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Infections with multidrug-resistant bacteria pose a major healthcare problem which urges the need for novel treatment options. Besides its potent antiplatelet properties, ticagrelor has antibacterial activity against Gram-positive bacteria, including methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). Several retrospective studies in cardiovascular patients support an antibacterial effect of this drug which is not related to its antiplatelet activity. We investigated the mechanism of action of ticagrelor in Staphylococcus aureus and model Bacillus subtilis, and assessed cross-resistance with two conventional anti-MRSA antibiotics, vancomycin and daptomycin. Bacillus subtilis bioreporter strains revealed ticagrelor-induced cell envelope-related stress responses. Sub-inhibitory drug concentrations caused membrane depolarization, impaired positioning of both the peripheral membrane protein MinD and the peptidoglycan precursor lipid II, and it affected cell shape. At the MIC, ticagrelor destroyed membrane integrity, indicated by the influx of membrane impermeable dyes, and lipid aggregate formation. Whole-genome sequencing of in vitro-generated ticagrelor-resistant MRSA clones revealed mutations in genes encoding ClpP, ClpX, and YjbH. Lipidomic analysis of resistant clones displayed changes in levels of the most abundant lipids of the Staphylococcus aureus membrane, for example, cardiolipins, phosphatidylglycerols, and diacylglycerols. Exogeneous cardiolipin, phosphatidylglycerol, or diacylglycerol antagonized the antibacterial properties of ticagrelor. Ticagrelor enhanced MRSA growth inhibition and killing by vancomycin and daptomycin in both exponential and stationary phases. Finally, no cross-resistance was observed between ticagrelor and daptomycin, or vancomycin. Our study demonstrates that ticagrelor targets multiple lipids in the cytoplasmic membrane of Gram-positive bacteria, thereby retaining activity against multidrug-resistant staphylococci including daptomycin- and vancomycin-resistant strains.IMPORTANCEInfections with multidrug-resistant bacteria pose a major healthcare problem with an urgent need for novel treatment options. The antiplatelet drug ticagrelor possesses antibacterial activity against Gram-positive bacteria including methicillin-resistant and vancomycin-resistant Staphylococcus aureus strains. We report a unique, dose-dependent, antibacterial mechanism of action of ticagrelor, which alters the properties and integrity of the bacterial cytoplasmic membrane. Ticagrelor retains activity against multidrug-resistant staphylococci, including isolates carrying the most common in vivo selected daptomycin resistance mutations and vancomycin-intermediate Staphylococcus aureus. Our data support the use of ticagrelor as adjunct therapy against multidrug-resistant strains. Because of the presence of multiple non-protein targets of this drug within the bacterial membrane, resistance development is expected to be slow. All these findings corroborate the accumulating observational clinical evidence for a beneficial anti-bacterial effect of ticagrelor in cardiovascular patients in need of such treatment.

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Vocal emotion recognition (VER) in natural speech, often referred to as speech emotion recognition (SER), remains challenging for both humans and computers. Applied fields including clinical diagnosis and intervention, social interaction research or Human Computer Interaction (HCI) increasingly benefit from efficient VER algorithms. Several feature sets were used with machine-learning (ML) algorithms for discrete emotion classification. However, there is no consensus for which low-level-descriptors and classifiers are optimal. Therefore, we aimed to compare the performance of machine-learning algorithms with several different feature sets. Concretely, seven ML algorithms were compared on the Berlin Database of Emotional Speech: Multilayer Perceptron Neural Network (MLP), J48 Decision Tree (DT), Support Vector Machine with Sequential Minimal Optimization (SMO), Random Forest (RF), k-Nearest Neighbor (KNN), Simple Logistic Regression (LOG) and Multinomial Logistic Regression (MLR) with 10-fold cross validation using four openSMILE feature sets (i.e., IS-09, emobase, GeMAPS and eGeMAPS). Results indicated that SMO, MLP and LOG show better performance (reaching to 87.85%, 84.00% and 83.74% accuracies, respectively) compared to RF, DT, MLR and KNN (with minimum 73.46%, 53.08%, 70.65% and 58.69% accuracies, respectively). Overall, the emobase feature set performed best. We discuss the implications of these findings for applications in diagnosis, intervention or HCI.

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Since COVID-19 has become a pandemic, everyday life has seen dramatic changes affecting individuals, families, and children with and without autism. Among other things, these changes entail more time at home, digital forms of communication, school closures, and reduced support and intervention. Here, we assess the effects of the pandemic on quality of life for school-age autistic and neurotypical children and adolescents. First, we provide a comprehensive review of the current relevant literature. Next, we report original data from a survey conducted in several countries, assessing activities, well-being, and social life in families with autism, and their changes over time. We focus on differences between children with and without autism from within the same families, and on different outcomes for children with high- or low-functioning autism. While individuals with autism scored lower in emotional and social functioning than their neurotypical siblings, both groups of children showed comparable decreases in well-being and increases in anxiety, compared to before the pandemic. By contrast, decreases in adaptability were significantly more pronounced in autistic children and adolescents compared to neurotypical children and adolescents. Overall, although individual families reported some positive effects of pandemic restrictions, our data provide no evidence that these generalize across children and adolescents with autism, or even just to individuals with high-functioning autism. We discuss the increased challenges that need to be addressed to protect children and adolescents' well-being under pandemic conditions, but also point out potentials in the present situation that could be used towards social participation and success in older children and young adults with autism.

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BACKGROUND: ABO antibody titres are important in many clinical decisions; however, much variability is observed in titre results. For reliable and reproducible titre results, automated ABO titration methods have been developed. In this 10-site study, we evaluated the equivalency of the automated ABO titration assays on the Galileo NEO, a fully automated blood bank analyzer (Immucor, Inc.) to manual titration with gel Column Agglutination Technology (CAT), as well as the reproducibility of both methods. MATERIALS AND METHODS: Ten different locations participated in this study. The equivalency study included 70 random samples at each site. The reproducibility study tested the same blinded 30-sample panel at each study site. Anti-A and anti-B IgM and IgG antibody titres were tested with both the automated and manual methods; additionally, dithiothreitol (DTT) treatment was used to inactivate IgM antibodies in the manual CAT method. RESULTS: The equivalency between CAT manual method and Galileo NEO automated titres at each site ranged from 38 to 88%; equivalency for each isotype was 66.2% for IgM, 60.6% for IgG, and 88.5% for DTT-treated IgG. The reproducibility study evaluated the titre variation of each sample obtained from the 10 sites. The average titre ranges (in doubling dilutions) for the automated and manual methods, respectively, were 2.15±1.0 and 4.03±1.8 for IgM, and 1.53±0.7 and 4.10±1.9 for IgG; for the manual DTT-treated IgG, the average titre range was 3.45±1.8 doubling dilutions. DISCUSSION: The results demonstrated that the Galileo NEO automated and manual CAT ABO titres are not equivalent. However, the study also demonstrated that titre reproducibility is enhanced with the Galileo NEO automated ABO titration assays relative to the manual CAT ABO titration method. Therefore, to improve management of patients receiving care across multiple institutions, our study supports the use of automated ABO titration.

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The present study sought to use a paradigm that allows the study of mental representations of observed actions. We investigated whether retrieval of observationally acquired stimulus-response bindings are impaired in participants with high (compared with low) autistic traits. In an extreme group comparison, participants with high versus low autistic traits worked through an observational SR binding and a standard SR binding task (to control for general deficits in cognitive performance). As expected, groups did not differ with regard to retrieval of transient bindings between stimuli and self-performed responses (standard SR binding & retrieval effects). Against our expectations, the same was true for the retrieval of observationally acquired SR bindings, which was of comparable magnitude in both high and low autistic trait groups. Bayes Factor analysis indicates that our evidence for this null finding has to be regarded as weak evidence. Our findings provide tentative evidence against the view that imitative effects are reduced (hypo-imitation) or increased (hyper-imitation) when autistic trait expression is high. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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Posed facial expressions of actors have often been used as stimuli to induce mental state inferences, in order to investigate 'Theory of Mind' processes. However, such stimuli make it difficult to determine whether perceivers are using a basic or more elaborated mentalizing strategy. The current study used as stimuli covert recordings of target individuals who viewed various emotional expressions, which caused them to spontaneously mimic these expressions. Perceivers subsequently judged these subtle emotional expressions of the targets: in one condition ('classification') participants were instructed to classify the target's expression (i.e. match it to a sample) and in another condition ('retrodicting') participants were instructed to retrodict (i.e. infer which emotional expression the target was viewing). When instructed to classify, participants showed more prevalent activations in event-related brain potentials (ERPs) at earlier and mid-latency ERP components N170, P200 and P300-600. By contrast, when instructed to retrodict participants showed enhanced late frontal and fronto-temporal ERPs (N800-1000), with more sustained activity over the right than the left hemisphere. These findings reveal different cortical processes involved when retrodicting about a facial expression compared to merely classifying it, despite comparable performance on the behavioral task.

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Recently, theory-of-mind research has been revolutionized by findings from novel implicit tasks suggesting that at least some aspects of false-belief reasoning develop earlier in ontogeny than previously assumed and operate automatically throughout adulthood. Although these findings are the empirical basis for far-reaching theories, systematic replications are still missing. This article reports a preregistered large-scale attempt to replicate four influential anticipatory-looking implicit theory-of-mind tasks using original stimuli and procedures. Results showed that only one of the four paradigms was reliably replicated. A second set of studies revealed, further, that this one paradigm was no longer replicated once confounds were removed, which calls its validity into question. There were also no correlations between paradigms, and thus, no evidence for their convergent validity. In conclusion, findings from anticipatory-looking false-belief paradigms seem less reliable and valid than previously assumed, thus limiting the conclusions that can be drawn from them.

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In a qualitative study, 119 women completed an online, open-ended survey about their childbirth experiences. In response to the question, "What ways, if any, did you experience failure?," 65% of women identified feelings of failure. Overwhelmingly attributing the failures to themselves, participants reported that they experienced failures of mind, body, action/inaction, representing "what I feel," "who I am," and "what I did or didn't do" and leading some participants to conclude that they were "less of woman," "less of a mother," or ultimately failed the baby. Such perceived failures can be unintentionally perpetuated by a system that neglects to address the complex experiences and interpretations of birthing women. Helping women anticipate and process the psychosocial and emotional aspects of the birth experience may serve as a protective factor against women internalizing perceived failures as their own, and preventing long term consequences of such feelings. The findings of this study highlight the importance of assessing women's personal experiences and interpretations of childbirth during the prenatal phase to address expectations and increase preparedness.

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Faces of one's own-age group are easier to recognize than other-age faces. Using behavioral measures and EEG, we studied whether an own-age bias (OAB) also exists in voice memory. Young (19 - 26 years) and old (60-75 years) participants studied young (18-25 years) and old (60-77 years) unfamiliar voices from short sentences. Subsequently, they classified studied and novel voices as "old" (i.e. studied) or "new", from the same sentences. Recognition performance was higher in young compared to old participants, and for old compared to young voices, with no OAB. At the same time, we found evidence for higher distinctiveness of old compared to young voices, both in terms of acoustic measures and subjective ratings (independent of rater age). Analyses of event-related brain potentials (ERPs) indicated more negative-going deflections (400-1000ms) for old compared to young voices in young participants. In old participants, we observed a reversed OLD/NEW memory effect, with overall more positive amplitudes for novel compared to studied old (but not young) voices (400-1000ms). Time-frequency analyses revealed less beta power (16-26Hz) for young compared to old voices at left anterior sites, and also reduced beta power for correctly recognized studied (compared to novel) voices at left posterior sites (300-900ms). These findings could suggest an engagement of cortical areas during stimulus-specific recollection from about 300ms, in a task that emphasized the analysis of individual acoustic features.

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Recent multinational disease outbreaks demonstrate the risk of disease spreading globally before public health systems can respond to an event. To ensure global health security, countries need robust multisectoral systems to rapidly detect and respond to domestic or imported communicable diseases. The US Centers for Disease Control and Prevention International Border Team works with the governments of Nigeria, Togo, and Benin, along with Pro-Health International and the Abidjan-Lagos Corridor Organization, to build sustainable International Health Regulations capacities at points of entry (POEs) and along border regions. Together, we strengthen comprehensive national and regional border health systems by developing public health emergency response plans for POEs, conducting qualitative assessments of public health preparedness and response capacities at ground crossings, integrating internationally mobile populations into national health surveillance systems, and formalizing cross-border public health coordination. Achieving comprehensive national and regional border health capacity, which advances overall global health security, necessitates multisectoral dedication to the aforementioned components.

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This case study is adapted from events that occurred along the Sierra Leone and Guinea land border during the 2014-2016 Ebola epidemic in West Africa. The response activities involved Sierra Leone and Guinea officials, along with assistance from U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organisation (WHO). This case study builds upon an understanding of basic surveillance systems and outbreak response activities. Through this exercise, students will understand how to incorporate communication and coordination into surveillance and response efforts with counterparts across the border in neighbouring countries. This integration is important to reduce the spread of communicable diseases between neighbouring countries. The time required to complete this case study is 2-3 hours.

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Humans rely on their ability to infer another person's mental state to understand and predict others' behavior ("theory of mind," ToM). Multiple lines of research suggest that not only are humans able to consciously process another person's belief state, but also are able to do so implicitly. Here we explored how general implicit belief states are represented in the brain, compared to those substrates involved in explicit ToM processes. Previous work on this topic has yielded conflicting results, and thus, the extent to which the implicit and explicit ToM systems draw on common neural bases is unclear. Participants were presented with "Sally-Anne" type movies in which a protagonist was falsely led to believe a ball was in one location, only for a puppet to later move it to another location in their absence (false-belief condition). In other movies, the protagonist had their back turned the entire time the puppet moved the ball between the two locations, meaning that they had no opportunity to develop any pre-existing beliefs about the scenario (no-belief condition). Using a group of independently localized explicit ToM brain regions, we found greater activity for false-belief trials, relative to no-belief trials, in the right temporoparietal junction, right superior temporal sulcus, precuneus, and left middle prefrontal gyrus. These findings extend upon previous work on the neural bases of implicit ToM by showing substantial overlap between this system and the explicit ToM system, suggesting that both abilities might recruit a common set of mentalizing processes/functional brain regions. Hum Brain Mapp 38:4760-4772, 2017. © 2017 Wiley Periodicals, Inc.

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We have proposed that the ancient ribosome increased in size during early evolution by addition of small folding-competent RNAs. In this Accretion Model, small RNAs and peptides were subsumed onto subunit surfaces, gradually encasing and freezing previously acquired components. The model predicts that appropriate rRNA fragments have inherited local autonomy of folding and local autonomy of assembly with ribosomal proteins (rProteins), and that the rProtein and rRNA are co-chaperones. To test these predictions, we investigate the rRNA interactions of rProtein uL23 and its tail, uL23tail, which is a ß-hairpin that penetrates deep into the core of the large ribosomal subunit. In the assembled ribosome, uL23tail associates with Domain III of the rRNA and a subdomain called "DIIIcore". Here using band shift assays, fluorescence Job plots, and yeast three-hybrid assays, we investigate the interactions of rProtein uL23 and its tail with Domain III and with DIIIcore rRNA. We observe rRNA1-uL23tail1 complexes in the absence of Mg2+ ions and rRNA1-uL23tailn (n > 1) complexes in the presence of Mg2+ ions. By contrast, the intact uL23 rProtein binds in slightly anticooperative complexes of various stoichiometries. The globular and tail regions of rProtein uL23 are distinctive in their folding behaviors and the ion dependences of their association with rRNA. For the globular region of the rProtein, folding is independent of rRNA, and rRNA association is predominantly by nonelectrostatic mechanisms. For the tail region of the protein, folding requires rRNA, and association is predominantly by electrostatic mechanisms. We believe these protein capabilities could have roots in ancient evolution and could be mechanistically important in co-chaperoning the assembly of the ribosome.

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Theory of Mind (ToM) is thought to play a key role in social information processing as it refers to the ability of individuals to represent the mental states of others (e.g., intentions, desires, beliefs). A provocative hypothesis has been put forward which espouses the existence of two ToM systems: one that is implicit and involves the automatic analysis of the belief states of others and another that is not automatic and is involved in explicitly reasoning about others' mental states. Recently, Phillips et al. (2015) have suggested that there is limited evidence for automatic ToM processing, after identifying a confound in a previous high-profile paper supporting the existence of this cognitive operation in infants and adults (Kovács, Téglás, & Endress, 2010). Here, we take a broader view of the literature and find, contrary to the conclusions of Phillips et al., that there is a substantial body of literature which demonstrates that adult humans are able to engage in unconscious and unintentional, and thus automatic, analyses of others' mental states. However, whether this ability is best described under a one, two or multiple systems ToM account remains to be determined.

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Wu, Sheppard, and Mitchell (Br. J. Psychol., 2016; 107, 1-22) investigate in a fascinating study the fact that adults can detect empathic traits in others after only briefly watching or listening to a person. In this commentary, we highlight how the processes of an efficient, implicit, but inflexible mentalizing system are likely to operate in such situations. Further, we specify how testing signature limits over time-, attribute-, and protagonist-restrictions can help distinguish whether an efficient-implicit or flexible-explicit mentalizing system is of relevance when processing complex social settings.

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There is now considerable evidence that neurotypical individuals track the internal cognitions of others, even in the absence of instructions to do so. This finding has prompted the suggestion that humans possess an implicit mental state tracking system (implicit Theory of Mind, ToM) that exists alongside a system that allows the deliberate and explicit analysis of the mental states of others (explicit ToM). Here we evaluate the evidence for this hypothesis and assess the extent to which implicit and explicit ToM operations are distinct. We review evidence showing that adults can indeed engage in ToM processing even without being conscious of doing so. However, at the same time, there is evidence that explicit and implicit ToM operations share some functional features, including drawing on executive resources. Based on the available evidence, we propose that implicit and explicit ToM operations overlap and should only be considered partially distinct.

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Eye-movement patterns in 'Sally-Anne' tasks reflect humans' ability to implicitly process the mental states of others, particularly false-beliefs - a key theory of mind (ToM) operation. It has recently been proposed that an efficient ToM system, which operates in the absence of awareness (implicit ToM, iToM), subserves the analysis of belief-like states. This contrasts to consciously available belief processing, performed by the explicit ToM system (eToM). The frontal, temporal and parietal cortices are engaged when humans explicitly 'mentalize' about others' beliefs. However, the neural underpinnings of implicit false-belief processing and the extent to which they draw on networks involved in explicit general-belief processing are unknown. Here, participants watched 'Sally-Anne' movies while fMRI and eye-tracking measures were acquired simultaneously. Participants displayed eye-movements consistent with implicit false-belief processing. After independently localizing the brain areas involved in explicit general-belief processing, only the left anterior superior temporal sulcus and precuneus revealed greater blood-oxygen-level-dependent activity for false- relative to true-belief trials in our iToM paradigm. No such difference was found for the right temporal-parietal junction despite significant activity in this area. These findings fractionate brain regions that are associated with explicit general ToM reasoning and false-belief processing in the absence of awareness.

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It has been hypothesized that humans are able to track other's mental states efficiently and without being conscious of doing so using their implicit theory of mind (iToM) system. However, while iToM appears to operate unconsciously recent work suggests it does draw on executive attentional resources (Schneider, Lam, Bayliss, & Dux, 2012) bringing into question whether iToM is engaged efficiently. Here, we examined other aspects relating to automatic processing: The extent to which the operation of iToM is controllable and how it is influenced by behavioral intentions. This was implemented by assessing how task instructions affect eye-movement patterns in a Sally-Anne false-belief task. One group of subjects was given no task instructions (No Instructions), another overtly judged the location of a ball a protagonist interacted with (Ball Tracking) and a third indicated the location consistent with the actor's belief about the ball's location (Belief Tracking). Despite different task goals, all groups' eye-movement patterns were consistent with belief analysis, and the No Instructions and Ball Tracking groups reported no explicit mentalizing when debriefed. These findings represent definitive evidence that humans implicitly track the belief states of others in an uncontrollable and unintentional manner.

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Eye movements during false-belief tasks can reveal an individual's capacity to implicitly monitor others' mental states (theory of mind - ToM). It has been suggested, based on the results of a single-trial-experiment, that this ability is impaired in those with a high-functioning autism spectrum disorder (ASD), despite neurotypical-like performance on explicit ToM measures. However, given there are known attention differences and visual hypersensitivities in ASD it is important to establish whether such impairments are evident over time. In addition, investigating implicit ToM using a repeated trial approach allows an assessment of whether learning processes can reduce the ASD impairment in this ability, as is the case with explicit ToM. Here we investigated the temporal profile of implicit ToM in individuals with ASD and a control group. Despite similar performance on explicit ToM measures, ASD-diagnosed individuals showed no evidence of implicit false-belief tracking even over a one-hour period and many trials, whereas control participants did. These findings demonstrate that the systems involved in implicit and explicit ToM are distinct and hint that impaired implicit false-belief tracking may play an important role in ASD. Further, they indicate that learning processes do not alleviate this impairment across the presentation of multiple trials.

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