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Ferris Wheels seem to fascinate film-directors – notably Carol Reed in The Third Man (1949), based on Graham Greene’s story and script. Though Ferris Wheels figure less conspicuously in twentieth-century novels, Malcolm Lowry provides an exception in Under the Volcano (1947), a novel also comparable to The Third Man in other ways. One explanation might be that Greene simply drew on Lowry’s example when developing his film-script (later published as a novella) – work begun very shortly after Under the Volcano had appeared. More plausibly, each writer might be understood to have responded separately, though similarly, to the unique pressures of their age. Identifying how these stresses were represented in their work, through cognate symbologies, may suggest some productive ways of reading historically.

Joseph Conrad’s fiction – Lord Jim especially – contains several instances of characters struggling with translation, or with foreign languages more generally, or transferring speech or syntactic patterns from one language to another. These features have much to suggest about Conrad’s own multilingual early life and his eventual adoption of English for his writing. They also have wider implications concerning his vision and tactics as a novelist – including his reliance on French fiction, and his regular emphases on cultural difference and on the cognitive and epistemological challenges of communicating experience. These challenges, in turn, initiate or anticipate concerns widely apparent in modernist fiction, indicating stresses in an advancing, globalised modernity which made its innovations so necessary. Appreciating Conrad’s interest in translation elucidates and confirms Fredric Jameson’s judgement of his writing as a key factor in the emergence of modernism in the early twentieth century.

Abstract Background Activation of the A2A adenosine receptor (A2AAR) decreases production of inflammatory cytokines, prevents C. difficile toxin A-induced enteritis and, in combination with antibiotics, increases survival from sepsis in mice. We investigated whether A2AAR activation improves and A2AAR deletion worsens outcomes in a murine model of C. difficile (strain VPI10463) infection (CDI). Methods C57BL/6 mice were pretreated with an antibiotic cocktail prior to infection and then treated with vancomycin with or without an A2AAR agonist. A2AAR-/- and littermate wild-type (WT) mice were similarly infected, and IFNγ and TNFα were measured at peak of and recovery from infection. Results Infected, untreated mice rapidly lost weight, developed diarrhea, and had mortality rates of 50-60%. Infected mice treated with vancomycin had less weight loss and diarrhea during antibiotic treatment but mortality increased to near 100% after discontinuation of antibiotics. Infected mice treated with both vancomycin and an A2AAR agonist, either ATL370 or ATL1222, had minimal weight loss and better long-term survival than mice treated with vancomycin alone. A2AAR KO mice were more susceptible than WT mice to death from CDI. Increases in cecal IFNγ and blood TNFα were pronounced in the absence of A2AARs. Conclusion In a murine model of CDI, vancomycin treatment resulted in reduced weight loss and diarrhea during acute infection, but high recurrence and late-onset death, with overall mortality being worse than untreated infected controls. The administration of vancomycin plus an A2AAR agonist reduced inflammation and improved survival rates, suggesting a possible benefit of A2AAR agonists in the management of CDI to prevent recurrent disease.

Youth diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) often show deficits in various measures of higher-level cognition, such as, executive functioning. Poorer cognitive functioning in children with ADHD has been associated with differences in functional connectivity across the brain. However, little is known about the developmental changes to the brain's functional properties linked to different cognitive abilities in this cohort. To characterize these changes, we analyzed fMRI data (ADHD = 373, NT = 106) collected while youth between the ages of 6 and 16 watched a short movie-clip. We applied machine learning models to identify patterns of network connectivity in response to movie-watching that differentially predict cognitive abilities in our cohort. Using out-of-sample cross validation, our models successfully predicted IQ, visual spatial, verbal comprehension, and fluid reasoning in children (ages 6 - 11), but not in adolescents with ADHD (ages 12-16). Connections with the default mode, memory retrieval, and dorsal attention were driving prediction during early and middle childhood, but connections with the somatomotor, cingulo-opercular, and frontoparietal networks were more important in middle childhood. This work demonstrated that machine learning approaches can identify distinct functional connectivity profiles associated with cognitive abilities at different developmental stages in children and adolescents with ADHD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Bobby Stojanoski reports financial support was provided by Natural Sciences and Engineering Research Council of Canada. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The reduction in spectral resolution by cochlear implants oftentimes requires complementary visual speech cues to facilitate understanding. Despite substantial clinical characterization of auditory-only speech measures, relatively little is known about the audiovisual (AV) integrative abilities that most cochlear implant (CI) users rely on for daily speech comprehension. In this study, we tested AV integration in 63 CI users and 69 normal-hearing (NH) controls using the McGurk and sound-induced flash illusions. To our knowledge, this study is the largest to-date measuring the McGurk effect in this population and the first that tests the sound-induced flash illusion (SIFI). When presented with conflicting AV speech stimuli (i.e., the phoneme "ba" dubbed onto the viseme "ga"), we found that 55 CI users (87%) reported a fused percept of "da" or "tha" on at least one trial. After applying an error correction based on unisensory responses, we found that among those susceptible to the illusion, CI users experienced lower fusion than controls-a result that was concordant with results from the SIFI where the pairing of a single circle flashing on the screen with multiple beeps resulted in fewer illusory flashes for CI users. While illusion perception in these two tasks appears to be uncorrelated among CI users, we identified a negative correlation in the NH group. Because neither illusion appears to provide further explanation of variability in CI outcome measures, further research is needed to determine how these findings relate to CI users' speech understanding, particularly in ecological listening conditions that are naturally multisensory.

Event knowledge, a person's understanding of patterns of activities in the world, is crucial for everyday social interactions. Social communication differences are prominent in autism, which may be related to atypical event knowledge, such as atypical knowledge of the sequences of activities that comprise the temporal structure of events. Previous research has found that autistic individuals have atypical event knowledge, but research in this area is minimal, particularly regarding autistic individuals' knowledge of the temporal structure of events. Furthermore, no studies have investigated the link between event knowledge and autistic traits in a non-clinical sample. We investigated relationships between event knowledge and autistic traits in individuals from the general population with varying degrees of autistic traits. We predicted that atypical ordering of event activities is related to autistic traits, particularly social communication abilities, but not other clinical traits. In Study 1, atypical ordering of event activities correlated with social ability, but not with most measures of repetitive behaviours and restricted interests. In Study 2, the typicality of activity ordering varied by participants' social ability and the social nature of the events. Relationships were not found between event activity ordering and other clinical traits. These findings suggest a relationship between autistic traits, specifically social abilities, and knowledge of the temporal structure of events in a general population sample., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects one in 66 children in Canada. The contributions of changes in the cortex and cerebellum to autism have been studied for decades. However, our understanding of brainstem contributions has only started to emerge more recently. Disruptions of sensory processing, startle response, sensory filtering, sensorimotor gating, multisensory integration and sleep are all features of ASD and are processes in which the brainstem is involved. In addition, preliminary research into brainstem contribution emphasizes the importance of the developmental timeline rather than just the mature brainstem. Therefore, the purpose of this systematic review is to compile histological, behavioral, neuroimaging, and electrophysiological evidence from human and animal studies about brainstem contributions and their functional implications in autism. Moreover, due to the developmental nature of autism, the review pays attention to the atypical brainstem development and compares findings based on age. Overall, there is evidence of an important role of brainstem disruptions in ASD, but there is still the need to examine the brainstem across the life span, from infancy to adulthood which could lead the way for early diagnosis and possibly treatment of ASD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Seif, Shea, Schmid and Stevenson.)

Background: Atypical reactions to the sensory environment are often reported in autistic individuals, with a high degree of variability across the sensory modalities. These sensory differences have been shown to promote challenging behaviours and distress in autistic individuals and are predictive of other functions including motor, social, and cognitive abilities. Preliminary research suggests that specific sensory differences may cluster together within individuals creating discrete sensory phenotypes. However, the manner in which these sensory differences cluster, and whether the resulting phenotypes are associated with specific cognitive and social challenges is unclear., Methods: Short sensory profile data from 599 autistic children and adults between the ages of 1 and 21 years were subjected to a K-means cluster analysis. Analysis of variances compared age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder across the resultant clusters., Results: A five-cluster model was found to minimize error variance and produce five sensory phenotypes: (1) sensory adaptive, (2) generalized sensory differences, (3) taste and smell sensitivity, (4) under-responsive and sensation seeking, and (5) movement difficulties with low energy. Age, adaptive behaviour, and traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder were found to differ significantly across the five phenotypes., Limitations: The results were based on parent-report measures of sensory processing, adaptive behaviour, traits associated with autism, attention-deficit and hyperactivity disorder, and obsessive and compulsive disorder, which may limit the generalizability of the findings. Further, not all measures are standardized, or psychometrically validated with an autism population. Autistic individuals with an intellectual disability were underrepresented in this sample. Further, as these data were obtained from established records from a large provincial database, not all measures were completed for all individuals., Conclusions: These findings suggest that sensory difficulties in autistic individuals can be clustered into sensory phenotypes, and that these phenotypes are associated with behavioural differences. Given the large degree of heterogeneity in sensory difficulties seen in the autistic population, these sensory phenotypes represent an effective way to parse that heterogeneity and create phenotypes that may aid in the development of effective treatments and interventions for sensory difficulties., (© 2021. The Author(s).)

Multisensory integration, the process by which sensory information from different sensory modalities are bound together, is hypothesized to contribute to perceptual symptomatology in schizophrenia, in whom multisensory integration differences have been consistently found. Evidence is emerging that these differences extend across the schizophrenia spectrum, including individuals in the general population with higher levels of schizotypal traits. In the current study, we used the McGurk task as a measure of multisensory integration. We measured schizotypal traits using the Schizotypal Personality Questionnaire (SPQ), hypothesizing that higher levels of schizotypal traits, specifically Unusual Perceptual Experiences and Odd Speech subscales, would be associated with decreased multisensory integration of speech. Surprisingly, Unusual Perceptual Experiences were not associated with multisensory integration. However, Odd Speech was associated with multisensory integration, and this association extended more broadly across the Disorganized factor of the SPQ, including Odd or Eccentric Behaviour. Individuals with higher levels of Odd or Eccentric Behaviour scores also demonstrated poorer lip-reading abilities, which partially explained performance in the McGurk task. This suggests that aberrant perceptual processes affecting individuals across the schizophrenia spectrum may relate to disorganized symptomatology., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

While atypical sensory processing is one of the more ubiquitous symptoms in autism spectrum disorder, the exact nature of these sensory issues remains unclear, with different studies showing either enhanced or deficient sensory processing. Using a well-established continuous cued-recall task that assesses visual working memory, the current study provides novel evidence reconciling these apparently discrepant findings. Autistic children exhibited perceptual advantages in both likelihood of recall and recall precision relative to their typically-developed peers. When autistic children did make errors, however, they showed a higher probability of erroneously binding a given colour with the incorrect spatial location. These data align with neural-architecture models for feature binding in visual working memory, suggesting that atypical population-level neural noise in the report dimension (colour) and cue dimension (spatial location) may drive both the increase in probability of recall and precision of colour recall as well as the increase in proportion of binding errors when making an error, respectively. These changes are likely to impact core symptomatology associated with autism, as perceptual binding and working memory play significant roles in higher-order tasks, such as communication.

The current study sought to examine the contribution of auditory and visual statistical learning on language and social competency abilities as well as whether decreased statistical learning abilities are related to increased autistic traits. To answer these questions, participants' (N = 95) auditory and visual statistical learning abilities, language, social competency, and level of autistic traits were assessed. Although the relationships observed were relatively small in magnitude, our results demonstrated that visual statistical learning related to language and social competency abilities and that auditory learning was more related to autism symptomatology than visual statistical learning. Furthermore, the relationship between visual statistical learning and social competency was mediated by language comprehension abilities, suggesting that impairments in statistical learning may cascade into impairments in language and social abilities.

Children who have been diagnosed with autism spectrum disorder (ASD) often show a marked deficit in measures of social cognition. In autistic adults, measures of social cognition have been shown to relate to differences in brain synchronization (as measured by fMRI) when individuals are processing naturalistic stimuli, such as movies. However, whether children who differ in their degree of autistic traits, with or without a diagnosis of ASD, differ in their neural responses to movies has not yet been investigated. In the current study, neural synchrony, measured using fMRI, was examined in three groups of children aged 7 to 12, who differed with respect to scores on a measure of autistic traits associated with social impairment and whether or not they had been diagnosed with ASD. While watching the movie 'Despicable Me', those diagnosed with ASD had significantly less neural synchrony in areas that have been previously shown to be associated with social cognition (e.g. areas related to 'theory of mind'), and plot following (e.g. the lateral prefrontal cortex), than those who did not have an ASD diagnosis. In contrast, two groups who differed in their degree of autistic traits, but did not have a diagnosis of ASD, showed no significant differences in neural synchrony across the whole brain. These results shed some light on how autistic traits may contribute to an individual's conscious experience of the world, and how, for children with ASD, that experience may differ markedly from that of those without ASD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Face processing in autism spectrum disorder (ASD) is thought to be atypical, but it is unclear whether differences in visual conjunctive processing are specific to faces. To address this, we adapted a previously established eye-tracking paradigm which modulates the need for conjunctive processing by varying the degree of feature ambiguity in faces and objects. Typically-developed (TD) participants showed a canonical pattern of conjunctive processing: High-ambiguity objects were processed more conjunctively than low-ambiguity objects, and faces were processed in an equally conjunctive manner regardless of ambiguity level. In contrast, autistic individuals did not show differences in conjunctive processing based on stimulus category, providing evidence that atypical visual conjunctive processing in ASD is the result of a domain general lack of perceptual specialization.

Statistical learning is an implicit process that allows individuals to track and predict incoming events from their environment. Given that information is highly structured over time, events become predictable, allowing these individuals to make better sense of their environment. Among the studies that have examined statistical learning in attention deficit/hyperactivity disorder (ADHD), findings have been mixed. Our goal was to examine whether increased ADHD symptomatology related to decreased auditory and visual statistical learning abilities. To investigate this, we examined the entire range of ADHD symptomatology using a Research Domain Criteria approach with a clinically reliable questionnaire in addition to well-established auditory and visual statistical learning paradigms. Total ADHD symptomatology was not related to auditory and visual statistical learning. An identical pattern emerged when inattention and hyperactivity components were separated, indicating that neither of these distinct behavioral symptoms of ADHD are related to statistical learning abilities. Findings from the current study converge with other studies but go beyond finding a lack of a significant relationship - through Bayesian analyses, these data provide novel evidence directly supporting the hypothesis that ADHD symptomatology and statistical learning are decoupled. This finding held for overall levels of ADHD symptomatology as well as the subdomains of inattention and hyperactivity, suggesting that the ability to pick up on patterns in both auditory and visual domains is intact in ADHD. Future work should consider investigating statistical learning in ADHD across ages and beyond auditory and visual domains.

For many cochlear implant (CI) users, visual cues are vitally important for interpreting the impoverished auditory speech information that an implant conveys. Although the temporal relationship between auditory and visual stimuli is crucial for how this information is integrated, audiovisual temporal processing in CI users is poorly understood. In this study, we tested unisensory (auditory alone, visual alone) and multisensory (audiovisual) temporal processing in postlingually deafened CI users (n = 48) and normal-hearing controls (n = 54) using simultaneity judgment (SJ) and temporal order judgment (TOJ) tasks. We varied the timing onsets between the auditory and visual components of either a syllable/viseme or a simple flash/beep pairing, and participants indicated either which stimulus appeared first (TOJ) or if the pair occurred simultaneously (SJ). Results indicate that temporal binding windows-the interval within which stimuli are likely to be perceptually 'bound'-are not significantly different between groups for either speech or non-speech stimuli. However, the point of subjective simultaneity for speech was less visually leading in CI users, who interestingly, also had improved visual-only TOJ thresholds. Further signal detection analysis suggests that this SJ shift may be due to greater visual bias within the CI group, perhaps reflecting heightened attentional allocation to visual cues.

Background: Medial humeral epicondyle fractures of the elbow are one of the most common injuries in childhood and often require surgery. There are currently no standardised outcome measures to assess progress after an elbow injury in a child. Wide variation in currently reported outcomes makes comparison of treatment difficult. This study aims to identify outcome measures that have previously been reported in studies evaluating the management of medial epicondyle fractures in children and to facilitate the development of a consensus core outcome set (COS) suitable for use in all future studies of medial humeral epicondyle fractures in children., Methods/design: This study will include a systematic review of the academic literature to identify a list of outcome measures that have previously been reported. The list of outcome measures will be used in a consensus setting exercise with focus groups of key stakeholders to identify key outcomes. A Delphi process to include two rounds will then be used to define the most important outcomes to all stakeholders forming the COS., Discussion: Core outcomes represent the minimum expected data reported for a specific condition and will improve the quality of future studies reducing bias, allowing easier comparison and enhancing opportunities for larger meta-analysis. It is anticipated that this COS will form part of the feasibility to a National Institute for Health Research (NIHR) Health Technology Assessment (HTA)-funded trial concerning the management of elbow fractures in children., Trial Registration: Core Outcome Measures in Effectiveness Trials Initiative (COMET), registration number: 949 . Registered on 17 January 2017. Prospero International prospective register of systematic reviews, registration number: CRD 42017057912 . Registered on 16 April 2017.

Recent empirical evidence suggests that autistic individuals perceive the world differently than their typically-developed peers. One theoretical account, the predictive coding hypothesis, posits that autistic individuals show a decreased reliance on previous perceptual experiences, which may relate to autism symptomatology. We tested this through a well-characterized, audiovisual statistical-learning paradigm in which typically-developed participants were first adapted to consistent temporal relationships between audiovisual stimulus pairs (audio-leading, synchronous, visual-leading) and then performed a simultaneity judgement task with audiovisual stimulus pairs varying in temporal offset from auditory-leading to visual-leading. Following exposure to the visual-leading adaptation phase, participants' perception of synchrony was biased towards visual-leading presentations, reflecting the statistical regularities of their previously experienced environment. Importantly, the strength of adaptation was significantly related to the level of autistic traits that the participant exhibited, measured by the Autism Quotient (AQ). This was specific to the Attention to Detail subscale of the AQ that assesses the perceptual propensity to focus on fine-grain aspects of sensory input at the expense of more integrative perceptions. More severe Attention to Detail was related to weaker adaptation. These results support the predictive coding framework, and suggest that changes in sensory perception commonly reported in autism may contribute to autistic symptomatology.

In contrast to annual plants, in perennial plants, the shoot apical meristem (SAM) can undergo seasonal transitions between dormancy and activity; understanding this transition is crucial for understanding growth in perennial plants. However, little is known about the molecular mechanisms of SAM development in trees. Here, light and transmission electron microscopy revealed that evident changes in starch granules, lipid bodies, and cell walls thickness of the SAM in C. lanceolata during the transition from dormancy to activation. HPLC-ESI-MS/MS analysis showed that levels of indole-3-acetic acid (IAA) increased and levels of abscisic acid (ABA) decreased from dormant to active stage. Examination of 20 genes and 132 differentially expressed proteins revealed that the expression of genes and proteins potentially involved in cell division and expansion significantly increased in the active stage, whereas those related to the abscisic acid insensitive 3(ABI3), the cytoskeleton and energy metabolism decreased in the dormant stage. These findings provide new insights into the complex mechanism of gene and protein expression and their relation to cytological and physiological changes of SAM in this coniferous species.

The Moscovian plant macroflora at Cottage Grove southeastern Illinois, USA, is a key example of Pennsylvanian (323-299 Million years ago) dryland vegetation. There is currently no palynological data from the same stratigraphic horizons as the plant macrofossils, leaves and other vegetative and reproductive structures, at this locality. Consequently, reconstructions of the standing vegetation at Cottage Grove from these sediments lack the complementary information and a more regional perspective that can be provided by sporomorphs (prepollen, pollen, megaspores and spores). In order to provide this, we have analysed the composition of fossil sporomorph assemblages in two rock samples taken from macrofossil-bearing inter-coal shale at Cottage Grove. Our palynological data differ considerably in composition and in the dominance-diversity profile from the macrofossil vegetation at this locality. Walchian conifers and pteridosperms are common elements in the macroflora, but are absent in the sporomorph assemblages. Reversely, the sporomorph assemblages at Cottage Grove comprise 17 spore taxa (∼16% and ∼63% of the total assemblages) that are known from the lycopsid orders Isoetales, Lepidodendrales and Selaginallales, while Cottage Grove's macrofloral record fails to capture evidence of a considerable population of coal forest lycopsids. We interpret our results as evidence that the Pennsylvanian dryland glacial landscape at Cottage Grove included fragmented populations of wetland plants living in refugia.

The pulse oximeter is a critical monitor in anesthesia practice designed to improve patient safety. Here, we present an approach to improve the ability of anesthesiologists to monitor arterial oxygen saturation via pulse oximetry through an audiovisual training process. Fifteen residents' abilities to detect auditory changes in pulse oximetry were measured before and after perceptual training. Training resulted in a 9% (95% confidence interval, 4%-14%, P = 0.0004, t(166) = 3.60) increase in detection accuracy, and a 72-millisecond (95% confidence interval, 40-103 milliseconds, P < 0.0001, t(166) = -4.52) speeding of response times in attentionally demanding and noisy conditions that were designed to simulate an operating room. This study illustrates the benefits of multisensory training and sets the stage for further work to better define the role of perceptual training in clinical anesthesiology.

The new DSM-5 diagnostic criteria for autism spectrum disorders (ASDs) include sensory disturbances in addition to the well-established language, communication, and social deficits. One sensory disturbance seen in ASD is an impaired ability to integrate multisensory information into a unified percept. This may arise from an underlying impairment in which individuals with ASD have difficulty perceiving the temporal relationship between cross-modal inputs, an important cue for multisensory integration. Such impairments in multisensory processing may cascade into higher-level deficits, impairing day-to-day functioning on tasks, such as speech perception. To investigate multisensory temporal processing deficits in ASD and their links to speech processing, the current study mapped performance on a number of multisensory temporal tasks (with both simple and complex stimuli) onto the ability of individuals with ASD to perceptually bind audiovisual speech signals. High-functioning children with ASD were compared with a group of typically developing children. Performance on the multisensory temporal tasks varied with stimulus complexity for both groups; less precise temporal processing was observed with increasing stimulus complexity. Notably, individuals with ASD showed a speech-specific deficit in multisensory temporal processing. Most importantly, the strength of perceptual binding of audiovisual speech observed in individuals with ASD was strongly related to their low-level multisensory temporal processing abilities. Collectively, the results represent the first to illustrate links between multisensory temporal function and speech processing in ASD, strongly suggesting that deficits in low-level sensory processing may cascade into higher-order domains, such as language and communication.

Background: Anesthesiology requires performing visually oriented procedures while monitoring auditory information about a patient's vital signs. A concern in operating room environments is the amount of competing information and the effects that divided attention has on patient monitoring, such as detecting auditory changes in arterial oxygen saturation via pulse oximetry., Methods: The authors measured the impact of visual attentional load and auditory background noise on the ability of anesthesia residents to monitor the pulse oximeter auditory display in a laboratory setting. Accuracies and response times were recorded reflecting anesthesiologists' abilities to detect changes in oxygen saturation across three levels of visual attention in quiet and with noise., Results: Results show that visual attentional load substantially affects the ability to detect changes in oxygen saturation concentrations conveyed by auditory cues signaling 99 and 98% saturation. These effects are compounded by auditory noise, up to a 17% decline in performance. These deficits are seen in the ability to accurately detect a change in oxygen saturation and in speed of response., Conclusions: Most anesthesia accidents are initiated by small errors that cascade into serious events. Lack of monitor vigilance and inattention are two of the more commonly cited factors. Reducing such errors is thus a priority for improving patient safety. Specifically, efforts to reduce distractors and decrease background noise should be considered during induction and emergence, periods of especially high risk, when anesthesiologists has to attend to many tasks and are thus susceptible to error.

We investigated the neural substrates involved in visuo-haptic neuronal convergence using an additive-factors design in combination with fMRI. Stimuli were explored under three sensory modality conditions: viewing the object through a mirror without touching (V), touching the object with eyes closed (H), or simultaneously viewing and touching the object (VH). This modality factor was crossed with a task difficulty factor, which had two levels. On the basis of an idea similar to the principle of inverse effectiveness, we predicted that increasing difficulty would increase the relative level of multisensory gain in brain regions where visual and haptic sensory inputs converged. An ROI analysis focused on the lateral occipital tactile-visual area found evidence of inverse effectiveness in the left lateral occipital tactile-visual area, but not in the right. A whole-brain analysis also found evidence for the same pattern in the anterior aspect of the intraparietal sulcus, the premotor cortex, and the posterior insula, all in the left hemisphere. In conclusion, this study is the first to demonstrate visuo-haptic neuronal convergence based on an inversely effective pattern of brain activation.

The crystal structure of eveite, ideally Mn(2)(AsO(4))(OH) [dimanganese(II) arsenate(V) hydroxide], was refined from a single crystal selected from a co-type sample from Långban, Filipstad, Varmland, Sweden. Eveite, dimorphic with sarkinite, is structurally analogous with the important rock-forming mineral andalusite, Al(2)OSiO(4), and belongs to the libethenite group. Its structure consists of chains of edge-sharing distorted [MnO(4)(OH)(2)] octa-hedra (..2 symmetry) extending parallel to [001]. These chains are cross-linked by isolated AsO(4) tetra-hedra (..m symmetry) through corner-sharing, forming channels in which dimers of edge-sharing [MnO(4)(OH)] trigonal bipyramids (..m symmetry) are located. In contrast to the previous refinement from Weissenberg photographic data [Moore & Smyth (1968 ▶). Am. Mineral.53, 1841-1845], all non-H atoms were refined with anisotropic displacement param-eters and the H atom was located. The distance of the donor and acceptor O atoms involved in hydrogen bonding is in agreement with Raman spectroscopic data. Examination of the Raman spectra for arsenate minerals in the libethenite group reveals that the position of the peak originating from the O-H stretching vibration shifts to lower wavenumbers from eveite, to adamite, zincolivenite, and olivenite.

The interoceptive effects of alcohol are major determinants of addiction liability. Metabotropic glutamate (mGlu) receptors are widely expressed in striatal circuits known to modulate drug-seeking. Given that the interoceptive effects of drugs can be important determinants of abuse liability, we hypothesized that striatal mGlu receptors modulate the interoceptive effects of alcohol. Using drug discrimination learning, rats were trained to discriminate alcohol (1 g/kg, i.g.) versus water. We found that systemic antagonism of metabotropic glutamate subtype 5 (mGlu5) receptors [10 mg/kg 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3 mg/kg 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine], but not mGlu1 receptors ([0.3-3 mg/kg JNJ16259685) (3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl) methanone)], inhibited the discriminative stimulus effects of alcohol. Furthermore, mGlu5 receptor antagonism (10 mg/kg MPEP) significantly inhibited neuronal activity in the nucleus accumbens core as levels of the transcription factor c-Fos were significantly reduced. Accordingly, targeted inhibition of mGlu5 receptors (20 microg of MPEP) in the nucleus accumbens core blunted the discriminative stimulus effects of alcohol (1 g/kg). Anatomical specificity was confirmed by the lack of effect of inhibition of mGlu5 receptors (10-30 microg of MPEP) in the dorsomedial caudate-putamen and the similar cytological expression patterns and relative density of mGlu5 receptors between the brain regions. Functional involvement of intra-accumbens mGlu5 receptors was confirmed as activation of mGlu5 receptors [10 microg of (RS)-2-amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt] enhanced the discriminative stimulus effects of a low alcohol dose (0.5 g/kg), and mGlu5 receptor inhibition (20 microg of MPEP) prevented the agonist-induced enhancement. These results show that mGlu5 receptor activity in the nucleus accumbens is required for the expression of the interoceptive effects of alcohol.

Plants uniquely contain large numbers of protein kinases, and for the vast majority of the 1,429 kinases predicted in the rice (Oryza sativa) genome, little is known of their functions. Genetic approaches often fail to produce observable phenotypes; thus, new strategies are needed to delineate kinase function. We previously developed a cost-effective high-throughput yeast two-hybrid system. Using this system, we have generated a protein interaction map of 116 representative rice kinases and 254 of their interacting proteins. Overall, the resulting interaction map supports a large number of known or predicted kinase-protein interactions from both plants and animals and reveals many new functional insights. Notably, we found a potential widespread role for E3 ubiquitin ligases in pathogen defense signaling mediated by receptor-like kinases, particularly by the kinases that may have evolved from recently expanded kinase subfamilies in rice. We anticipate that the data provided here will serve as a foundation for targeted functional studies in rice and other plants. The application of yeast two-hybrid and TAPtag analyses for large-scale plant protein interaction studies is also discussed.

Equine rhinitis A virus (ERAV) is a significant pathogen of horses and is also closely related to Foot-and-mouth disease virus (FMDV). Despite these facts, knowledge of the prevalence and importance of ERAV infections remains limited, largely due to the absence of a simple, robust diagnostic assay. In this study, we compared the antigenicities of recombinant full-length and fragmented ERAV capsid proteins expressed in Escherichia coli by using sera from experimentally infected and naturally exposed horses. We found that, from the range of antigens tested, recombinant proteins encompassing the C-terminal region of VP1, full-length VP2, and the N-terminal region of VP2 reacted specifically with antibodies present in sera from each of the five experimentally infected horses examined. Antibodies to epitopes on VP2 (both native and recombinant forms) persisted longer postinfection (>105 days) than antibodies specific for epitopes on other fragments. Our data also suggest that B-cell epitopes within the C terminus of VP1 and N terminus of VP2 contribute to a large proportion of the total reactivity of recombinant VP1 and VP2, respectively. Importantly, the reactivity of these VP1 and VP2 recombinant proteins in enzyme-linked immunosorbent assays (ELISAs) correlated well with the results from a range of native antigen-based serological assays using sera from 12 field horses. This study provides promising candidates for development of a diagnostic ERAV ELISA.

Equine rhinitis A virus (ERAV) is a member of the genus Aphthovirus, family Picornaviridae, and causes respiratory disease in horses worldwide. To characterize the putative receptor molecule(s) of the ERAV isolate 393/76 (ERAV.393/76) on the surface of Vero and other cells, an assay was developed to measure the binding of purified biotinylated ERAV.393/76 virions to cells by flow cytometry. Using this assay, the level of binding to different cell types correlated with the relative infectivity of ERAV in each cell type. In particular, equine fetal kidney cells, mouse fibroblast cells, rabbit kidney-13 and Crandell feline kidney cells bound virus at high levels and produced high virus yields (> or =10(7) TCID50 ml(-1)). Madin-Darby bovine kidney and baby hamster kidney cells showed little or no binding of virus, producing yields of < or =10(1.8) TCID50 ml(-1). Treatment of Vero and other cells with sodium periodate and the metabolic inhibitors tunicamycin, benzyl N-acetyl-alpha-D-galactosamide, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol and proteases indicated that part of the receptor-binding and entry complex for ERAV.393/76 is on N-linked carbohydrates and that the carbohydrate is likely to be present on a protein rather than a lipid backbone. The effect of carbohydrate-specific lectins and neuraminidases on ERAV.393/76 binding and infection of Vero and other cell types implicated alpha2,3-linked sialic acid residues on the carbohydrate complex in the binding and infection of ERAV.

Equine rhinitis A virus strain 393/76 (ERAV.393/76) was passaged in the presence of post-infection ERAV.393/76 equine polyclonal antiserum (EPA). Viruses with increased resistance to neutralization by EPA were obtained after 15 passages. Compared with the parent virus, five plaque-purified, neutralization-resistant mutant viruses, in addition to the non-plaque-purified viruses that were examined, had a Glu-->Lys change at position 658, which is located in the predicted betaE-betaF (EF) loop of VP1. Rabbit antiserum was prepared against the isolated EF loop of ERAV.393/76 VP1 expressed as a fusion protein with glutathione S-transferase. This antiserum bound to purified ERAV.393/76 in Western blots, but not to the neutralization-resistant mutant virus or to ERAV.PERV/62, a naturally occurring ERAV strain that has a Lys residue at position 658. These results suggest that the EF loop of VP1 is involved in a neutralization epitope of ERAV.

Verticillium dahliae Klebahn is a soil-borne fungal pathogen causing vascular diseases. The pathogen penetrates the host through the roots, spreads through the xylem, and systemically colonizes both resistant and susceptible genotypes. To elucidate the genetic and molecular bases of plant-Verticillium interactions, we have developed a pathosystem utilizing Arabidopsis thaliana and an isolate of V. dahliae pathogenic to both cruciferous and non-cruciferous crops. Relative tolerance (based on symptom severity) but no immunity was found in a survey of Arabidopsis ecotypes. Anthocyanin accumulation, stunting, and chlorosis were common symptoms. Specific responses of the more susceptible ecotype Columbia were induction of early flowering and dying. The more tolerant ecotype C-24 was characterized by pathogen-induced delay of transition to flowering and mild chlorosis symptoms. Genetic analysis indicated that a single dominant locus, Verticillium dahliae-tolerance (VET1), likely functioning also as a negative regulator of the transition to flowering, was able to convey increased tolerance. VET1 was mapped on chromosome IV. The differential symptom responses observed between ecotypes were not correlated with different rates of fungal tissue colonization or with differential transcript accumulation of PR-1 and PDF1.2 defense genes whose activation was not detected during the Arabidopsis-V. dahliae interaction. Impairment in salicylic acid (SA)- or jasmonic acid (JA)-dependent signaling did not cause hypersensitivity to the fungal infection, whereas ethylene insensitivity led to reduced chlorosis and ABA deficiency to reduced anthocyanin accumulation. The results of this study clearly indicated that the ability of V. dahliae to induce disease symptoms is also connected to the genetic control of development and life span in Arabidopsis.

Equine rhinitis A virus (ERAV) is an important respiratory pathogen of horses and is of additional interest because of its close relationship and common classification with foot-and-mouth disease virus (FMDV). As is the case with FMDV, the VP1 capsid protein of ERAV has been shown to be a target of neutralizing antibodies. In FMDV VP1, such antibodies commonly recognize linear epitopes present in the betaG-betaH loop region. To map linear B cell epitopes in ERAV VP1, overlapping fragments spanning its length were expressed in Escherichia coli as glutathione S-transferase (GST) fusion proteins. These fusion proteins were tested for reactivity with sera from ERAV-infected horses and with polyclonal sera from ERAV-immunized rabbits and mice. Regions at the N- and C-termini as well as the betaE-betaF and the betaG-betaH loop regions contained B cell epitopes that elicited antibodies in the natural host. GST fusion proteins of these regions also elicited antibodies following immunization of rabbits and mice, which, in general, strongly recognized native ERAV VP1 but which were non-neutralizing. It is concluded that the N-terminal region of ERAV VP1, in particular, contains strong B cell epitopes.

Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-chromosome inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-inactivation assay to determine X-inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, approximately 50% demonstrate markedly skewed X inactivation (i.e., patterns > or =80:20), compared with only approximately 10% of female control subjects (P<.001). Thus, skewed X inactivation is a relatively common feature of XLMR disorders. Of the 20 distinct XLMR disorders, 4 demonstrate a strong association with skewed X inactivation, since all carriers of these mutations demonstrate X-inactivation patterns > or =80:20. The XLMR mutations are present on the preferentially inactive X chromosome in all 20 informative female subjects from these families, indicating that skewing is due to selection against those cells in which the XLMR mutation is on the active X chromosome.

The nucleotide and deduced amino acid sequences of the P1 region of the genomes of 10 independent equine rhinitis A virus (ERAV) isolates were determined and found to be very closely related. A panel of seven monoclonal antibodies to the prototype virus ERAV.393/76 that bound to nonneutralization epitopes conserved among all 10 isolates was raised. In serum neutralization assays, rabbit polyclonal sera and sera from naturally and experimentally infected horses reacted in a consistent and discriminating manner with the 10 isolates, which indicated the existence of variation in the neutralization epitopes of these viruses.

Equine rhinitis A virus (ERAV) is a respiratory pathogen of horses and is classified as an Aphthovirus, the only non-Foot-and-mouth disease virus (FMDV) member of this genus. In FMDV, virion protein 1 (VP1) is a major target of protective antibodies and is responsible for viral attachment to permissive cells via an RGD motif located in a distal surface loop. Although both viruses share considerable sequence identity, ERAV VP1 does not contain an RGD motif. To investigate antibody and receptor-binding properties of ERAV VP1, we have expressed full-length ERAV VP1 in Escherichia coli as a glutathione S-transferase (GST) fusion protein (GST-VP1). GST-VP1 reacted specifically with antibodies present in serum from a rabbit immunized with purified ERAV virions and also in convalescent-phase sera from horses experimentally infected with ERAV. An antiserum raised in rabbits to GST-VP1 reacted strongly with viral VP1 and effectively neutralized ERAV infection in vitro. Using a flow cytometry-based binding assay, we found that GST-VP1, but not other GST fusion proteins, bound to cell surface receptors. This binding was reduced in a dose-dependent manner by the addition of purified ERAV virions, demonstrating the specificity of this interaction. A separate cell-binding assay also implicated GST-VP1 in receptor binding. Importantly, anti-GST-VP1 antibodies inhibited the binding of ERAV virions to Vero cells, suggesting that these antibodies exert their neutralizing effect by blocking viral attachment. Thus ERAV VP1, like its counterpart in FMDV, appears to be both a target of protective antibodies and involved directly in receptor binding. This study reveals the potential of recombinant VP1 molecules to serve as vaccines and diagnostic reagents for the control of ERAV infections.