Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are ...sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
► Pre-experimental training prevents stress and habituation biases. ► No relation was found between sample trial exploration and memory performance. ► Test trail exploration was positively correlated ...to absolute discrimination measures. ► Relative discrimination measures were unaffected by test trial exploration levels. ► Wistar rats remembered object information for 9 days after a single 3min exposure.
The object recognition task (ORT) is a popular one-trial learning test for animals. In the current study, we investigated several methodological issues concerning the task. Data was pooled from 28 ORT studies, containing 731 male Wistar rats. We investigated the relationship between 3 common absolute- and relative discrimination measures, as well as their relation to exploratory activity. In this context, the effects of pre-experimental habituation, object familiarity, trial duration, retention interval and the amnesic drugs MK-801 and scopolamine were investigated. Our analyses showed that the ORT is very sensitive, capable of detecting subtle differences in memory (discrimination) and exploratory performance. As a consequence, it is susceptible to potential biases due to (injection) stress and side effects of drugs. Our data indicated that a minimum amount of exploration is required in the sample and test trial for stable significant discrimination performance. However, there was no relationship between the level of exploration in the sample trial and discrimination performance. In addition, the level of exploration in the test trial was positively related to the absolute discrimination measure, whereas this was not the case for relative discrimination measures, which correct for exploratory differences, making them more resistant to exploration biases. Animals appeared to remember object information over multiple test sessions. Therefore, when animals have encountered both objects in prior test sessions, the object preference observed in the test trial of 1h retention intervals is probably due to a relative difference in familiarity between the objects in the test trial, rather than true novelty per se. Taken together, our findings suggest to take into consideration pre-experimental exposure (familiarization) to objects, habituation to treatment procedures, and the use of relative discrimination measures when using the ORT.
This study derived Species Sensitivity Distributions (SSD), representing a cumulative stressor-response distribution based on single-species sensitivity data, for ozone exposure on natural ...vegetation. SSDs were constructed for three species groups, i.e. trees, annual grassland and perennial grassland species, using species-specific exposure–response data. The SSDs were applied in two ways. First, critical levels were calculated for each species group and compared to current critical levels for ozone exposure. Second, spatially explicit estimates of the potentially affected fraction of plant species in Northwestern Europe were calculated, based on ambient ozone concentrations. We found that the SSD-based critical levels were lower than for the current critical levels for ozone exposure, with conventional critical levels for ozone relating to 8–20% affected plant species. Our study shows that the SSD concept can be successfully applied to both derive critical ozone levels and estimate the potentially affected species fraction of plant communities along specific ozone gradients.
► Plant Species Sensitivity Distributions were derived for ozone exposure. ► Annual grassland species, as a species assemblage, tend to be most sensitive to ozone. ► Conventional critical levels for ozone relate to 8–20% affected plant species. ► The affected fraction of plant species for current ozone exposure in Northwestern Europe is estimated.
Species Sensitivity Distributions offer opportunities in ozone risk assessment to both derive critical levels and estimate the affected fraction of a plant community.
This article presents the range of manifestations of tuberculosis (TB) of the craniospinal axis. Central nervous system (CNS) infection with Mycobacterium tuberculosis occurs either in a diffuse form ...as basal exudative leptomeningitis or in a localized form as tuberculoma, abscess, or cerebritis. In addition to an extensive review of computed tomography and magnetic resonance features, the pathogenesis and the relevant clinical setting are discussed. Modern imaging is a cornerstone in the early diagnosis of CNS tuberculosis and may prevent unnecessary morbidity and mortality. Contrast-enhanced MR imaging is generally considered as the modality of choice in the detection and assessment of CNS tuberculosis.
High accuracy proton relative stopping power measurement van Abbema, J.K.; van Goethem, M.-J.; Mulder, J. ...
Nuclear instruments & methods in physics research. Section B, Beam interactions with materials and atoms,
12/2018, Letnik:
436
Journal Article
Recenzirano
Odprti dostop
Proton therapy is a fast growing treatment modality for cancer and is in selected cases preferred over conventional radiotherapy with photons because of the highly conformal dose distribution that ...can be achieved with protons due to their steep dose gradients. However, these steep gradients also make proton therapy sensitive to range uncertainties. Proton ranges are calculated from proton stopping powers relative to that in water (Relative Stopping Power, RSP). The RSPs needed for a treatment plan can be estimated from CT (Computed Tomography) data of a patient. High accuracy reference values of RSPs are required to assess the accuracy of these CT based estimates. In this paper we present a water phantom that enables accurate measurement of depth dose profiles in water. Experimental RSPs with a relative standard uncertainty smaller than 0.4% (1σ) for samples with a water equivalent thickness of about 2 cm can be derived from the measured depth dose distributions. Most CT based RSP estimates use an approximate RSP model based on the Bethe-Bloch formula without the shell, density, Barkas and Bloch correction. In the Geant4 Monte Carlo code these corrections are included and RSP calculations with this code are expected to be more accurate. In this work, a set of 32 well defined (composition and density), mostly clinically relevant materials is used to assess the correspondence between RSPs that were measured, that were estimated from the approximate RSP model and that were calculated from Monte Carlo simulations. With the measured RSPs we provide a ground-truth bench mark to test the validity of RSPs derived from CT imaging and Monte Carlo simulations.
Purpose:
Spectral information of the output of x‐ray tubes in (dual source) computer tomography (CT) scanners can be used to improve the conversion of CT numbers to proton stopping power and can be ...used to advantage in CT scanner quality assurance. The purpose of this study is to design, validate, and apply a compact portable Compton spectrometer that was constructed to accurately measure x‐ray spectra of CT scanners.
Methods:
In the design of the Compton spectrometer, the shielding materials were carefully chosen and positioned to reduce background by x‐ray fluorescence from the materials used. The spectrum of Compton scattered x‐rays alters from the original source spectrum due to various physical processes. Reconstruction of the original x‐ray spectrum from the Compton scattered spectrum is based on Monte Carlo simulations of the processes involved. This reconstruction is validated by comparing directly and indirectly measured spectra of a mobile x‐ray tube. The Compton spectrometer is assessed in a clinical setting by measuring x‐ray spectra at various tube voltages of three different medical CT scanner x‐ray tubes.
Results:
The directly and indirectly measured spectra are in good agreement (their ratio being 0.99) thereby validating the reconstruction method. The measured spectra of the medical CT scanners are consistent with theoretical spectra and spectra obtained from the x‐ray tube manufacturer.
Conclusions:
A Compton spectrometer has been successfully designed, constructed, validated, and applied in the measurement of x‐ray spectra of CT scanners. These measurements show that our compact Compton spectrometer can be rapidly set‐up using the alignment lasers of the CT scanner, thereby enabling its use in commissioning, troubleshooting, and, e.g., annual performance check‐ups of CT scanners.
The high resolution array (HiRA) for rare isotope beam experiments Wallace, M.S.; Famiano, M.A.; van Goethem, M.-J. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2007, Letnik:
583, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The High Resolution Array (HiRA) is a large solid-angle array of silicon strip-detectors that has been developed for use in a variety of nuclear structure, nuclear astrophysics and nuclear reaction ...experiments with short lived beta-unstable beams. It consists of 20 identical telescopes each composed of a thin
(
65
μ
m
)
single-sided silicon strip-detector, a thick (1.5
mm) double-sided silicon strip-detector, and four CsI(Tl) crystals read out by photodiodes. The array can be easily configured to meet the detection requirements of specific experiments. To process the signals from the 1920 strips in the array, an Application Specific Integrated Circuit (ASIC) was developed. The design and performance characteristics of HiRA are described.
Monte Carlo simulations based on the Geant4 simulation toolkit were performed for the carbon wedge degrader used in the beam line at the Center of Proton Therapy of the Paul Scherrer Institute (PSI). ...The simulations are part of the beam line studies for the development and understanding of the GANTRY2 and OPTIS2 treatment facilities at PSI, but can also be applied to other beam lines. The simulated stopping power, momentum distributions at the degrader exit and beam line transmission have been compared to accurate benchmark measurements. Because the beam transport through magnetic elements is not easily modeled using Geant4a connection to the TURTLE beam line simulation program was made. After adjusting the mean ionization potential of the carbon degrader material from 78 eV to 95 eV, we found an accurate match between simulations and benchmark measurements, so that the simulation model could be validated. We found that the degrader does not completely erase the initial beam phase space even at low degraded beam energies. Using the validation results, we present a study of the usability of beryllium as a degrader material (mean ionization potential 63.7 eV). We found an improvement in the transmission of 30-45%, depending on the degraded beam energy, the higher value for the lower energies.
Traumatic injuries of the spine and spinal cord are common and potentially devastating lesions. We present a comprehensive overview of the classification of vertebral fractures, based on morphology ...(e.g., wedge, (bi)concave, or crush fractures) or on the mechanism of injury (flexion-compression, axial compression, flexion-distraction, or rotational fracture-dislocation lesions). The merits and limitations of different imaging techniques are discussed, including plain X-ray films, multi-detector computed tomography (MDCT), and magnetic resonance imaging (MRI) for the detection. There is growing evidence that state-of-the-art imaging techniques provide answers to some of the key questions in the management of patients with spine and spinal cord trauma: is the fracture stable or unstable? Is the fracture recent or old? Is the fracture benign or malignant? In summary, we show that high-quality radiological investigations are essential in the diagnosis and management of patients with spinal trauma.
The present work investigates methods for dose and dose rate measurements in proton beams using the luminescence of beryllium oxide (BeO). Experiments are carried out to determine the response of the ...optically stimulated luminescence (OSL) of BeO as well as the radioluminescence (RL) of BeO within the depth dose profile of a 190 MeV scattered proton beam. The acquired data is compared to an ionization chamber reference and a Monte Carlo simulation. Both dose readings from the RL and OSL measurements show accurate values in the entrance path with an increasing underestimation in the high LET region of the Bragg peak. The amount of this quenching is different for RL and OSL so that the ratio of RL to OSL dose measurements opens venues to correct the measurements to the accurate dose.
PDF
