Circulating antibodies against Plasmodium falciparum histidine-rich proteins 2 interfere with antigen detection by rapid diagnostic tests

Background Rapid diagnostic tests (RDTs) for detection of Plasmodium falciparum infection that target P. falciparum histidine-rich protein 2 (PfHRP2), a protein that circulates in the blood of patients infected with this species of malaria, are widely used to guide case management. Understanding determinants of PfHRP2 availability in circulation is therefore essential to understanding the performance of PfHRP2-detecting RDTs. Methods The possibility that pre-formed host anti-PfHRP2 antibodies may block target antigen detection, thereby causing false negative test results was investigated in this study. Results Anti-PfHRP2 antibodies were detected in 19/75 (25%) of plasma samples collected from patients with acute malaria from Cambodia, Nigeria and the Philippines, as well as in 3/28 (10.7%) asymptomatic Solomon Islands residents. Pre-incubation of plasma samples from subjects with high-titre anti-PfHRP2 antibodies with soluble PfHRP2 blocked the detection of the target antigen on two of the three brands of RDTs tested, leading to false negative results. Pre-incubation of the plasma with intact parasitized erythrocytes resulted in a reduction of band intensity at the highest parasite density, and a reduction of lower detection threshold by ten-fold on all three brands of RDTs tested. Conclusions These observations indicate possible reduced sensitivity for diagnosis of P. falciparum malaria using PfHRP2-detecting RDTs among people with high levels of specific antibodies and low density infection, as well as possible interference with tests configured to detect soluble PfHRP2 in saliva or urine samples. Further investigations are required to assess the impact of pre-formed anti-PfHRP2 antibodies on RDT performance in different transmission settings.

DNA molecules and human therapeutics

Nucleic acid molecules are championing a new generation of reverse engineered biopharmaceuticals. In terms of potential application in gene medicine, plasmid DNA (pDNA) vectors have exceptional therapeutic and immunological profiles as they are free from safety concerns associated with viral vectors, display non-toxicity and are simpler to develop. This review addresses the potential applications of pDNA molecules in vaccine design/development and gene therapy via recombinant DNA technology as well as a staged delivery mechanism for the introduction of plasmid-borne gene to target cells via the nasal route.

Perturbed Lignification Impacts Tree Growth in Hybrid Poplar-A Function of Sink Strength, Vascular Integrity, and Photosynthetic Assimilation

The effects of reductions in cell wall lignin content, manifested by RNA interference suppression of coumaroyl 3'-hydroxylase, on plant growth, water transport, gas exchange, and photosynthesis were evaluated in hybrid poplar trees (Populus alba 3 grandidentata). The growth characteristics of the reduced lignin trees were significantly impaired, resulting in smaller stems and reduced root biomass when compared to wild-type trees, as well as altered leaf morphology and architecture. The severe inhibition of cell wall lignification produced trees with a collapsed xylem phenotype, resulting in compromised vascular integrity, and displayed reduced hydraulic conductivity and a greater susceptibility to wall failure and cavitation. In the reduced lignin trees, photosynthetic carbon assimilation and stomatal conductance were also greatly reduced, however, shoot xylem pressure potential and carbon isotope discrimination were higher and water-use efficiency was lower, inconsistent with water stress. Reductions in assimilation rate could not be ascribed to increased stomatal limitation. Starch and soluble sugars analysis of leaves revealed that photosynthate was accumulating to high levels, suggesting that the trees with substantially reduced cell wall lignin were not carbon limited and that reductions in sink strength were, instead, limiting photosynthesis.

Modelling the BRT station capacity and queuing for all stopping busway operation

Stations on Bus Rapid Transit (BRT) lines ordinarily control line capacity because they act as bottlenecks. At stations with passing lanes, congestion may occur when buses maneuvering into and out of the platform stopping lane interfere with bus flow, or when a queue of buses forms upstream of the station blocking inflow. We contend that, as bus inflow to the station area approaches capacity, queuing will become excessive in a manner similar to operation of a minor movement on an unsignalized intersection. This analogy was used to treat BRT station operation and to analyze the relationship between station queuing and capacity. We conducted microscopic simulation to study and analyze operating characteristics of the station under near steady state conditions through output variables of capacity, degree of saturation and queuing. In the first of two stages, a mathematical model was developed for all stopping buses potential capacity with bus to bus interference and the model was validated. Secondly, a mathematical model was developed to estimate the relationship between average queue and degree of saturation and calibrated for a specified range of controlled scenarios of mean and coefficient of variation of dwell time.

Indoor air: Contemporary sources, exposures and global implications

Recent 'Global Burden of Disease' studies have provided quantitative evidence of the significant role air pollution plays as a human health risk factor (Lim et al., The Lancet, 380: 2224–2260, 2012). Tobacco smoke, including second hand smoke, household air pollution from solid fuels and ambient particulate matter are among the top risks, leading to lower life expectancy around the world. Indoor air constitutes an environment particularly rich in different types of pollutants, originating from indoor sources, as well as penetrating from outdoors, mixing, interacting or growing (when considering microbes) under the protective enclosure of the building envelope. Therefore, it is not a simple task to follow the dynamics of the processes occurring there, or to quantify the outcomes of the processes in terms of pollutant concentrations and other characteristics. This is further complicated by limitations such as building access for the purpose of air quality monitoring, or the instrumentation which can be used indoors, because of their possible interference with the occupants comfort (due to their large size, noise generated or amount of air drawn). European studies apportioned contributions of indoor versus outdoor sources of indoor air contaminants in 26 European countries and quantified IAQ associated DALYs (Disability-Adjusted Life Years) in those countries (Jantunen et al., Promoting actions for healthy indoor air (IAIAQ), European Commission Directorate General for Health and Consumers, Luxembourg, 2011). At the same time, there has been an increase in research efforts around the world to better understand the sources, composition, dynamics and impacts of indoor air pollution. Particular focus has been directed towards the contemporary sources, novel pollutants and new detection methods. The importance of exposure assessment and personal exposure, the majority of which occurs in various indoor micro¬environments, has also been realized. Overall, this emerging knowledge has been providing input for global assessments of indoor environments, the impact of indoor pollutants and their science based management and control. It was a major outcome of recent international conferences that interdisciplinarity and especially a better colla¬boration between exposure and indoor sciences would be of high benefit for the health related evaluation of environmental stress factors and pollutants. A very good example is the combination of biomonitoring and indoor air, particle and dust analysis to study the exposure routes of semi volatile organic compounds (SVOCs). We have adopted the idea of combining the forces of exposure and indoor sciences for this Special Issue, identified new and challenging topics and have attracted colleagues who are top researchers in their field to provide their inputs. The Special Issue includes papers, which collectively present advances in current research topics and in our view, build the bridge between indoor and exposure sciences.

WT1 interacts with MAD2 and regulates mitotic checkpoint function

Tumour suppressors safeguard the fidelity of the mitotic checkpoint by transcriptional regulation of genes that encode components of the mitotic checkpoint complex (MCC). Here we report a new role for the tumour suppressor and transcription factor, WT1, in the mitotic checkpoint. We show that WT1 regulates the MCC by directly interacting with the spindle assembly checkpoint protein, MAD2. WT1 colocalizes with MAD2 during mitosis and preferentially binds to the functionally active, closed-conformer, C-MAD2. Furthermore, WT1 associates with the MCC containing MAD2, BUBR1 and CDC20, resulting in prolonged inhibition of the anaphase-promoting complex/cyclosome (APC/C) and delayed degradation of its substrates SECURIN and CYCLIN B1. Strikingly, RNA interference-mediated depletion of WT1 leads to enhanced turnover of SECURIN, decreased lag time to anaphase and defects in chromosome segregation. Our findings identify WT1 as a regulator of the mitotic checkpoint and chromosomal stability.

A perfusion fMRI investigation of thematic and categorical context effects in the spoken production of object names

The context in which objects are presented influences the speed at which they are named. We employed the blocked cyclic naming paradigm and perfusion functional magnetic resonance imaging (fMRI) to investigate the mechanisms responsible for interference effects reported for thematicallyand categorically related compared to unrelated contexts. Naming objects in categorically homogeneous contexts induced a significant interference effect that accumulated from the second cycle onwards. This interference effect was associated with significant perfusion signal decreases in left middle and posterior lateral temporal cortex and the hippocampus. By contrast, thematically homogeneous contexts facilitated naming latencies significantly in the first cycle and did not differ from heterogeneous contexts thereafter, nor were they associated with any perfusion signal changes compared to heterogeneous contexts. These results are interpreted as being consistent with an account in which the interference effect both originates and has its locus at the lexical level, with an incremental learning mechanism adapting the activation levels of target lexical representations following access. We discuss the implications of these findings for accounts that assume thematic relations can be active lexical competitors or assume mandatory involvement of top-down control mechanisms in interference effects during naming.

Differential processing of thematic and categorical conceptual relations in spoken word production

Studies of semantic context effects in spoken word production have typically distinguished between categorical (or taxonomic) and associative relations. However, associates tend to confound semantic features or morphological representations, such as whole-part relations and compounds (e.g., BOAT-anchor, BEE-hive). Using a picture-word interference paradigm and functional magnetic resonance imaging (fMRI), we manipulated categorical (COW-rat) and thematic (COW-pasture) TARGET-distractor relations in a balanced design, finding interference and facilitation effects on naming latencies, respectively, as well as differential patterns of brain activation compared with an unrelated distractor condition. While both types of distractor relation activated the middle portion of the left middle temporal gyrus (MTG) consistent with retrieval of conceptual or lexical representations, categorical relations involved additional activation of posterior left MTG, consistent with retrieval of a lexical cohort. Thematic relations involved additional activation of the left angular gyrus. These results converge with recent lesion evidence implicating the left inferior parietal lobe in processing thematic relations and may indicate a potential role for this region during spoken word production.

Auditory context effects in picture naming investigated with event-related fMRI

Naming an object entails a number of processing stages, including retrieval of a target lexical concept and encoding of its phonological word form. We investigated these stages using the picture-word interference task in an fMRI experiment. Participants named target pictures in the presence of auditorily presented semantically related, phonologically related, or unrelated distractor words or in isolation. We observed BOLD signal changes in left-hemisphere regions associated with lexical-conceptual and phonological processing, including the midto-posterior lateral temporal cortex. However, these BOLD responses manifested as signal reductions for all distractor conditions relative to naming alone. Compared with unrelated words, phonologically related distractors showed further signal reductions, whereas only the pars orbitalis of the left inferior frontal cortex showed a selective reduction in response in the semantic condition. We interpret these findings as indicating that the word forms of lexical competitors are phonologically encoded and that competition during lexical selection is reduced by phonologically related distractors. Since the extended nature of auditory presentation requires a large portion of a word to be presented before its meaning is accessed, we attribute the BOLD signal reductions observed for semantically related and unrelated words to lateral inhibition mechanisms engaged after target name selection has occurred, as has been proposed in some production models.

Orthographic/phonological facilitation of naming responses in the picture-word task: An event-related fMRI study using overt vocal responding

In the picture-word interference task, naming responses are facilitated when a distractor word is orthographically and phonologically related to the depicted object as compared to an unrelated word. We used event-related functional magnetic resonance imaging (fMRI) to investigate the cerebral hemodynamic responses associated with this priming effect. Serial (or independent-stage) and interactive models of word production that explicitly account for picture-word interference effects assume that the locus of the effect is at the level of retrieving phonological codes, a role attributed recently to the left posterior superior temporal cortex (Wernicke's area). This assumption was tested by randomly presenting participants with trials from orthographically related and unrelated distractor conditions and acquiring image volumes coincident with the estimated peak hemodynamic response for each trial. Overt naming responses occurred in the absence of scanner noise, allowing reaction time data to be recorded. Analysis of this data confirmed the priming effect. Analysis of the fMRI data revealed blood oxygen level-dependent signal decreases in Wernicke's area and the right anterior temporal cortex, whereas signal increases were observed in the anterior cingulate, the right orbitomedial prefrontal, somatosensory, and inferior parietal cortices, and the occipital lobe. The results are interpreted as supporting the locus for the facilitation effect as assumed by both classes of theoretical model of word production. In addition, our results raise the possibilities that, counterintuitively, picture-word interference might be increased by the presentation of orthographically related distractors, due to competition introduced by activation of phonologically related word forms, and that this competition requires inhibitory processes to be resolved. The priming effect is therefore viewed as being sufficient to offset the increased interference. We conclude that information from functional imaging studies might be useful for constraining theoretical models of word production.

No specific role for the manual motor system in processing the meanings of words related to the hand

The present study explored whether semantic and motor systems are functionally interwoven via the use of a dual-task paradigm. According to embodied language accounts that propose an automatic and necessary involvement of the motor system in conceptual processing, concurrent processing of hand-related information should interfere more with hand movements than processing of unrelated body-part (i.e., foot, mouth) information. Across three experiments, 100 right-handed participants performed left- or right-hand tapping movements while repeatedly reading action words related to different body-parts, or different body-part names, in both aloud and silent conditions. Concurrent reading of single words related to specific body-parts, or the same words embedded in sentences differing in syntactic and phonological complexity (to manipulate context-relevant processing), and reading while viewing videos of the actions and body-parts described by the target words (to elicit visuomotor associations) all interfered with right-hand but not left-hand tapping rate. However, this motor interference was not affected differentially by hand-related stimuli. Thus, the results provide no support for proposals that body-part specific resources in cortical motor systems are shared between overt manual movements and meaning-related processing of words related to the hand.

The roles of shared vs. Distinctive conceptual features in lexical access

Contemporary models of spoken word production assume conceptual feature sharing determines the speed with which objects are named in categorically-related contexts. However, statistical models of concept representation have also identified a role for feature distinctiveness, i.e., features that identify a single concept and serve to distinguish it quickly from other similar concepts. In three experiments we investigated whether distinctive features might explain reports of counter-intuitive semantic facilitation effects in the picture word interference (PWI) paradigm. In Experiment 1, categorically-related distractors matched in terms of semantic similarity ratings (e.g., zebra and pony) and manipulated with respect to feature distinctiveness (e.g., a zebra has stripes unlike other equine species) elicited interference effects of comparable magnitude. Experiments 2 and 3 investigated the role of feature distinctiveness with respect to reports of facilitated naming with part-whole distractor-target relations (e.g., a hump is a distinguishing part of a CAMEL, whereas knee is not, vs. an unrelated part such as plug). Related part distractors did not influence target picture naming latencies significantly when the part denoted by the related distractor was not visible in the target picture (whether distinctive or not; Experiment 2). When the part denoted by the related distractor was visible in the target picture, non-distinctive part distractors slowed target naming significantly at SOA of -150 ms (Experiment 3). Thus, our results show that semantic interference does occur for part-whole distractor-target relations in PWI, but only when distractors denote features shared with the target and other category exemplars. We discuss the implications of these results for some recently developed, novel accounts of lexical access in spoken word production.

Orthographic effects on picture naming in Chinese: A 4T erfMRI study

The presence of a phonological relationship between a context word (cap) and the name of a target picture (cat) facilitates picture naming in the picture–word interference task in alphabetic languages such as English and Dutch. Neuroimaging studies of picture naming in English suggest distinct regions of brain activity are involved in phonological priming relative to a baseline control.

Do repeated rumble strip hits improve driver alertness?

Driving while sleepy is associated with increased crash risk. Rumble strips are designed to alert a sleepy or inattentive driver when they deviate outside their driving lane. The current study sought to examine the effects of repeated rumble strip hits on levels of physiological and subjective sleepiness as well as simulated driving performance. In total, 36 regular shift workers drove a high-fidelity moving base simulator on a simulated road with rumble strips installed at the shoulder and centre line after a working a full night shift. The results show that on average, the first rumble strip occurred after 20 minutes of driving, with subsequent hits occurring 10 minutes later, with the last three occurring approximately every 5 minutes thereafter. Specifically, it was found that the first rumble strip hit reduced physiological sleepiness; however, subsequent hits did not increase alertness. Moreover, the results also demonstrate that increased subjective sleepiness levels, via the Karolinska Sleepiness Scale, were associated with a greater probability of hitting a rumble strip. The present results suggest that sleepiness is very resilient to even strongly arousing stimuli, with physiologicl and subjective sleepiness increasing over the duration of the drive, despite the interference by rumble strips.

Legal translation

Legal translation theory brooks little interference with the source legal text. With few exceptions (Joseph 2005; Hammel 2008; Harvey 2002; Kahaner 2005; Kasirer 2001; Lawson 2006), lawyers and linguists tend to tether themselves to the pole of literalism. More a tight elastic band than an unyielding rope, this tether constrains — rather than prohibits — liberal legal translations. It can stretch to accommodate a degree of freedom by the legal translator however, should it go too far, it snaps back to the default position of linguistic fidelity. This ‘stretch and snap’ gives legal translation a unique place in general translation theory. In the general debate over the ‘degree of freedom’ the translator enjoys in conveying the meaning of the text, legal translation theory has reached its own settlement. Passivity is the default; creativity, the ‘qualified’ exception (Hammel 2008: 275).