10 research outputs found
Proofreading deficiency of Pol I increases the levels of spontaneous rpoB mutations in E. coli
No full textThe fidelity role of DNA polymerase I in chromosomal DNA replication in E. coli was investigated using the rpoB forward target. These experiments indicated that in a strain carrying a proofreading-exonuclease-defective form of Pol I (polAexo mutant) the frequency of rpoB mutations increased by about 2-fold, consistent with a model that the fidelity of DNA polymerase I is important in controlling the overall fidelity of chromosomal DNA replication. DNA sequencing of rpoB mutants revealed that the Pol I exonuclease deficiency lead to an increase in a variety of base-substitution mutations. A polAexo mutator effect was also observed in strains defective in DNA mismatch repair and carrying the dnaE915 antimutator allele. Overall, the data are consistent with a proposed role of Pol I in the faithful completion of Okazaki fragment gaps at the replication fork
Synthese van vasoactive intestinal peptide via de gemengd anhydride methode
No full textBiotechnologyApplied Science
Discovery and in vivo evaluation of new melanocortin-4 receptor-selective peptides
No full textThe melanocortin-4 receptor (MC4R) is involved in several physiological processes, including body weight regulation and grooming behaviour in rats. It has also been suggested that the MC4R mediates the effects of melanocortin ligands on neuropathic pain. Selective compounds are needed to study the exact role of the MC4R in these different processes. We describe here the development and evaluation of new melanocortin compounds that are selective for the MC4R as compared with the other centrally expressed receptors, MC3R and MC5R. First, a library of 18 peptides, in which a melanocortin-based sequence was systematically point-mutated, was screened for binding to and activity on the MC3R, MC4R and MC5R. Compound Ac-Nle-Gly-Lys-d-Phe-Arg-Trp-Gly-NH<sub>2</sub> (JK1) appeared to be the most selective MC4R compound, based on affinity. This compound is 90- and 110-fold selective for the MC4R as compared to the MC3R and MC5R, respectively. Subsequent modification of JK1 yielded compound Ac-Nle-Gly-Lys-d-Nal(2)-Arg-Trp-Gly-NH<sub>2</sub> (JK7), a selective MC4R antagonist with 34-fold MC4R/MC3R and 109-fold MC4R/MC5R selectivity. The compounds were active in vivo as determined in a grooming assay and a model for neuropathic pain in rats. Intravenous (i.v.) injections suggested that they were able to pass the blood–brain barrier.
The compounds identified here will be useful in further research on the physiological roles of the MC4R
Multinational Sales Management of Foreign Subsidiaries: A Case Study on the German Mittlestand
No full textThis research study provides insights into “How to manage foreign subsidiaries in a multinational company (MNC) belonging to the German Mittelstand” by applying a contingency perspective. Existing MNC knowledge focuses on large MNCs whereas contributions regarding an application to the German Mittelstand are scant. In particular, a framework for multinational sales management with patterns for foreign subsidiaries is missing for both academia and management. Thus, the findings of this research study contribute to existing MNC knowledge and provide ideas and guidance for managerial practice.
A review of the literature identifies MNC typologies (Bartlett & Beamish, 2014; Bartlett & Ghoshal, 1988), subsidiary role models (Bartlett & Beamish, 2014; Bartlett & Ghoshal, 1986), and the corresponding MNC factors. This serves as a starting point from which a conceptual framework is derived accordingly. Thereafter, a plausibility check with industry experts verifies and ensures the suitability of the identified MNC factors to the characteristics of the German Mittelstand. Then, an in-depth case study consisting of documentary, semi-structured interviews, and focus group interviews, applies the conceptual framework to the selected case of the German Mittelstand.
The described research design operationalizes and modifies the selected MNC models in such a way that they suit the identified Mittelstand characteristics. This facilitates an application of the framework for multinational sales management consisting of the selected and operationalized MNC models for the MNC typology and the foreign subsidiaries.
The main contribution of this research study is the framework for multinational sales management, which fills the gaps identified in existing knowledge. In particular, this research study contributes existing to knowledge by: (1 and 2) operationalizing the models for MNC typology and subsidiary roles for the German Mittelstand, (3) providing the key MNC factors for the German Mittelstand, and (4) elaborating the patterns for multinational sales management to improve the subsidiary competences and to increase the market importance of their local market with respect to their subsidiary role
Structural and functional studies of novel mechanisms of Lassa fever virus nucleoprotein in immune suppression, viral RNA transcription and replication
No full textLassa fever virus is one of the most dangerous viruses of arenaviridae family,
causing more than 500,000 infections per year in Africa. The fatality rate for
hospitalized patients is as high as 20%. Due to the high fatality and lack of efficient licensed drugs and vaccines to treat and prevent, Lassa fever virus is classified as a Category A priority pathogen and biosafety level-4 agent by the Centers for Disease Control and Prevention of the USA. Cases were also found in the Americas and European countries, highlighting its potency to be a
bioterrorism weapon.
Like other areanaviruses, Lassa virus has developed a unique interferon suppression mechanism to evade from the host immune system, in which Lassa
nucleoprotein plays the key role. To understand the LASV nucleoprotein functions, we tried to determine the first arenaviral nucleoprotein structure, LASV nucleoprotein. The LASV nucleoprotein (NP) was overexpressed and purified. The NP protein was crystallized and the structure was determined to 1.80 Å resolution. The crystals belong to space group P3, with the unit cell parameters a = b = 177.16 Å, c = 56.49 Å, α= β= 90° and γ= 120°. The LASV NP
structure contains two domains, which are not similar to any reported viral nucleoprotein structures. The N-terminal domain has a novel structure with a
cavity, which we proposed for cap binding, and the C-terminus is a 3’-5' ribonuclease, which is responsible for suppressing interferon production. To characterize the possible interaction between NP and other arenaviral protein, we also overexpressed and purified LASV Z. Interestingly, both NP and Z proteins have two forms and the purified NP protein and monomeric Z protein bind RNA.
It is surprising that only the oligomeric Z protein interacts with NP protein but
the monomeric Z protein does not as determined by Isothermal Titration
Calorimetry (ITC). Our studies have reported the first arenaviral nucleoprotein
structure, revealed the novel mechanism for the cap binding and immune
suppression, which set up a platform for the development of novel drugs and vaccines
to treat deadly arenaviral infections
New drugs against trypanosomatid parasites : rediscovery of fexinidazole
No full textNeglected tropical diseases (NTDs) are a group of communicable diseases mostly affecting people in developing countries. These diseases are responsible for a major part of the global morbidity, mortality and poverty. There is no doubt that the well-being of people in the developing world can only be improved if the NTDs are controlled. An important tool for disease control is the drug treatment. The few available drugs are unsatisfactory because of the limited efficacy, adverse effects and the high price. Chagas disease, leishmaniasis and human African trypanosomiasis belong to this group of NTDs. They are caused by infections with protozoa of the family Trypanosomatidae. For these three diseases new drugs are urgently needed.
By definition there is no commercial market for drugs against NTDs. Drug research and development (R&D) for NTDs is mainly driven by the public sector, the so-called product development partnerships (PDPs). Drug R&D is a very long (10-15 years), risky and therefore expensive process. Three different series of compounds (agrochemicals, marketed drugs and nitro-heterocyclic compounds) were tested for their antiparasitic effects, with the aim to identify new lead compounds or even clinical candidates against leishmaniasis, sleeping sickness, and Chagas disease.
Agrochemicals are used worldwide on a large scale in food production. They undergo a rigorous toxicological testing prior to launch. Over 600 compounds were screened for their antiparasitic activity. Agrochemicals are not optimized for use in mammals, yet a significant number of molecules were found with good and selective in vitro activity. Some of them showed also efficacy in the corresponding rodent model. These results indicate that agrochemicals can provide very interesting starting structures for drug research against parasitic diseases.
Drugs or drug-like compounds are an ideal starting point for antiparasitic drug discovery, because very often pharmacokinetic and toxicological data are available. A number of drugs, including antibiotics, antivirals, antifungals, and anti-psychotics were assayed for antiparasitic activity. Some of the drugs tested showed selective antiparasitic activity. These compounds can be regarded as new lead structures and should be further investigated.
Nitroheterocycles belong to a well- known class of compounds with the stigma of being mutagenic or genotoxic. Over 700 compounds, mainly nitroimidazoles, have been systematically tested for their antiparasitic activity, and their pharmacokinetics and mutagenicity was investigated. A number of effective, non-mutagenic and non- genotoxic compounds was identified. So fexinidazole was rediscovered, a drug that had been in clinical development already in the 70’s as a broad-spectrum antimicrobial drug. Fexinidazole is rapidly metabolized to fexinidazole-sulfoxide and -sulfone. The parent compound and the two principle metabolites showed in vitro trypanocidal activity against all (sensitive and resistant) tested T. brucei strains (IC50 of 0.2 - 0.9 ug / ml). Fexinidazole cured the first stage mouse model with a 4-day oral treatment of 100 mg/kg/day and the 2nd stage mouse model with a 5-day oral treatment of 200 mg/kg/day. The two metabolites are mainly responsible for the good efficacy in animal models. Both reach very high concentrations in blood and brain tissue. Fexinidazole has successfully completed preclinical development and Phase I clinical trials and is currently in a clinical phase II / III study.
With the approach of phenotypic screening of compounds that have been developed for other purposes, new leads for drug R&D against Chagas’ disease, leishmaniasis and human African trypanosomiasis were identified.
Fexinidazole is the first drug candidate in clinical Phase II / III trials since decades. It would be the first oral drug for the treatment of stage 1 and 2 of human African sleeping sickness. If fexinidazole overcomes all obstacles, this would be a major breakthrough in the fight against African sleeping sickness. With a well tolerated, orally active drug like Fexinidazole the elimination of sleeping sickness seems finally tangible
Cloning Of The Transmembrane Glycoproteins G And F From A Brazilian Isolate Of Bovine Respiratory Syncytial Virus In A Prokaryotic System
No full textThe aim of this work was the cloning of those transmembrane glycoproteins G and F from an isolate bovine respiratory syncytial viruses (BRSV) - a Brazilian isolate of BRSV, named BRSV-25-BR in previous studies, in a prokaryotic system to proceed the sequencing of larger genomic fragments. The nucleotide substitutions were confirmed and these clones may also be used in further studies regarding the biological effects of those proteins in vitro and in vivo.633552558Almeida, R.S., Spilki, F.R., Roehe, P.M., Detection of Brazilian bovine respiratory syncytial virus strain by a reverse transcriptase-nested-polymerase chain reaction in experimentally infected calves (2005) Vet. Microbiol., 105, pp. 131-135Arns, C.W., Campalans, J., Costa, S.C.B., Characterization of bovine respiratory syncytial virus isolated in Brazil (2003) Braz. J. Med. Biol. 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Virol., 82, pp. 631-640Langedijk, J.P., Schaaper, W.M., Meleon, R.H., Proposed three-dimensional model for the attachment protein G of respiratory syncytial virus (1996) J. Gen. Virol., 77, pp. 1249-1257Langedijk, J.P., Meleon, R.H., Taylor, G., Antigenic structure of the central conserved region of protein G of bovine respiratory syncytial virus (1997) J. Virol, 243, pp. 293-302Larsen, L.E., Bovine respiratory syncytial virus (BRSV): a review (2000) Acta Vet. Scand., 41, pp. 1-21Lerch, R.A., Anderson, K., Wertz, G.W., Nucleotide sequence analysis and expression from recombinant vectors demonstrate that the attachment protein G of bovine respiratory syncytial virus (1990) J. Virol., 64, pp. 5559-5569Levine, S., Klaiber Franco, R., Paradiso, P.R., Demonstration that glycoprotein G is the attachment protein of respiratory syncytial virus (1987) J. Gen. Virol., 68, pp. 2521-2524Martinez, I., Dopazo, J., Melero, J.A., Antigenic structure of the human respiratory syncytial virus G glycoprotein and relevance of hypermutation events for the generation of antigenic variants (1997) J. Gen. Virol., 74, pp. 2001-2004Melero, J.A., Garcia-Barreno, B., Martinez, I., Antigenic structure, evolution and immunobiology of human respiratory syncytial virus attachment (G) protein (1997) J. Gen. Virol., 78, pp. 2411-2418Paccaud, M.F., Jacquier, C.A., Respiratory syncytial virus of bovine origin (1970) Archiv. Gesamte Virusforschung, 30, p. 327Pastey, M.K., Samal, S.K., Structure and sequence comparison of bovine respiratory syncytial virus fusion protein (1993) Virus Res., 29, pp. 195-202Schrijver, R.S., Langedijk, J.P.M., vander Poel, J.P.M., Antibody responses against the G and F proteins of bovine respiratory syncytial virus after experimental and natural infections (1996) Clin. Diagn. Lab. 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The <i>Salmonella</i> Mutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21st Century
No full textObjectives: According to the 2007 National Research Council report Toxicology for the Twenty-First Century, modern methods (e.g., "omics," in vitro assays, high-throughput testing, computational methods) will lead to the emergence of a new approach to toxicology. The Salmonella mammalian microsome mutagenicity assay has been central to the field of genetic toxicology since the 1970s. Here we document the paradigm shifts engendered by the assay, the validation and applications of the assay, and how the assay is a model for future in vitro toxicology assays. Data sources: We searched PubMed, Scopus, and Web of Knowledge using key words relevant to the Salmonella assay and additional genotoxicity assays. Data extraction: We merged the citations, removing duplicates, and categorized the papers by year and topic. Data synthesis: The Salmonella assay led to two paradigm shifts: that some carcinogens were mutagens and that some environmental samples (e.g., air, water, soil, food, combustion emissions) were mutagenic. Although there are > 10,000 publications on the Salmonella assay, covering tens of thousands of agents, data on even more agents probably exist in unpublished form, largely as proprietary studies by industry. The Salmonella assay is a model for the development of 21st century in vitro toxicology assays in terms of the establishment of standard procedures, ability to test various agents, transferability across laboratories, validation and testing, and structure-activity analysis. Conclusions: Similar to a stethoscope as a first-line, inexpensive tool in medicine, the Salmonella assay can serve a similar, indispensable role in the foreseeable future of 21st century toxicology.1181115151522Aguayo, S., Munoz, M.J., de la Torre, A., Roset, J., de la Pena, E., Carballo, M., Identification of organic compounds and ecotoxicological assessment of sewage treatment plants (STP) effluents (2004) Sci Total Environ, 328, pp. 69-81Ames, B.N., The detection of chemical mutagens with enteric bacteria (1971) Chemical Mutagens: Principles and Methods For their Detection, 1, pp. 267-282. , (Hollaender A, ed). New York:Plenum PressAmes, B.N., Identifying environmental chemicals causing mutations and cancer (1979) Science, 204, pp. 587-593Ames, B.N., Durston, W.E., Yamasaki, E., Lee, F.D., Carcinogens are mutagens: A simple test system combining liver homogenates for activation and bacteria for detection (1973) Proc Natl Acad Sci USA, 70, pp. 2281-2285Ames, B.N., Gurney, E.G., Miller, J.A., Bartsch, H., Carcinogens as frameshift mutagens: Metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens (1972) Proc Natl Acad Sci USA, 69, pp. 3128-3132Ames, B.N., Lee, F.D., Durston, W.E., An improved bacterial test system for the detection and classification of mutagens and carcinogens (1973) Proc Natl Acad Sci USA, 70, pp. 782-786Ames, B.N., McCann, J., Yamasaki, E., Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test (1975) Mutat Res, 31, pp. 347-364Ashby, J., Fundamental structural alerts to potential carcinogenicity or noncarcinogenicity (1985) Environ Mutagen, 7, pp. 919-921(1985) Evaluation of Short-Term Tests For Carcinogens: Report of The IPCS Collaborative Study On In Vitro Assays, , Ashby J, de Serres F, Draper M, Ishidate M, Margolin B, Matter B, et al., eds., Amsterdam:Elsevier(1988) Evaluation of Short-Term Tests For Carcinogens: Report of The International Programme On Chemical Safety's Collaborative Study On In Vivo Assays, , Ashby J, de Serres F, Shelby M, Margolin B, Ishidate MJ, Becking G, eds., Cambridge:Cambridge University PressAshby, J., Paton, D., The influence of chemical structure on the extent and sites of carcinogenesis for 522 rodent carcinogens and 55 different human carcinogen exposures (1993) Mutat Res, 286, pp. 3-74Lewtas, J., King, L.C., Williams, K., Ball, L.M., DeMarini, D.M., Bioassay-directed fractionation of 1-nitropyrene metabolites: Generation of mutagrams by coupling reverse-phase HPLC with microsuspension mutagenicity assays (1990) Mutagenesis, 5, pp. 481-489Loper, J.C., Lang, D.R., Schoeny, R.S., Richmond, B.B., Gallagher, P.M., Smith, C.C., Residue organic mixtures from drinking water show in vitro mutagenic and transforming activity (1978) J Toxicol Environ Health, 4, pp. 919-938Macphee, D.G., Development of bacterial mutagenicity tests: A view from afar (1989) Environ Mol Mutagen, 16, pp. 35-38Maertens, R.M., Bailey, J., White, P.A., The mutagenic hazards of settled house dust: A review (2004) Mutat Res, 567, pp. 401-425Malling, H.V., Hydroxylamine as a mutagenic agent for Neurospora crassa (1966) Mutat Res, 3, pp. 470-476Malling, H.V., Mutagenicity of two potent carcinogens, dimethylnitrosamine and diethylnitrosamine, in Neurospora crassa (1966) Mutat Res, 3, pp. 537-540Malling, H.V., Dimethylnitrosamine: Formation of mutagenic compounds by interaction with mouse liver microsomes (1971) Mutat Res, 13, pp. 425-429Margolin, B.H., Kaplan, N., Zeiger, E., Statistical analysis of the Ames Salmonella/microsome test (1981) Proc Natl Acad Sci USA, 78, pp. 3779-3783Margolin, B.H., Risko, K.J., Shelby, M.D., Zeiger, E., Sources of variability in Ames Salmonella typhimurium tester strains: Analysis of the International Collaborative Study on 'Genetic Drift' (1984) Mutat Res, 130, pp. 11-25Maron, D.M., Ames, B.N., Revised methods for the Salmonella mutagenicity test (1983) Mutat Res, 113, pp. 173-215Ashby, J., Tennant, R.W., Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP (1988) Mutat Res, 204, pp. 17-115Martin, M.T., Dix, D.J., Judson, R.S., Kavlock, R.J., Reif, D.M., Richard, A.M., Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA's ToxCast program (2010) Chem Res Toxicol, 23, pp. 578-590Marvin, C.H., Hewitt, L.M., Analytical methods in bioassay-directed investigations of mutagenicity of air particulate material (2007) Mutat Res, 636, pp. 4-35McCann, J., Ames, B.N., Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals: Discussion (1976) Proc Natl Acad Sci USA, 73, pp. 950-954McCann, J., Choi, E., Yamasaki, E., Ames, B.N., Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals (1975) Proc Natl Acad Sci USA, 72, pp. 5135-5139McCann, J., Horn, L., Kaldor, J., An evaluation of Salmonella (Ames) test data in the published literature: Application of statistical procedures and analysis of mutagenic potency (1984) Mutat Res, 134, pp. 1-47Meek, B., Doull, J., Pragmatic challenges for the vision of toxicity testing in the 21st century in a regulatory context: Another Ames test? or a new edition of "The Red Book"? 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Pressure mapping of medical compression bandages used for venous leg ulcer treatment
No full textChronic leg ulcers affect 1% of the adult population in the developed countries. The majority of leg ulcers are due to venous disease. The impact of venous ulcers on the quality of life is significant, and it costs the NHS £300 − 600m annually. Medical compression bandages (MCBs) are the cornerstone in the treatment of chronic venous ulcers. MCBs should be applied with a pressure gradient reducing from the ankle to the knee. Visual inspection of bandages in situ for the amount of extension and overlap in the MCBs is normally what nurses use in day by day clinical practice to control the pressure they apply to patients’ legs. Interface pressure produced by a bandage is proportional to the tension which, in turn, is proportional to the extension of the bandage, and pressure is inversely proportional to the limb radius. Experts in the field believe that applying MCBs with a constant extension will enable users to achieve the required gradient pressure profile, as the circumference of the leg increases from the ankle towards the mid-calf. Despite the many studies published investigating the effectiveness of different MCBs, very little work has been done to understand the underpinning physics of how MCBs apply pressure to the leg. In addition, although many types of pressure measurement systems have been developed and used by various researchers, most of these devices have not been systematically tested for their performance and measurement reliability. In this thesis, the physics behind compression therapy is investigated and modeled using mathematical equations, some of which are validated experimentally. Analytical results suggest that ignoring MCBs thickness when computing the interface pressure will have a negligible effect on the accuracy of the pressure calculation produced by singlelayer MCBs. However, MCBs thickness should be considered in computing the interface pressure produced by multi-layer MCBs. Moreover, a model developed by other researchers to explain the impact of the pressure sensor’s physical dimensions on the interface pressure is tested experimentally. Results suggest that the model is not sufficient to estimate the amount of perturbation in the pressure, and a better model is needed. Furthermore, the thesis outlines experiments conducted to study MCBs and obtain polynomial expressions to describe the MCBs tension-elongation curves. The polynomial expressions are used in conjunction with mathematical models to compute the interface pressure induced by MCBs. In addition, the thesis demonstrates how the information obtained from these experiments is used in line with a mathematical model to classify compression bandages and simulate the impact of limb shape change secondary to calf muscle activity on the interface pressure. Moreover, the thesis reports on the evaluation of various types of resistive-based flexible pressure sensors. It illustrates that FlexiForce outperforms other resistive-based flexible sensors in static evaluation for sensitivity to low pressures, nonlinearity, repeatability, hysteresis and drift. However, the typical accuracy of FlexiForce sensor is found to be ±12% full scale, where full scale in this case is 120mmHg. The accuracy error is further reduced to approximately ±6% full scale by arranging the sensors in arrays and using averaging techniques. Arrays of FlexiForce sensors are used then to map the interface pressure under MCBs applied to different mediums. The pressure maps obtained by FlexiForce sensors are compared with the maps obtained using microelectromechanical systems (MEMS) force sensors and PicoPress transducer, a commercial medical pressure transducer used currently to study the pressure induced under MCBs. Furthermore, the measured pressures in all these cases are compared with the pressures computed theoretically from the bandage extension. Results show low levels of agreement or, in some cases, no agreement between the measured and computed pressures, which lead to question the reliability of using extension as a feedback method to control the interface pressure applied by MCBs. Additionally, in spite of some deficiencies in the performance of FlexiForce sensors, the thesis demonstrates that they could be used to obtain pressure maps for qualitative purposes. This, in some cases, is found to provide more reliable pressure readings than commercial sensors like PicoPress. Generally, current medical pressure transducers are thick; thus, they tend to overestimate the pressure applied by compression bandages significantly. The thesis details the assessment of pressure-mapping bandage prototypes and the associated tests carried out to evaluate their performance. Preliminary results suggest that the pressure-mapping bandage prototypes cannot be used to have accurate measurements. Nevertheless, they can provide the user with qualitative information about the pressure profile in terms of pressure levels and gradient. Finally, the thesis presents the usage of a pressure-mapping leg for training purposes for student nurses. This involved studying student nurses’ bandaging techniques and pinpointing their main bandaging technique pitfalls. Compared with experienced nurses, fewer of the student nurses applied MCBs with reverse pressure gradient
