristics, can be used both as controls for an overall QTL detection strategy for diversely affected traits and as a scale for detected QTL effect...

  12. Proteomic Analysis of Intact Flagella of Procyclic Trypanosoma brucei Cells Identifies Novel Flagellar Proteins with Unique Sub-localization and Dynamics*

    Science.gov (United States)

    Subota, Ines; Julkowska, Daria; Vincensini, Laetitia; Reeg, Nele; Buisson, Johanna; Blisnick, Thierry; Huet, Diego; Perrot, Sylvie; Santi-Rocca, Julien; Duchateau, Magalie; Hourdel, Véronique; Rousselle, Jean-Claude; Cayet, Nadège; Namane, Abdelkader; Chamot-Rooke, Julia; Bastin, Philippe

    2014-01-01

    Cilia and flagella are complex organelles made of hundreds of proteins of highly variable structures and functions. Here we report the purification of intact flagella from the procyclic stage of Trypanosoma brucei using mechanical shearing. Structural preservation was confirmed by transmission electron microscopy that showed that flagella still contained typical elements such as the membrane, the axoneme, the paraflagellar rod, and the intraflagellar transport particles. It also revealed that flagella severed below the basal body, and were not contaminated by other cytoskeletal structures such as the flagellar pocket collar or the adhesion zone filament. Mass spectrometry analysis identified a total of 751 proteins with high confidence, including 88% of known flagellar components. Comparison with the cell debris fraction revealed that more than half of the flagellum markers were enriched in flagella and this enrichment criterion was taken into account to identify 212 proteins not previously reported to be associated to flagella. Nine of these were experimentally validated including a 14-3-3 protein not yet reported to be associated to flagella and eight novel proteins termed FLAM (FLAgellar Member). Remarkably, they localized to five different subdomains of the flagellum. For example, FLAM6 is restricted to the proximal half of the axoneme, no matter its length. In contrast, FLAM8 is progressively accumulating at the distal tip of growing flagella and half of it still needs to be added after cell division. A combination of RNA interference and Fluorescence Recovery After Photobleaching approaches demonstrated very different dynamics from one protein to the other, but also according to the stage of construction and the age of the flagellum. Structural proteins are added to the distal tip of the elongating flagellum and exhibit slow turnover whereas membrane proteins such as the arginine kinase show rapid turnover without a detectible polarity. PMID:24741115

  13. Proteomic analysis of intact flagella of procyclic Trypanosoma brucei cells identifies novel flagellar proteins with unique sub-localization and dynamics.

    Science.gov (United States)

    Subota, Ines; Julkowska, Daria; Vincensini, Laetitia; Reeg, Nele; Buisson, Johanna; Blisnick, Thierry; Huet, Diego; Perrot, Sylvie; Santi-Rocca, Julien; Duchateau, Magalie; Hourdel, Véronique; Rousselle, Jean-Claude; Cayet, Nadège; Namane, Abdelkader; Chamot-Rooke, Julia; Bastin, Philippe

    2014-07-01

    Cilia and flagella are complex organelles made of hundreds of proteins of highly variable structures and functions. Here we report the purification of intact flagella from the procyclic stage of Trypanosoma brucei using mechanical shearing. Structural preservation was confirmed by transmission electron microscopy that showed that flagella still contained typical elements such as the membrane, the axoneme, the paraflagellar rod, and the intraflagellar transport particles. It also revealed that flagella severed below the basal body, and were not contaminated by other cytoskeletal structures such as the flagellar pocket collar or the adhesion zone filament. Mass spectrometry analysis identified a total of 751 proteins with high confidence, including 88% of known flagellar components. Comparison with the cell debris fraction revealed that more than half of the flagellum markers were enriched in flagella and this enrichment criterion was taken into account to identify 212 proteins not previously reported to be associated to flagella. Nine of these were experimentally validated including a 14-3-3 protein not yet reported to be associated to flagella and eight novel proteins termed FLAM (FLAgellar Member). Remarkably, they localized to five different subdomains of the flagellum. For example, FLAM6 is restricted to the proximal half of the axoneme, no matter its length. In contrast, FLAM8 is progressively accumulating at the distal tip of growing flagella and half of it still needs to be added after cell division. A combination of RNA interference and Fluorescence Recovery After Photobleaching approaches demonstrated very different dynamics from one protein to the other, but also according to the stage of construction and the age of the flagellum. Structural proteins are added to the distal tip of the elongating flagellum and exhibit slow turnover whereas membrane proteins such as the arginine kinase show rapid turnover without a detectible polarity. © 2014 by The

  14. Coenzyme Q10 prevented full blown splenomegaly and decreased melarsoprol-induced reactive encephalopathy in mice infected with Trypanosoma brucei rhodesiense

    Directory of Open Access Journals (Sweden)

    James Nyabuga Nyariki

    2015-03-01

    Full Text Available Objective: To establish the modulatory effects of coenzyme Q10 on experimental trypanosome infections in mice and evaluate the risk of occurrence and severity of melarsoprol-induced post treatment reactive encephalopathy (PTRE. Methods: Female Swiss white mice were orally administered with 200 mg/kg of coenzyme Q10 after which they were intraperitoneally inoculated with Trypanasoma brucei rhodesiense (T. b. rhodesiense. The resultant infection was allowed to develop and simulate all phases of human African trypanosomiasis and PTRE. Parasitaemia development, packed cell volume, haematological and pathological changes were determined. Results: A histological study in the brain tissue of T. b. rhodesiense infected mice demonstrated neuroinflammatory pathology which was highly amplified in the PTRE-induced groups. A prominent reduction in the severity of the neuroinflammatory response was detected when coenzyme-Q10 was administered. Furthermore, the mean tissue weight of spleen to body ratio in coenzyme Q10 supplemented group was significantly (P<0.05 different compared to un-supplemented groups, and clearly indicated that coenzyme Q10 prevented full blown splenomegaly pathogenesis by T. b. rhodesiense. A significant (P<0.05 increase in hemoglobin levels and red blood cells was observed in coenzyme Q10 mice compared to those infected and un-supplemented with coenzyme Q10. Conclusions: The capacity of coenzyme Q10 to alter the pathogenesis of T. b. rhodesiense infection in mice and following treatment with melarsoprol, may find application by rendering humans and animals less susceptible to deleterious effects of trypanosome infection such as splenomegaly and melarsoprol-induced PTRE and neurotoxicity.

  15. Structure determination of glycogen synthase kinase-3 from Leishmania major and comparative inhibitor structure-activity relationships with Trypanosoma brucei GSK-3

    Energy Technology Data Exchange (ETDEWEB)

    Ojo, Kayode K; Arakaki, Tracy L; Napuli, Alberto J; Inampudi, Krishna K; Keyloun, Katelyn R; Zhang, Li; Hol, Wim G.J.; Verlind, Christophe L.M.J.; Merritt, Ethan A; Van Voorhis, Wesley C [UWASH

    2012-04-24

    Glycogen synthase kinase-3 (GSK-3) is a drug target under intense investigation in pharmaceutical companies and constitutes an attractive piggyback target for eukaryotic pathogens. Two different GSKs are found in trypanosomatids, one about 150 residues shorter than the other. GSK-3 short (GeneDB: Tb927.10.13780) has previously been validated genetically as a drug target in Trypanosoma brucei by RNAi induced growth retardation; and chemically by correlation between enzyme and in vitro growth inhibition. Here, we report investigation of the equivalent GSK-3 short enzymes of L. major (LmjF18.0270) and L. infantum (LinJ18_V3.0270, identical in amino acid sequences to LdonGSK-3 short) and a crystal structure of LmajGSK-3 short at 2 Å resolution. The inhibitor structure-activity relationships (SARs) of L. major and L. infantum are virtually identical, suggesting that inhibitors could be useful for both cutaneous and visceral leishmaniasis. Leishmania spp. GSK-3 short has different inhibitor SARs than TbruGSK-3 short, which can be explained mostly by two variant residues in the ATP-binding pocket. Indeed, mutating these residues in the ATP-binding site of LmajGSK-3 short to the TbruGSK-3 short equivalents results in a mutant LmajGSK-3 short enzyme with SAR more similar to that of TbruGSK-3 short. The differences between human GSK-3β (HsGSK-3β) and LmajGSK-3 short SAR suggest that compounds which selectively inhibit LmajGSK-3 short may be found.

  16. Glycolipid precursors for the membrane anchor of Trypanosoma brucei variant surface glycoproteins. II. Lipid structures of phosphatidylinositol-specific phospholipase C sensitive and resistant glycolipids

    International Nuclear Information System (INIS)

    Mayor, S.; Menon, A.K.; Cross, G.A.

    1990-01-01

    A common diagnostic feature of glycosylinositol phospholipid (GPI)-anchored proteins is their release from the membrane by a phosphatidylinositol-specific phospholipase C (PI-PLC). However, some GPI-anchored proteins are resistant to this enzyme. The best characterized example of this subclass is the human erythrocyte acetylcholinesterase, where the structural basis of PI-PLC resistance has been shown to be the acylation of an inositol hydroxyl group(s). Both PI-PLC-sensitive and resistant GPI-anchor precursors (P2 and P3, respectively) have been found in Trypanosoma brucei, where the major surface glycoprotein is anchored by a PI-PLC-sensitive glycolipid anchor. The accompanying paper shows that P2 and P3 have identical glycans, indistinguishable from the common core glycan found on all the characterized GPI protein anchors. This paper shows that the single difference between P2 and P3, and the basis for the PI-PLC insusceptibility of P3, is a fatty acid, ester-linked to the inositol residue in P3. The inositol-linked fatty acid can be removed by treatment with mild base to restore PI-PLC sensitivity. Biosynthetic labeling experiments with [3H]palmitic acid and [3H]myristic acid show that [3H]palmitic acid specifically labels the inositol residue in P3 while [3H]myristic acid labels the diacylglycerol portion. Possible models to account for the simultaneous presence of PI-PLC-resistant and sensitive glycolipids are discussed in the context of available information on the biosynthesis of GPI-anchors

  17. Refinements on the inferred causative faults of the great 2012 Indian Ocean earthquakes

    Science.gov (United States)

    Revathy, P. M.; Rajendran, K.

    2014-12-01

    As the largest known intra-plate strike-slip events, the pair of 2012 earthquakes in the Wharton Basin is a rarity. Separated in time by 2 hours these events rouse interest also because of their short inter-event duration, complex rupture mechanism, and spatial-temporal proximity to the great 2004 Sumatra plate boundary earthquake. Reactivation of fossil ridge-transform pairs is a favoured mechanism for large oceanic plate earthquakes and their inherent geometry triggers earthquakes on conjugate fault systems, as observed previously in the Wharton Basin. The current debate is whether the ruptures occurred on the WNW-ESE paleo ridges or the NNE-SSW paleo transforms. Back-projection models give a complex rupture pattern that favours the WNW-ESE fault [1]. However, the static stress changes due to the 2004 Sumatra earthquake and 2005 Nias earthquake favour the N15°E fault [2]. We use the Teleseismic Body-Wave Inversion Program [3] and waveform data from Global Seismic Network, to obtain the best fit solutions using P and S-wave synthetic modelling. The preliminary P-wave analysis of both earthquakes gives source parameters that are consistent with the Harvard CMT solutions. The obtained slip distribution complies with the NNE-SSW transforms. Both these earthquakes triggered small tsunamis which appear as two distinctive pulses on 13 Indian Ocean tide gauges and buoys. Frequency spectra of the tsunami recordings from various azimuths provide additional constraint for the choice of the causative faults. References: [1] Yue, H., T. Lay, and K. D. Koper (2012), En echelon and orthogonal fault ruptures of the 11 April 2012 great intraplate earthquakes, Nature, 490, 245-249, doi:10.1038/nature11492 [2] Delescluse, M., N. Chamot-Rooke, R. Cattin, L. Fleitout, O. Trubienko and C. Vigny April 2012 intra-oceanic seismicity off Sumatra boosted by the Banda-Aceh megathrust, Nature, 490(2012), pp. 240-244, doi:10.1038/nature11520 [3] M. Kikuchi and H. Kanamori, Note on

  18. Radiation-induced cranial nerve palsy and its causative factors in nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Kong Lin; Zhang Youwang; Wu Yongru; Guo Xiaomao; Li Longgen

    2005-01-01

    Objective: To analyze the incidence and causative factors of radiation-induced cranial nerve palsy in patients with nasopharyngeal carcinoma (NPC). Methods: 512 NPC patients who underwent radiotherapy from January 1, 1989 to December 31, 1990 and from January 1, 1994 to December 31, 1995 were retrospectively analyzed. According to Fuzhou' 92 NPC Staging Classification, there are 31 patients in stage I, 212 in stage II, 198 in stage III and 71 in stage IV. All patients were treated by 60 Co or 6 MV X-ray with faciocervical fields or pre-auricular fields to primary area. Some patients were boosted by post-auricular fields or cranial fields. The median dose to the nasopharyngeal region was 7130 cGy by external beam radiotherapy. Thirty-four patients were boosted by brachytherapy. The medial dose to cervical lymph nodes was 6410 cGy as definitive treatment and 5480 cGy as prophylactic treatment. 101 patients were treated with combined chemotherapy. Results: The median follow-up was 6.7 years . Radiation-induced cranial nerve palsies occurred in 81 among the 512 patients. The 5- and 10-year cumulative incidences were 10.3%, 25.4%, respectively. The most common affected nerve was XII. On multivariates analysis, cranial nerve invasion before radiation, chemotherapy, dose to the nasopharyngeal region and age were the independent factors of radiation-induced cranial nerve palsy on nerve I-VII, while the N stage and the radiation fields were independent factors on nerve IX-XII. The cumulative incidence of cranial nerve I-VII palsies increased in patients with cranial nerve invasion, chemotherapy and the dose to the nasopharyngeal region (>7000 cGy). The cumulative incidence of cranial nerve IX- XII palsies increased in patients with advanced N stage. Patients in the first group of treatment field had the highest risk to progress cranial nerve IX-XII palsies, followed by the second group, and the third group had the lowest risk. Only 1 in 34 patients with brachytherapy

  19. Clonal structure in Ichthyobacterium seriolicida, the causative agent of bacterial haemolytic jaundice in yellowtail, Seriola quinqueradiata, inferred from molecular epidemiological analysis.

    Science.gov (United States)

    Matsuyama, T; Fukuda, Y; Sakai, T; Tanimoto, N; Nakanishi, M; Nakamura, Y; Takano, T; Nakayasu, C

    2017-08-01

    Bacterial haemolytic jaundice caused by Ichthyobacterium seriolicida has been responsible for mortality in farmed yellowtail, Seriola quinqueradiata, in western Japan since the 1980s. In this study, polymorphic analysis of I. seriolicida was performed using three molecular methods: amplified fragment length polymorphism (AFLP) analysis, multilocus sequence typing (MLST) and multiple-locus variable-number tandem repeat analysis (MLVA). Twenty-eight isolates were analysed using AFLP, while 31 isolates were examined by MLST and MLVA. No polymorphisms were identified by AFLP analysis using EcoRI and MseI, or by MLST of internal fragments of eight housekeeping genes. However, MLVA revealed variation in repeat numbers of three elements, allowing separation of the isolates into 16 sequence types. The unweighted pair group method using arithmetic averages cluster analysis of the MLVA data identified four major clusters, and all isolates belonged to clonal complexes. It is likely that I. seriolicida populations share a common ancestor, which may be a recently introduced strain. © 2016 John Wiley & Sons Ltd.

  20. Distribution and environmental persistence of the causative agent of white-nose syndrome, Geomyces destructans, in bat hibernacula of the eastern United States

    Science.gov (United States)

    Lorch, Jeffrey M.; Muller, Laura K.; Russell, Robin E.; O'Connor, Michael; Lindner, Daniel L.; Blehert, David S.

    2013-01-01

    White-nose syndrome (WNS) is an emerging disease of hibernating bats caused by the recently described fungus Geomyces destructans. First isolated in 2008, the origins of this fungus in North America and its ability to persist in the environment remain undefined. To investigate the correlation between manifestation of WNS and distribution of G. destructans in the U.S., we analyzed sediment samples collected from 55 bat hibernacula (caves and mines) both within and outside the known range of WNS using a newly developed real-time PCR assay. Geomyces destructans was detected in 17 of 21 sites within the known range of WNS at the time the samples were collected; the fungus was not found in 28 sites beyond the known range of the disease at the time that environmental samples were collected. These data indicate that distribution of G. destructans is correlated with disease in hibernating bats and support the hypothesis that the fungus is likely an exotic species in North America. Additionally, we examined whether G. destructans persists in infested bat hibernacula when bats are absent. Sediment samples were collected from 14 WNS-positive hibernacula, and the samples were screened for viable fungus using a culture technique. Viable G. destructans was cultivated from 7 of the 14 sites sampled during late summer when bats were no longer in hibernation, suggesting the fungus can persist in the environment in the absence of bat hosts for long periods of time.