Lipoproteome screening of the Lyme disease agent identifies inhibitors of antibody-mediated complement killing.

Spirochetal pathogens, such as the causative agent of Lyme disease, Borrelia burgdorferi sensu lato, encode an abundance of lipoproteins; however, due in part to their evolutionary distance from more well-studied bacteria, such as Proteobacteria and Firmicutes, few spirochetal lipoproteins have assigned functions. Indeed, B. burgdorferi devotes almost 8% of its genome to lipoprotein genes and interacts with its environment primarily through the production of at least 80 surface-exposed lipoproteins throughout its tick vector­vertebrate host lifecycle. Several B. burgdorferi lipoproteins have been shown to serve roles in cellular adherence or immune evasion, but the functions for most B. burgdorferi surface lipoproteins remain unknown. In this study, we developed a B. burgdorferi lipoproteome screening platform utilizing intact spirochetes that enables the identification of previously unrecognized host interactions. As spirochetal survival in the bloodstream is essential for dissemination, we targeted our screen to C1, the first component of the classical (antibody-initiated) complement pathway. We identified two high-affinity C1 interactions by the paralogous lipoproteins, ElpB and ElpQ (also termed ErpB and ErpQ, respectively). Using biochemical, microbiological, and biophysical approaches, we demonstrate that ElpB and ElpQ bind the activated forms of the C1 proteases, C1r and C1s, and represent a distinct mechanistic class of C1 inhibitors that protect the spirochete from antibody-mediated complement killing. In addition to identifying a mode of complement inhibition, our study establishes a lipoproteome screening methodology as a discovery platform for identifying direct host­pathogen interactions that are central to the pathogenesis of spirochetes, such as the Lyme disease agent.

Preserved Metacognition for Undetected Visuomotor Deviations.

Humans can successfully correct deviations of movements without conscious detection of such deviations, suggesting limited awareness of movement details. We ask whether such limited awareness impairs confidence (metacognition). We recorded functional magnetic resonance imaging data while 31 human female and male participants detected cursor deviations during a visuomotor reaching task and rated their confidence retrospectively. We show that participants monitor a summary statistic of the unfolding visual feedback (the peak cursor error) to detect visuomotor deviations and adjust their confidence ratings, even when they report being unaware of a deviation. Crucially, confidence ratings were as metacognitively efficient for aware and unaware deviations. At the neural level, activity in the ventral striatum tracks high confidence, whereas a broad network encodes cursor error but not confidence. These findings challenge the notion of limited conscious action monitoring and uncover how humans monitor their movements as they unfold, even when unaware of ongoing deviations.SIGNIFICANCE STATEMENT We are unaware of the small corrections we apply to our movements as long as our goals are achieved. Here, although we replicate the finding that participants deny perceiving small deviations they correct, we show that their confidence reliably reflects the presence or absence of a deviation. This observation shows they can metacognitively monitor the presence of a deviation, even when they deny perceiving it. We also describe the hemodynamic correlates of confidence ratings. Our study questions the extent to which humans are unaware of the details of their movements; describes a plausible mechanism for metacognition in a visuomotor task, along with its neural correlates; and has important implications for the construction of the sense of self.

VlsE, the nexus for antigenic variation of the Lyme disease spirochete, also mediates early bacterial attachment to the host microvasculature under shear force.

Hematogenous dissemination is a critical step in the evolution of local infection to systemic disease. The Lyme disease (LD) spirochete, which efficiently disseminates to multiple tissues, has provided a model for this process, in particular for the key early event of pathogen adhesion to the host vasculature. This occurs under shear force mediated by interactions between bacterial adhesins and mammalian cell-surface proteins or extracellular matrix (ECM). Using real-time intravital imaging of the Lyme spirochete in living mice, we previously identified BBK32 as the first LD spirochetal adhesin demonstrated to mediate early vascular adhesion in a living mouse; however, deletion of bbk32 resulted in loss of only about half of the early interactions, suggesting the existence of at least one other adhesin (adhesin-X) that promotes early vascular interactions. VlsE, a surface lipoprotein, was identified long ago by its capacity to undergo rapid antigenic variation, is upregulated in the mammalian host and required for persistent infection in immunocompetent mice. In immunodeficient mice, VlsE shares functional overlap with OspC, a multi-functional protein that displays dermatan sulfate-binding activity and is required for joint invasion and colonization. In this research, using biochemical and genetic approaches as well as intravital imaging, we have identified VlsE as adhesin-X; it is a dermatan sulfate (DS) adhesin that efficiently promotes transient adhesion to the microvasculature under shear force via its DS binding pocket. Intravenous inoculation of mice with a low-passage infectious B. burgdorferi strain lacking both bbk32 and vlsE almost completely eliminated transient microvascular interactions. Comparative analysis of binding parameters of VlsE, BBK32 and OspC provides a possible explanation why these three DS adhesins display different functionality in terms of their ability to promote early microvascular interactions.

Disentangling the origins of confidence in speeded perceptual judgments through multimodal imaging.

The human capacity to compute the likelihood that a decision is correct-known as metacognition-has proven difficult to study in isolation as it usually cooccurs with decision making. Here, we isolated postdecisional from decisional contributions to metacognition by analyzing neural correlates of confidence with multimodal imaging. Healthy volunteers reported their confidence in the accuracy of decisions they made or decisions they observed. We found better metacognitive performance for committed vs. observed decisions, indicating that committing to a decision may improve confidence. Relying on concurrent electroencephalography and hemodynamic recordings, we found a common correlate of confidence following committed and observed decisions in the inferior frontal gyrus and a dissociation in the anterior prefrontal cortex and anterior insula. We discuss these results in light of decisional and postdecisional accounts of confidence and propose a computational model of confidence in which metacognitive performance naturally improves when evidence accumulation is constrained upon committing a decision.

Increased Functional Connectivity of the Intraparietal Sulcus Underlies the Attenuation of Numerosity Estimations for Self-Generated Words.

Previous studies have shown that self-generated stimuli in auditory, visual, and somatosensory domains are attenuated, producing decreased behavioral and neural responses compared with the same stimuli that are externally generated. Yet, whether such attenuation also occurs for higher-level cognitive functions beyond sensorimotor processing remains unknown. In this study, we assessed whether cognitive functions such as numerosity estimations are subject to attenuation in 56 healthy participants (32 women). We designed a task allowing the controlled comparison of numerosity estimations for self-generated (active condition) and externally generated (passive condition) words. Our behavioral results showed a larger underestimation of self-generated compared with externally generated words, suggesting that numerosity estimations for self-generated words are attenuated. Moreover, the linear relationship between the reported and actual number of words was stronger for self-generated words, although the ability to track errors about numerosity estimations was similar across conditions. Neuroimaging results revealed that numerosity underestimation involved increased functional connectivity between the right intraparietal sulcus and an extended network (bilateral supplementary motor area, left inferior parietal lobule, and left superior temporal gyrus) when estimating the number of self-generated versus externally generated words. We interpret our results in light of two models of attenuation and discuss their perceptual versus cognitive origins.SIGNIFICANCE STATEMENT We perceive sensory events as less intense when they are self-generated compared with when they are externally generated. This phenomenon, called attenuation, enables us to distinguish sensory events from self and external origins. Here, we designed a novel fMRI paradigm to assess whether cognitive processes such as numerosity estimations are also subject to attenuation. When asking participants to estimate the number of words they had generated or passively heard, we found bigger underestimation in the former case, providing behavioral evidence of attenuation. Attenuation was associated with increased functional connectivity of the intraparietal sulcus, a region involved in numerosity processing. Together, our results indicate that the attenuation of self-generated stimuli is not limited to sensory consequences but is also impact cognitive processes such as numerosity estimations.

Confidence in visual motion discrimination is preserved in individuals with schizophrenia.

BACKGROUND: Metacognition is the set of reflexive processes that allows humans to evaluate the accuracy of their mental operations. Metacognitive deficits have been described in people with schizophrenia using mostly narrative assessment, and they have been linked to several key symptoms. METHODS: We assessed metacognitive performance objectively by asking people with schizophrenia or schizoaffective disorder (n = 20) and matched healthy participants (n = 21) to perform a visual discrimination task and report their confidence in their performance. Metacognitive performance was defined as the adequacy between visual discrimination performance and confidence. RESULTS: Bayesian analyses revealed equivalent metacognitive performance in the 2 groups, despite a weaker association between confidence and trajectory tracking during task execution among people with schizophrenia. We reproduced these results using an evidence accumulation model, which showed similar decisional processes in the 2 groups. LIMITATIONS: These results from a relatively small study sample cannot be generalized to other perceptual and nonperceptual tasks. To meet this purpose, ecological tasks are needed. As well, the role of antipsychotic medication and design deserves greater attention in the future. CONCLUSION: We found similar decisional and metacognitive capabilities between people with schizophrenia and healthy controls in a visual discrimination task.

Improved Aerodynamics of a Hollow-Blade Axial Flow Fan by Controlling the Leakage Flow Rate by Air Injection at the Rotating Shroud.

Axial flow fans are used in many fields in order to ensure the mass and heat transfer from air, chiefly in the heating, ventilation and air conditioning industry (HVAC). A more proper understanding of the airflow behavior through the systems is necessary to manage and optimize the fan operation. Computational fluid dynamics (CFD) represents a real tool providing the ability to access flow structures in areas that measuring equipment cannot reach. Reducing the leakage flow rate, inherent in operation, by synthetic-jet techniques improves performance. This paper presents the CFD results performed on a hollow blade fan developed by our team. The leakage flow is controlled by blowing air from 16 designated circular holes and arranged on the fan shroud. We discuss the results for two rotational speeds (1000 and 2000 rpm) and two injection rates (400 and 800 L/min). The numerical results consistent with the experimental show, for the low rotation speed and high injection ratio, significant gains in power (53%), torque (80%) and leakage flow rate (80%).

Real-time EEG Feedback on Alpha Power Lateralization Leads to Behavioral Improvements in a Covert Attention Task.

Visual attention can be spatially oriented, even in the absence of saccadic eye-movements, to facilitate the processing of incoming visual information. One behavioral proxy for this so-called covert visuospatial attention (CVSA) is the validity effect (VE): the reduction in reaction time (RT) to visual stimuli at attended locations and the increase in RT to stimuli at unattended locations. At the electrophysiological level, one correlate of CVSA is the lateralization in the occipital [Formula: see text]-band oscillations, resulting from [Formula: see text]-power increases ipsilateral and decreases contralateral to the attended hemifield. While this [Formula: see text]-band lateralization has been considerably studied using electroencephalography (EEG) or magnetoencephalography (MEG), little is known about whether it can be trained to improve CVSA behaviorally. In this cross-over sham-controlled study we used continuous real-time feedback of the occipital [Formula: see text]-lateralization to modulate behavioral and electrophysiological markers of covert attention. Fourteen subjects performed a cued CVSA task, involving fast responses to covertly attended stimuli. During real-time feedback runs, trials extended in time if subjects reached states of high [Formula: see text]-lateralization. Crucially, the ongoing [Formula: see text]-lateralization was fed back to the subject by changing the color of the attended stimulus. We hypothesized that this ability to self-monitor lapses in CVSA and thus being able to refocus attention accordingly would lead to improved CVSA performance during subsequent testing. We probed the effect of the intervention by evaluating the pre-post changes in the VE and the [Formula: see text]-lateralization. Behaviorally, results showed a significant interaction between feedback (experimental-sham) and time (pre-post) for the validity effect, with an increase in performance only for the experimental condition. We did not find corresponding pre-post changes in the [Formula: see text]-lateralization. Our findings suggest that EEG-based real-time feedback is a promising tool to enhance the level of covert visuospatial attention, especially with respect to behavioral changes. This opens up the exploration of applications of the proposed training method for the cognitive rehabilitation of attentional disorders.

A non-randomised trial of video and written educational adjuncts in undergraduate ophthalmology.

BACKGROUND: Provision of relevant pre-learning materials has been shown to increase student engagement and improve outcomes in medical education. This non-randomised study attempts to quantify the educational gains, and relative efficacy of video and written pre-learning materials, in ophthalmology undergraduate teaching. METHODS: Ninety-eight final year medical students were contacted prior to their three-day ophthalmology placements at a British tertiary ophthalmology unit. All participants were sent welcome packs prior to arrival requesting they undertake 90 min of work focusing on a list of specified ophthalmic conditions. One cohort (N = 33) were sent written materials, another (N = 32) was provided with video materials and a third cohort (N = 33) were not sent any materials. On arrival participants completed a simple knowledge test, a questionnaire estimating the time they spent preparing for the placement and a self-reported knowledge score. The teaching on placement was the same for all cohorts. At the conclusion of each placement participants completed a challenging knowledge test, a clinical skills test and repeated self-reported knowledge scores. RESULTS: Eighty seven percent of students receiving specified materials claimed to complete pre-placement work compared to 70% of those receiving learning outcomes alone (p = 0.05). Students receiving learning materials scored higher in the post-placement tests of knowledge (p < 0.001), 74.8% (72.4-77.2%) vs 63.6% (95%CI 59.3-67.9%) and skills (p = 0.04), 86.9% (83.9-89.9%) vs 81.3% (77.2-85.4%). Students using video resources outperformed students using written materials in their visual acuity assessment test (p = 0.03), 90.4% (86.6-94.2%) vs 83.6% (80.1-87.1%) whilst those receiving written rather than video material performed better in the end of placement knowledge test (p = 0.03), 77.7% (74.3-81.1%) vs 72.0% (68.9-75.1%). CONCLUSION: This study showed that providing pre-placement learning materials improves undergraduates' commitment and achievement. Written materials better facilitate knowledge acquisition while video materials preferentially promote skill acquisition. This is a novel demonstration within ophthalmology and can help address the imbalance between the expectations placed on undergraduates and the resources committed to ensuring they are met.

Sensory threshold neuromuscular electrical stimulation fosters motor imagery performance.

Motor imagery (MI) has been largely studied as a way to enhance motor learning and to restore motor functions. Although it is agreed that users should emphasize kinesthetic imagery during MI, recordings of MI brain patterns are not sufficiently reliable for many subjects. It has been suggested that the usage of somatosensory feedback would be more suitable than standardly used visual feedback to enhance MI brain patterns. However, somatosensory feedback should not interfere with the recorded MI brain pattern. In this study we propose a novel feedback modality to guide subjects during MI based on sensory threshold neuromuscular electrical stimulation (St-NMES). St-NMES depolarizes sensory and motor axons without eliciting any muscular contraction. We hypothesize that St-NMES does not induce detectable ERD brain patterns and fosters MI performance. Twelve novice subjects were included in a cross-over design study. We recorded their EEG, comparing St-NMES with visual feedback during MI or resting tasks. We found that St-NMES not only induced significantly larger desynchronization over sensorimotor areas (p<0.05) but also significantly enhanced MI brain connectivity patterns. Moreover, classification accuracy and stability were significantly higher with St-NMES. Importantly, St-NMES alone did not induce detectable artifacts, but rather the changes in the detected patterns were due to an increased MI performance. Our findings indicate that St-NMES is a promising feedback in order to foster MI performance and cold be used for BMI online applications.

Human EEG reveals distinct neural correlates of power and precision grasping types.

Hand grasping is a sophisticated motor task that has received much attention by the neuroscientific community, which demonstrated how grasping activates a network involving parietal, pre-motor and motor cortices using fMRI, ECoG, LFPs and spiking activity. Yet, there is a need for a more precise spatio-temporal analysis as it is still unclear how these brain activations over large cortical areas evolve at the sub-second level. In this study, we recorded ten human participants (1 female) performing visually-guided, self-paced reaching and grasping with precision or power grips. Following the results, we demonstrate the existence of neural correlates of grasping from broadband EEG in self-paced conditions and show how neural correlates of precision and power grasps differentially evolve as grasps unfold. 100 ms before the grasp is secured, bilateral parietal regions showed increasingly differential patterns. Afterwards, sustained differences between both grasps occurred over the bilateral motor and parietal regions, and medial pre-frontal cortex. Furthermore, these differences were sufficiently discriminable to allow single-trial decoding with 70% decoding performance. Functional connectivity revealed differences at the network level between grasps in fronto-parietal networks, in terms of upper-alpha cortical oscillatory power with a strong involvement of ipsilateral hemisphere. Our results supported the existence of fronto-parietal recurrent feedback loops, with stronger interactions for precision grips due to the finer motor control required for this grasping type.

Rifapentine-proliposomes for inhalation: in vitro and in vivo toxicity.

BACKGROUND: Oral therapy for pulmonary tuberculosis (TB) treatment suffers from the limitation of hepatic metabolism leading insufficient concentration of antitubercular (anti-TB) drugs in alveolar macrophage which harbors Mycobacterium tuberculosis (MTB). Targeted aerosol delivery of antituberculous drug to lung is efficient for treating local lung TB infection. OBJECTIVE: The present study was aimed to evaluate rifapentine (RPT) loaded proliposomal dry powder for inhalation (RLDPI) for anti-TBactivity and cytotoxicity in vitro. In vivo toxicity study was also undertaken in Wistar rats to determine safe concentration of RLDPI for administration. MATERIALS AND METHODS: Anti-TB activity of developed RLDPI was assessed using drug susceptibility testing (DST) on Mycobacteria growth indicator tube (MGIT) method. In vitro cytotoxicity was performed in A549 cell lines and IC50 values were used to compare the cytotoxicity of formulation with pure RPT. In vivo repeated dose toxicity study was undertaken using Wistar rats at three different doses for 28-days by intratracheal insufflations method. RESULTS: The results of DST study revealed sensitivity of tubercle bacteria to RLDPI at concentration equivalent to 10 µg/mL of RPT. This study confirmed anti-TB potential of RPT in spray-dried RLDPI, though the spray drying method is reported to reduce activity of drugs. Cytotoxicity study in A549 cells demonstrated that RPT when encapsulated in liposomes as RLDPI was safe to cells as compared to pure RPT. In vivo toxicity study revealed that RPT in the form of RLDPI was safe at 1 and 5 mg/kg dose. However, mortality was seen at higher dose (10 mg/kg), possibly because of liver and kidney damage. CONCLUSION: Thus, these studies demonstrated safety of RLDPI for the treatment of pulmonary TB.

Prior information differentially affects discrimination decisions and subjective confidence reports.

According to Bayesian models, both decisions and confidence are based on the same precision-weighted integration of prior expectations ("priors") and incoming information ("likelihoods"). This assumes that priors are integrated optimally and equally in decisions and confidence, which has not been tested. In three experiments, we quantify how priors inform decisions and confidence. With a dual-decision task we create pairs of conditions that are matched in posterior information, but differ on whether the prior or likelihood is more informative. We find that priors are underweighted in discrimination decisions, but are less underweighted in confidence about those decisions, and this is not due to differences in processing time. The same patterns remain with exogenous probabilistic cues as priors. With a Bayesian model we quantify the weighting parameters for the prior at both levels, and find converging evidence that priors are more optimally used in explicit confidence, even when underused in decisions.

Preserved electrophysiological markers of confidence in schizophrenia spectrum disorder.

A large number of behavioral studies suggest that confidence judgments are impaired in schizophrenia, motivating the search for neural correlates of an underlying metacognitive impairment. Electrophysiological studies suggest that a specific evoked response potential reflecting performance monitoring, namely the error-related negativity (ERN), is blunted in schizophrenia compared to healthy controls. However, attention has recently been drawn to a potential confound in the study of metacognition, namely that lower task-performance in schizophrenia compared to healthy controls involves a decreased index of metacognitive performance (where metacognitive performance is construed as the ability to calibrate one's confidence relative to response correctness), independently of metacognitive abilities among patients. Here, we assessed how this confound might also apply to ERN-blunting in schizophrenia. We used an adaptive staircase procedure to titrate task-performance on a motion discrimination task in which participants (N = 14 patients and 19 controls) had to report their confidence after each trial while we recorded high density EEG. Interestingly, not only metaperceptual abilities were preserved among patients at the behavioral level, but contrary to our hypothesis, we also found no electrophysiological evidence for altered EEG markers of performance monitoring. These results bring additional evidence suggesting an unaltered ability to monitor perceptual performance on a trial by trial basis in schizophrenia.

Confidence in visual detection, familiarity and recollection judgments is preserved in schizophrenia spectrum disorder.

An effective way to quantify metacognitive performance is to ask participants to estimate their confidence in the accuracy of their response during a cognitive task. A recent meta-analysis1 raised the issue that most assessments of metacognitive performance in schizophrenia spectrum disorders may be confounded with cognitive deficits, which are known to be present in this population. Therefore, it remains unclear whether the reported metacognitive deficits are metacognitive in nature or rather inherited from cognitive deficits. Arbitrating between these two possibilities requires equating task performance between experimental groups. Here, we aimed to characterize metacognitive performance among individuals with schizophrenia across three tasks (visual detection, familiarity, recollection) using a within-subject design while controlling experimentally for intra-individual task performance and statistically for between-subject task performance. In line with our hypotheses, we found no metacognitive deficit for visual detection and familiarity judgments. While we expected metacognition for recollection to be specifically impaired among individuals with schizophrenia, we found evidence in favor of an absence of a deficit in that domain also. We found no specific metacognitive deficit in schizophrenia spectrum disorder in the visual or memory domain. The clinical relevance of our findings is discussed in light of a hierarchical framework of metacognition.

Chemoprevention of mouse lung and colon tumors by suberoylanilide hydroxamic acid and atorvastatin.

Atorvastatin and suberoylanilide hydroxamic acid (SAHA) were evaluated for chemoprevention of mouse lung tumors. In Experiment 1, lung tumors were induced by vinyl carbamate in strain A/J mice followed by 500 mg/kg SAHA, 60 or 180 mg/kg atorvastatin, and combinations containing SAHA and atorvastatin administered in their diet. SAHA and both combinations, but not atorvastatin, decreased the multiplicity of lung tumors, including large adenomas and adenocarcinomas with the combinations demonstrating the greatest efficacy. In Experiment 2, lung tumors were induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol in strain A/J mice followed by 180 mg/kg atorvastatin, 500 mg/kg SAHA, or both drugs administered in the diet. SAHA and the combination of both drugs, but not atorvastatin alone, decreased the multiplicity of lung tumors and large tumors, with the combination demonstrating greater efficacy. In Experiment 3, lung tumors were induced by 1,2-dimethylhydrazine in Swiss-Webster mice followed by 160 mg/kg atorvastatin, 400 mg/kg SAHA, or a combination of both drugs administered in the diet. SAHA and the combination, but not atorvastatin, decreased the multiplicity of lung tumors with the combination demonstrating greater efficacy. The multiplicity of colon tumors was decreased by SAHA, atorvastatin, and the combination, without any significant difference in their efficacy. mRNA expression analysis of lung tumor bearing mice suggested that the enhanced chemopreventive activity of the combination is related to atorvastatin modulation of DNA repair, SAHA modulation of angiogenesis, and both drugs modulating invasion and metastasis pathways. Atorvastatin demonstrated chemoprevention activity as indicated by the enhancement of the efficacy of SAHA to prevent mouse lung tumors.

A leaky evidence accumulation process for perceptual experience.

The neural correlates supporting our perceptual experience of the world remain largely unknown. Recent studies have shown how stimulus detection and related confidence involve evidence accumulation (EA) processes similar to those involved in perceptual decision-making. Here, we propose that independently from any tasks, percepts are not static but fade in and out of consciousness according to the dynamics of a leaky evidence accumulation process (LEAP), and that confidence corresponds to the maximal evidence accumulated by this process. We discuss the implications and limitations of our proposal, assess how it may qualify as a neural correlate of consciousness, and illustrate how it brings us closer to a mechanistic understanding of phenomenal aspects of perceptual experience like intensity and duration, beyond mere detection.