Deamplification of pfmdr1-Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro

Amplification of the Plasmodium falciparum multidrug resistance 1 gene (pfmdr1) has been implicated in multidrug resistance, including in vitro resistance to artelinic acid (AL). The stability and fitness of having multiple copies of pfmdr1 are important factors due to their potential effects on the resistance phenotype of parasites. These factors were investigated by using an AL-resistant line of P. falciparum (W2AL80) and clones originating from W2AL80. A rapid reduction in pfmdr1 copy number (CN) was observed in the uncloned W2AL80 line; 63% of this population reverted to a CN of <3 without exposure to the drug. Deamplification of the pfmdr1 amplicon was then determined in three clones, each initially containing three copies of pfmdr1. Interestingly, two outcomes were observed during 3 months without drug pressure. In one clone, parasites with fewer than 3 copies of pfmdr1 emerged rapidly. In two other clones, the reversion was significantly delayed. In all subclones, the reduction in pfmdr1 CN involved the deamplification of the entire amplicon (19 genes). Importantly, deamplification of the pfmdr1 amplicon resulted in partial reversal of resistance to AL and increased susceptibility to mefloquine. These results demonstrate that multiple copies of the pfmdr1-containing amplicon in AL-resistant parasites are unstable when drug pressure is withdrawn and have practical implications for the maintenance and spread of parasites resistant to artemisinin derivatives.

No genetic bottleneck in Plasmodium falciparum wild-type Pfcrt alleles reemerging in Hainan Island, China, following high-level chloroquine resistance

Chloroquine-resistant Plasmodium falciparum was highly prevalent in Hainan, China, in the 1970s. Twenty-five years after cessation of chloroquine therapy, the prevalence of P. falciparum wild-type Pfcrt alleles has risen to 36% (95% confidence interval, 22.1 to 52.4%). The diverse origins of wild-type alleles indicate that there was no genetic bottleneck caused by high chloroquine resistance.

Measurement of contact voltage drop and resistance in organic solar cells

Bulk heterojunction organic solar cells based on poly[4,7-bis(3- dodecylthiophene-2-yl) benzothiadiazole-co-benzothiadiazole] and [6,6]-phenyl C71-butyric acid methyl ester are investigated. A prominent kink is observed in the fourth quadrant of the current density-voltage (J-V) response. Annealing the active layer prior to cathode deposition eliminates the kink. The kink is attributed to an extraction barrier. The J-V response in these devices is well described by a power law. This behavior is attributed to an imbalance in charge carrier mobility. An expected photocurrent for the device displaying a kink in the J-V response is determined by fitting to a power law. The difference between the expected and measured photocurrent allows for the determination of a voltage drop within the device. Under simulated 1 sun irradiance, the peak voltage drop and contact resistance at short circuit are 0.14 V and 90 Ω, respectively. © 2012 American Institute of Physics.

An investigation into resistance practices at an SME consultancy

Purpose Prior research emphasizes that organizational founders have a good deal of influence in organizational development and, where ICTs are involved, a generic strategy is usually deployed by managers in order to deal with any resistance that might occur. Cognisant of this, we investigated the role played by a Managing Director of an SME consultancy in an ICT project associated with organizational development. Design/methodology/approach This study is based on an ethnography of a ICT related change management initiative which, theoretically, takes into account though from the social shaping of technology – speifically the idea that technologies in their broadest sense are subject to ongoing work beyond the design stage. Findings We argue that Markus’ Interaction Theory of resistance still has relevance today and we extend it by emphasizing the problem of homogenizing users and downplaying their ability to appropriate resistance strategies in situ. Research limitations/implications Our study is based upon one group of individual’s experiences. Further case studies of resistance success are required which further highlight how such this is achieved and why. Practical implications Those engaged with organisational development projects need to be better educated as to the reasons for resistance, particularly positive ones, and the methods by which this might take place. Originality/value This study conceptualises strategies for ‘overcoming’ resistance as managerial technologies. Conceptualising them in this way, shows the deployement of such technologies to be a complicated and active process where the audience for such things are involved in how they are received and appropriated to suite differing agendas.

Investigations of dielectric monitoring on an energised transformer oil–paper insulation system

Frequency domain spectroscopy (FDS) is being used to assess the insulation condition of oil–paper power transformers. However, it has to date only been implemented on de-energised transformers, which requires the transformers to be shut down for an extended period and may cause significant costs. To solve this issue, a newly improved monitoring method based on the FDS principle is proposed to implement the dielectric measurement on energised transformers. Moreover, a chirp waveform excitation and its novel processing method are introduced. Compared with the conventional FDS results, dielectric results from the energised insulation system have higher tanδ values because of the increased losses. To further understand the insulation ageing process, the effects of the geometric capacitance are removed from the measured imaginary admittance of the insulation system to enhance the ageing signature. The resulting imaginary admittance is then shown to correlate well with the central time constant in return voltage measurements results. The proposed methods address the issues on techniques used on energised transformers and provide a clue for on-line FDS diagnostic application.

Reduced resting skeletal muscle protein synthesis is rescued by resistance exercise and protein ingestion following short-term energy deficit

The myofibrillar protein synthesis (MPS) response to resistance exercise (REX) and protein ingestion during energy deficit (ED) is unknown. We determined, in young men (n=8) and women (n=7), protein signaling, resting post-absorptive MPS during energy balance [EB: 45 kcal∙(kg FFM∙d)-1] and after 5d of ED [30 kcal∙(kg FFM∙d)-1] as well as MPS while in ED after acute REX in the fasted state and with the ingestion of whey protein (15 and 30 g). Post-absorptive rates of MPS were 27% lower in ED than EB (P<0.001), but REX stimulated MPS to rates equal to EB. Ingestion of 15 and 30 g of protein after REX in ED increased MPS ~16 and ~34% above resting EB, (P<0.02). p70 S6Kthr389 phosphorylation increased above EB only with combined exercise and protein intake (~2-7 fold; P<0.05). In conclusion, short-term ED reduces post-absorptive MPS, however, a bout of REX in ED restores MPS to values observed at rest in EB. The ingestion of protein after REX further increases MPS above resting EB in a dose-dependent manner. We conclude that combining REX with increased protein availability after exercise enhances rates of skeletal muscle protein synthesis during short term ED and could, in the long term, preserve muscle mass.

Simulation study for analysis of online dielectric measurement problems on transformer insulation system

Determining the condition as well as the remaining life of an insulation system is essential for the reliable operation of large oil-filled power transformers. Frequency-domain spectroscopy (FDS) is one of the diagnostic techniques used to identify the dielectric status of a transformer. Currently, this technique can only be implemented on a de-energized transformer. This paper presents an initial investigation into a novel online monitoring method based on FDS dielectric measurements for transformers. The proposed technique specifically aims to address the real operational constraints of online testing. This is achieved by designing an online testing model extending the basic “extended Debye” linear dielectric model and taking unique noise issues only experienced during online measurements into account via simulations. Approaches to signal denoising and potential problems expected to be encountered during online measurements will also be discussed. Using fixed-frequency sinusoidal excitation waveforms will result in a long measurement times. The use of alternatives such as a chirp has been investigated using simulations. The results presented in the paper predict that reliable measurements should be possible during online testing.

Data mining the relationship between road crash and skid resistance

Road asset managers are seeking analysis of the whole road network to supplement statistical analyses of small subsets of homogeneous roadway. This study outlines the use of data mining capable of analyzing the wide range of situations found on the network, with a focus on the role of skid resistance in the cause of crashes. Results from the analyses show that on non-crash-prone roads with low crash rates, skid resistance contributes only in a minor way, whereas on high-crash roadways, skid resistance often contributes significantly in the calculation of the crash rate. The results provide evidence supporting a causal relationship between skid resistance and crashes and highlight the importance of the role of skid resistance in decision making in road asset management.

Resistance or covert infection : baculovirus studies re-examined

Recently, Boots & Begon (1993) described the development of resistance to granulosis virus (GV) (Baculoviridae) infection in the moth Plodia interpunctella, following prolonged exposure to virus in laboratory cultures. Resistant insects exhibited reduced fitness in other respects, namely slower development and reduced egg viability, compared to control insects. These results were interpreted as pleiotropic effects of selection at the loci controlling resistance. Similar results have been described in a previous study: Fuxa & Richter (1989) used artificial selection to increase resistance to nuclear polyhedrasis virus (NPV) (Baculoviridae) infection in the moth Spodoptera frugiperda. The resulting gain in resistance they interpreted as the result of an increase in the frequency of alleles conferring resistance. Again, resistant insects exhibited maladaptive traits compared to controls, including a shorter adult life span, reduced number of eggs and reduced egg viability. In both studies the suggestion is made that selection against maladaptive traits will result in a decline in resistance, once selection for resistance is removed. Boots & Begon (1993) described a decrease in development time (towards that of control insects) within two generations of removing selection for resistance. Fuxa & Richter (1989) describe a decrease in resistance, so that within two generations of relaxing selection, previously resistant lines were not significantly more resistant than control insects. . .

Unswitch-ABL drugs overcome resistance in chronic myeloid leukemia

ABL inhibitors have revolutionized the clinical management of chronic myeloid leukemia, but the BCR-ABLT315I mutation confers resistance to currently approved drugs. Chan et al. show, in this issue of Cancer Cell, that " switch-control" inhibitors block BCR-ABLT315I activity by preventing ABL from switching from the inactive to active conformation.

Fire performance of LSF wall panels using numerical parametric studies

Light Gauge Steel Framing (LSF) walls made of cold-formed and thin-walled steel lipped channel studs with plasterboard linings on both sides are commonly used in commercial, industrial and residential buildings. However, there is limited data about their structural and thermal performances under fire conditions. Recent research at the Queensland University of Technology has investigated the structural and thermal behaviour of load bearing LSF wall systems. In this research a series of full scale fire tests was conducted first to evaluate the performance of LSF wall systems with eight different wall configurations under standard fire conditions. Finite element models of LSF walls were then developed, analysed under transient and steady state conditions, and validated using full scale fire tests. This paper presents the details of an investigation into the fire performance of LSF wall panels based on an extensive finite element analysis based parametric study. The LSF wall panels with eight different plasterboard-insulation configurations were considered under standard fire conditions. Effects of varying steel grades, steel thicknesses, screw spacing, plasterboard restraint, insulation materials and load ratio on the fire performance of LSF walls were investigated and the results of extensive fire performance data are presented in the form of load ratio versus time and critical hot flange (failure) temperature curves.

Characterisation of a cell wall-anchored protein of Staphylococcus saprophyticus associated with linoleic acid resistance

The Gram-positive bacterium Staphylococcus saprophyticus is the second most frequent causative agent of community-acquired urinary tract infections (UTI), accounting for up to 20% of cases. A common feature of staphylococci is colonisation of the human skin. This involves survival against innate immune defenses including antibacterial unsaturated free fatty acids such as linoleic acid which act by disrupting bacterial cell membranes. Indeed, S. saprophyticus UTI is usually preceded by perineal skin colonisation.

B-lactamase-mediated resistance to antimicrobials : the relationship between genotype and phenotype

This thesis examined the ability to predict the emergence of bacteria resistant to antibiotics using genetic markers in the bacteria. Bacteria containing the genetic markers were able to become resistant to antibiotics, whereas bacteria that did not have the genetic markers remained susceptible. Existing techniques can identify the presence of resistance by looking at the characteristics of the bacteria during growth. However, having the ability to predict antibiotic resistance before it emerges could improve the preservation of currently available antibiotics and minimise treatment failure.

Experimental investigations of improved dielectric condition monitoring methods on transformer oil-paper insulation system

Frequency Domain Spectroscopy (FDS) is successfully being used to assess the insulation condition of oil filled power transformers. However, it has to date only been implemented on de-energized transformers, which requires the transformers to be shut down for an extended period which can result in significant costs. To solve this issue, a method of implementing FDS under energized condition is proposed here. A chirp excitation waveform is used to replace the conventional sinusoidal waveform to reduce the measurement time in this method. Investigation of the dielectric response under the influence of a high voltage stress at power frequency is reported based on experimental results. To further understand the insulation ageing process, the geometric capacitance effect is removed to enhance the detection of the ageing signature. This enhancement enables the imaginary part of admittance to be used as a new indicator to assess the ageing status of the insulation.