| 1. |
- Richards, Stephen, et al.
(författare)
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The genome of the model beetle and pest Tribolium castaneum.
- 2008
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Ingår i: Nature. - 1476-4687. ; 452:7190, s. 949-55
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Tidskriftsartikel (refereegranskat)abstract
- Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
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| 2. |
- Abulfathi, Ahmed Aliyu, et al.
(författare)
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Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis
- 2019
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 58:9, s. 1103-1129
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Forskningsöversikt (refereegranskat)abstract
- The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (C-max) > 8.2 mu g/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >= 8 mu g/mL. A higher rifampicin C-max is required for severe forms TB such as TB meningitis, with C-max >= 22 mu g/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC(6)) >= 70 mu g.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C-max/MIC (minimum inhibitory concentration) and AUC/MIC.
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| 3. |
- Abulfathi, Ahmed A., et al.
(författare)
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Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens
- 2020
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Nature. - 0031-6970 .- 1432-1041. ; 76:11, s. 1557-1565
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens.Methods To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER. Results The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for >= 98% of the dosing interval in all the evaluated PASER regimens.Conclusion The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.
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| 4. |
- Abulfathi, Ahmed A., et al.
(författare)
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The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance
- 2020
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Ingår i: British Journal of Clinical Pharmacology. - : WILEY. - 0306-5251 .- 1365-2125. ; 86:11, s. 2123-2132
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Forskningsöversikt (refereegranskat)abstract
- Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.
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| 5. |
- Abulfathi, Ahmed A., et al.
(författare)
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The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis
- 2021
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
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| 6. |
- Ryder, Edward, et al.
(författare)
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The DrosDel deletion collection : A Drosophila genomewide chromosomal deficiency resource
- 2007
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Ingår i: Genetics. - Austin, Tex. : Genetics Society of America. - 0016-6731 .- 1943-2631. ; 177:1, s. 615-629
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Tidskriftsartikel (refereegranskat)abstract
- We describe a second-generation deficiency kit for Drosophila melanogaster composed of molecularly mapped deletions on an isogenic background, covering 77% of the Release 5.1 genome. Using a previously reported collection of FRT-bearing P-element insertions, we have generated 655 new deletions and verified a set of 209 deletion-bearing fly stocks. In addition to deletions, we demonstrate how the P elements may also be used to generate a set of custom inversions and duplications, particularly useful for balancing difficult regions of the genome carrying haplo-insufficient loci. We describe a simple computational resource that facilitatesselection of appropriate elements for generating custom deletions. Finally, we provide a computational resource that facilitates selection of other mapped FRT-bearing elements that, when combined with the DrosDel collection, can theoretically generate over half a million precisely mapped deletions.
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| 7. |
- Schwack, Fabian, et al.
(författare)
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Comparison of life calculations for oscillating bearings considering individual pitch control in wind turbines
- 2016
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596.
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Konferensbidrag (refereegranskat)abstract
- The fatigue life calculation of bearings under rotating conditions has been well researched and standardized. In contrast, for bearings in oscillating applications no international standards exist. As a result, pitch bearings in wind turbines are designed with different, non standardized approaches. Furthermore, the impact of individual pitch control on pitch bearings has not yet been studied. In this paper four approaches for fatigue life calculation will be applied and compared under individual pitch control conditions. For comparison, the loads and the bearing geometry of the reference turbine IWT 7.5 MW, which is individual pitch controlled, are used. This paper will show how the bearing life calculated by different approaches reacts to individual pitch control conditions. Furthermore, the factors for the modified rating life, according to the ABMA and ISO standards, which implement different operation conditions on the bearings in rotating applications, are calculated for the given loads and the given bearing geometry in oscillating applications.
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| 8. |
- Schwack, Fabian
(författare)
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Untersuchungen zumBetriebsverhalten oszillierender Wälzlager am Beispiel von Rotorblattlagern in Windenergieanlagen
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pitch bearings in wind turbines are typical examples for oscillating rollingelement bearings. On the one hand pitch bearings are aected by intentionaloscillations due to the adaption of the aerodynamic angle of attack of the rotorblade. On the other hand, unwanted micro-oscillations (vibrations) are causedby turbulence when the wind turbine is at standstill. The occurring damagemechanisms can reduce the service life of component and, in the worst casescenario, lead to a failure of the whole technical system.On basis of the operating conditions of a reference wind turbine and loadsimulations for the reference pitch bearing, the occurring wear phenomena areanalysed. For this purpose, experimental investigations for the identicationand determination of inuencing parameters are undertaken. The experimentalinvestigations are carried out on angular contact ball bearings of the size7208. The operating conditions of the reference pitch bearing are transferredto the test bearing size using a scaling method. A time-dependent connectionof wear phenomena is established by the incubation hypotheses. The inuenceof the oscillation amplitude and frequency on occurring wear becomesclear through the investigations. In addition, experiments are carried out onfour-point contact ball bearing with a pitch diameter of 675 mm.The results of the experimental investigations are used to set up a simulationmodel which is focused on the contact kinematics between rolling elementsand raceways. The occurrence and the form of the wear can be explainedwith the simulated frictional work. Using the fully parametric structure of themodel, the inuence of the bearing geometry and input parameters on thefrictional work can be analysed.In order to determine the inuence of the type of lubricating grease, afurther series of experiments is carried out. In this experiments common usedlubricants for pitch bearings are tested. The results show that none of theexamined lubricants can prevent wear for all operating conditions. However,statements on suitable grease compositions can be made for certain operatingparameters.The results show the relationship between wear and operating parametersin pitch bearings based on experimental investigations and simulations.
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| 9. |
- Schwiegelshohn, Uwe, et al.
(författare)
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Perspectives on grid computing
- 2010
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Ingår i: Future generations computer systems. - : Elsevier BV. - 0167-739X .- 1872-7115. ; 26:8, s. 1104-1115
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Tidskriftsartikel (refereegranskat)abstract
- Grid computing has been the subject of many large national and international IT projects. However, not all goals of these projects have been achieved. In particular. the number of users lags behind the initial forecasts laid out by proponents of grid technologies. This underachievement may have led to claims that the grid concept as a whole is on its way to being replaced by Cloud computing and various X-as-a-Service approaches. In this paper, we try to analyze the current situation and to identify promising directions for future grid development. Although there are shortcomings in current grid systems, we are convinced that the concept as a whole remains valid and can benefit from new developments, including Cloud computing. Furthermore, we strongly believe that some future applications will require the grid approach and that, as a result, further research is required in order to turn this concept into reliable, efficient and user-friendly computing platforms. (c) 2010 Elsevier B.V. All rights reserved.
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| 10. |
- Solaki, Maria, et al.
(författare)
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Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia
- 2022
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:7, s. 832-858
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Tidskriftsartikel (refereegranskat)abstract
- Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying “likely disease-causing” variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as “likely disease-causing” according to ACMG/AMP criteria. We report 48 novel “likely disease-causing” variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
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