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Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity.

Abstract Background Attributions are the processes by which individuals explain the causes of positive and negative events. A maladaptive attributional style has been associated with reduced self-esteem, psychosocial functioning, and mental health. Although many psychosocial interventions target an individual’s attributional style in mental disorders, studies of its alterations in Borderline Personality Disorder (BPD) are sparse. This study aimed to investigate the attributional style in patients with BPD in comparison to healthy control individuals (HC) and its association with self-esteem and psychosocial functioning. Methods The participants (32 patients with a diagnosis of BPD, 32 HC, groups were balanced for sex, age and education) assessed their attributional style in regard to locus of control, stability and globality for positive and negative scenarios. Attributional style was compared between groups and linked to self-reports of self-esteem, loneliness and psychosocial functioning in different social domains while controlling for BPD and depressive symptom severity. Results Individuals diagnosed with BPD reported a maladaptive attributional style for both positive and negative events. This was found to be strongly related with lower self-esteem and higher levels of loneliness, but not with psychosocial dysfunctions assessed in different social domains. The severity of BPD and depressive symptoms did not fully explain the association of attributional style with self-esteem and loneliness. In contrast, correcting for acute psychopathology actually strengthened the relationship between self-esteem and maladaptive inferring causality for positive events. Conclusion The differential association of attributional style for positive and negative events with self-esteem and psychosocial functioning highlights the importance of considering the different facets of inferring causality during psychosocial interventions. Our findings suggest that the significance of cognitive alterations may change with remission of acute BPD and depressive psychopathology, depending on the valence of an event.

Abstract Background Evolution of novelty is a central theme in evolutionary biology, yet studying the origins of traits with an apparently discontinuous origin remains a major challenge. Venom systems are a well-suited model for the study of this phenomenon because they capture several aspects of novelty across multiple levels of biological complexity. However, while there is some knowledge on the evolution of individual toxins, not much is known about the evolution of venom systems as a whole. One way of shedding light on the evolution of new traits is to investigate less specialised serial homologues, i.e. repeated traits in an organism that share a developmental origin. This approach can be particularly informative in animals with repetitive body segments, such as centipedes. Results Here, we investigate morphological and biochemical aspects of the defensive telopodal glandular organs borne on the posterior legs of venomous stone centipedes (Lithobiomorpha), using a multimethod approach, including behavioural observations, comparative morphology, proteomics, comparative transcriptomics and molecular phylogenetics. We show that the anterior venom system and posterior telopodal defence system are functionally convergent serial homologues, where one (telopodal defence) represents a model for the putative early evolutionary state of the other (venom). Venom glands and telopodal glandular organs appear to have evolved from the same type of epidermal gland (four-cell recto-canal type) and while the telopodal defensive secretion shares a great degree of compositional overlap with centipede venoms in general, these similarities arose predominantly through convergent recruitment of distantly related toxin-like components. Both systems are composed of elements predisposed to functional innovation across levels of biological complexity that range from proteins to glands, demonstrating clear parallels between molecular and morphological traits in the properties that facilitate the evolution of novelty. Conclusions The evolution of the lithobiomorph telopodal defence system provides indirect empirical support for the plausibility of the hypothesised evolutionary origin of the centipede venom system, which occurred through functional innovation and gradual specialisation of existing epidermal glands. Our results thus exemplify how continuous transformation and functional innovation can drive the apparent discontinuous emergence of novelties on higher levels of biological complexity.

INTRODUCTION: We are developing the California Cognitive Assessment Battery (CCAB) to provide neuropsychological assessments to patients who lack test access due to cost, capacity, mobility, and transportation barriers. METHODS: The CCAB consists of 15 non-verbal and 17 verbal subtests normed for telemedical assessment. The CCAB runs on calibrated tablet computers over cellular or Wi-Fi connections either in a laboratory or in participants homes. Spoken instructions and verbal stimuli are delivered through headphones using naturalistic text-to-speech voices. Verbal responses are scored in real time and recorded and transcribed offline using consensus automatic speech recognition which combines the transcripts from seven commercial ASR engines to produce timestamped transcripts more accurate than those of any single ASR engine. The CCAB is designed for supervised self-administration using a web-browser application, the Examiner. The Examiner permits examiners to record observations, view subtest performance in real time, initiate video chats, and correct potential error conditions (e.g., training and performance failures, etc.,) for multiple participants concurrently. RESULTS: Here we describe (1) CCAB usability with older (ages 50 to 89) participants; (2) CCAB psychometric properties based on normative data from 415 older participants; (3) Comparisons of the results of at-home vs. in-lab CCAB testing; (4) We also present preliminary analyses of the effects of COVID-19 infection on performance. Mean z-scores averaged over CCAB subtests showed impaired performance of COVID+ compared to COVID- participants after factoring out the contributions of Age, Education, and Gender (AEG). However, inter-cohort differences were no longer significant when performance was analyzed with a comprehensive model that factored out the influences of additional pre-existing demographic factors that distinguished COVID+ and COVID- cohorts (e.g., vocabulary, depression, race, etc.,). In contrast, unlike AEG scores, comprehensive scores correlated significantly with the severity of COVID infection. (5) Finally, we found that scoring models influenced the classification of individual participants with Mild Cognitive Impairment (MCI, z-scores < -1.50) where the comprehensive model accounted for more than twice as much variance as the AEG model and reduced racial bias in MCI classification. DISCUSSION: The CCAB holds the promise of providing scalable laboratory-quality neurodiagnostic assessments to underserved urban, exurban, and rural populations.

IntroductionThe specific role that Broca's area plays in speech and language has been hotly debated in the literature. Some research has pointed to a specific role in particular aspects of speech production, while other findings have suggested additional roles in aspects of language comprehension. In the current study, we had the opportunity to take a broad approach by analyzing lesion and behavioral data from a large cohort of left hemisphere stroke patients. In this brief report, our objective was to identify which speech-language measures show a significant association with Broca's area, specifically pars opercularis and pars triangularis.MethodsLesion site and neuropsychological data from 173 chronic left hemisphere stroke patients were analyzed in the current study. Univariate lesion-symptom mapping (LSM) with rigorous correction was used to identify brain regions associated with individual test performance on a large battery of speech and language tasks. Multivariate LSM analyses were conducted in subsequent runs to confirm findings.ResultsThe LSM results identified many predictable left hemisphere gray and white matter regions significantly associated with the speech-language data, but Broca's area was not implicated in performance on any speech or language measure. Regions adjacent to Broca's area, however, in left central opercular, precentral, and insular cortices were associated with speech production and motor speech performance.DiscussionThe current study failed to identify a single speech or language measure in our comprehensive test battery that was dependent on Broca's area. This finding could not be attributed to a lack of power, as Broca's area had among the highest power values and substantial lesion coverage. Interrogation of data at the individual patient level revealed the likely source of this null finding: Patients with lesions involving Broca's area varied widely in their speech-language performance, with profiles ranging from non-aphasic to Broca's to global aphasia. Given previous studies in acute stroke patients and healthy participants implicating Broca's area in speech-language, the current findings suggest that Broca's area plays a more supplementary than critical role and can be compensated by surrounding brain regions in chronic stroke.

In diesem Beitrag soll die kritische Weiterentwicklung des kantischen Aufklärungsbegriffs durch Moses Mendelssohn untersucht werden. Kant fasst die Aufklärung als Emanzipation auf: Kraft seines Verstandes befreit sich der Mensch aus den selbstverschuldeten Verhältnissen der Unmündigkeit. Der jüdische Aufklärer Mendelssohn macht darauf aufmerksam, dass die Kultur als identitätsstiftendes Moment des Einzelnen, aber auch als kollektive Eigenschaft einer Gesellschaft ebenso in Rechnung zu stellen ist. Insbesondere darf die Aufklärung nicht kulturfeindlich auftreten, indem sie die Emanzipation zum Preis der Entwurzelung aus einer angeblich rückständigen Kultur durchsetzt. Wie weit aber kann dieser Kulturvorbehalt gehen? In der folgenden Untersuchung zeigt sich, dass Mendelssohns Pochen auf die Kultur in der Tat einen blinden Fleck Kants berührt und eine entscheidende Erweiterung darstellt, die gleichfalls nicht allen Einwänden standhält. Im Ergebnis korrigieren sich Kant und Mendelssohn wechselseitig. Die Erkenntnis vertieft unser Verständnis der Aufklärung in systematischer Hinsicht.

Abstract G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.

Abstract Passively administered monoclonal antibodies (mAbs) given before or after viral infection can prevent or blunt disease. Here, we examine the efficacy of aerosol mAb delivery to prevent infection and disease in rhesus macaques inoculated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant via intranasal and intratracheal routes. SARS-CoV-2 human mAbs or a human mAb directed to respiratory syncytial virus (RSV) are nebulized and delivered using positive airflow via facemask to sedated macaques pre- and post-infection. Nebulized human mAbs are detectable in nasal, oropharyngeal, and bronchoalveolar lavage (BAL) samples. SARS-CoV-2 mAb treatment significantly reduces levels of SARS-CoV-2 viral RNA and infectious virus in the upper and lower respiratory tracts relative to controls. Reductions in lung and BAL virus levels correspond to reduced BAL inflammatory cytokines and lung pathology. Aerosolized antibody therapy for SARS-CoV-2 could be effective for reducing viral burden and limiting disease severity.

While critical thinking is widely regarded as a key outcome of higher education, research has shown that in practice it is only developed when certain conditions are in place, relating to the pedagogical approach, the nature of the curriculum and the level of challenge, amongst other factors. This article reports on findings from a four-year mixed methods study in Botswana, Ghana and Kenya, aiming to investigate the factors underpinning the successful development of critical thinking amongst undergraduate students. A two-stage critical thinking assessment was conducted with students in 15 sites, showing that only some of the institutions were ensuring significant gains in students' critical thinking, even when endorsing learner-centred methods. The study points to the central importance of teaching orientations amongst lecturers, involving a deep shift in approaches to knowledge, and a facilitation rather than a transmission approach.

Satisfaction with the detection process of autism and its determinants was investigated using data from the Autism Spectrum Disorder in the European Union (2015-2018) network. A total of 1342 family members, including 1278 parents, completed an online survey collecting information about their experience and satisfaction with the early detection of autism in their child. Overall, the level of satisfaction varied considerably from one respondent to another. Difficulty in finding information about detection services, lack of professional guidance and support in response to first concerns, finding a diagnostic service on one's own, and a delay of more than 4 months between the confirmation of concerns and the first appointment with a specialist were all experiences individually associated with greater odds of being less satisfied. Using a dominance analysis approach, we further identified professional guidance and support in response to first concerns as the most important predictor of the level of satisfaction. These findings highlight the aspects of the process that need to be improved to enhance the experience of the detection process and are therefore relevant to guide health administrations toward actions to be implemented to this effect.

IntroductionWe are developing the California Cognitive Assessment Battery (CCAB) to provide neuropsychological assessments to patients who lack test access due to cost, capacity, mobility, and transportation barriers.MethodsThe CCAB consists of 15 non-verbal and 17 verbal subtests normed for telemedical assessment. The CCAB runs on calibrated tablet computers over cellular or Wi-Fi connections either in a laboratory or in participants’ homes. Spoken instructions and verbal stimuli are delivered through headphones using naturalistic text-to-speech voices. Verbal responses are scored in real time and recorded and transcribed offline using consensus automatic speech recognition which combines the transcripts from seven commercial ASR engines to produce timestamped transcripts more accurate than those of any single ASR engine. The CCAB is designed for supervised self-administration using a web-browser application, the Examiner. The Examiner permits examiners to record observations, view subtest performance in real time, initiate video chats, and correct potential error conditions (e.g., training and performance failures, etc.,) for multiple participants concurrently.ResultsHere we describe (1) CCAB usability with older (ages 50 to 89) participants; (2) CCAB psychometric properties based on normative data from 415 older participants; (3) Comparisons of the results of at-home vs. in-lab CCAB testing; (4) We also present preliminary analyses of the effects of COVID-19 infection on performance. Mean z-scores averaged over CCAB subtests showed impaired performance of COVID+ compared to COVID- participants after factoring out the contributions of Age, Education, and Gender (AEG). However, inter-cohort differences were no longer significant when performance was analyzed with a comprehensive model that factored out the influences of additional pre-existing demographic factors that distinguished COVID+ and COVID- cohorts (e.g., vocabulary, depression, race, etc.,). In contrast, unlike AEG scores, comprehensive scores correlated significantly with the severity of COVID infection. (5) Finally, we found that scoring models influenced the classification of individual participants with Mild Cognitive Impairment (MCI, z-scores < –1.50) where the comprehensive model accounted for more than twice as much variance as the AEG model and reduced racial bias in MCI classification.DiscussionThe CCAB holds the promise of providing scalable laboratory-quality neurodiagnostic assessments to underserved urban, exurban, and rural populations.

The Autism Spectrum Disorders in the European Union (ASDEU) survey investigated local services' use experiences of autistic adults, carers and professionals with interventions for autistic adults. The majority of the 697 participants experienced recommended considerations prior to deciding on intervention and during the intervention plan and implementation. Psychosocial interventions were the most commonly experienced interventions, while pharmacological interventions NOT recommended for core autistic symptoms were reported by fairly large proportions of participants. Family interventions were experienced slightly more commonly by carers than adults or professionals. Less than the 26% of autistic adult responders who had experienced challenging behaviors reported receiving an intervention to change them. These results provide insights for improving gaps in service provision of interventions among autistic adults.

Abstract Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons.

The role of white matter pathways in cognition is a topic of active investigation that is vital to both the fields of clinical neurology and cognitive neuroscience. White matter pathways provide critical connectivity amongst numerous specialized brain regions thereby enabling higher level cognition. While the effects of dissections and lesions of the corpus callosum have been reported, it is less understood how unilateral focal white matter lesions may impact cognitive processes. Here, we report a unique case study in which a small left lateralized stroke in the white matter adjacent to the body of the corpus callosum selectively impaired the ability to name letters and numbers presented to the ipsilesional, left hand. Naming of letters, numbers and objects was tested in both the visual and tactile modalities in both hands. Diffusion-weighted imaging showed a marked reduction in white matter pathway integrity through the body of the corpus callosum. Clinically, this case highlights the significant impact that a focal white matter lesion can have on higher-level cognition, specifically the integration of verbal and tactile information. Moreover, this case adds to prior reports on tactile agnosia by including DTI imaging data and emphasizing the role that white matter pathways through the body of the corpus callosum play in integrating tactile input from the right hemisphere with verbal naming capabilities of the left hemisphere. Finally, the findings also provoke fresh insight into alternative strategies for rehabilitating cognitive functioning when structural connectivity may be compromised.

Introduction: One of the most challenging symptoms of aphasia is an impairment in auditory comprehension. The inability to understand others has a direct impact on a person's quality of life and ability to benefit from treatment. Despite its importance, limited research has examined the recovery pattern of auditory comprehension and instead has focused on aphasia recovery more generally. Thus, little is known about the time frame for auditory comprehension recovery following stroke, and whether specific neurologic and demographic variables contribute to recovery and outcome. Methods: This study included 168 left hemisphere chronic stroke patients stroke patients with auditory comprehension impairments ranging from mild to severe. Univariate and multivariate lesion-symptom mapping (LSM) was used to identify brain regions associated with auditory comprehension outcomes on three different tasks: Single-word comprehension, yes/no sentence comprehension, and comprehension of sequential commands. Demographic variables (age, gender, and education) were also examined for their role in these outcomes. In a subset of patients who completed language testing at two or more time points, we also analyzed the trajectory of recovery in auditory comprehension using survival curve-based time compression. Results: LSM analyses revealed that poor single-word auditory comprehension was associated with lesions involving the left mid- to posterior middle temporal gyrus, and portions of the angular and inferior-middle occipital gyri. Poor yes/no sentence comprehension was associated almost exclusively with the left mid-posterior middle temporal gyrus. Poor comprehension of sequential commands was associated with lesions in the left posterior middle temporal gyrus. There was a small region of convergence between the three comprehension tasks, in the very posterior portion of the left middle temporal gyrus. The recovery analysis revealed that auditory comprehension scores continued to improve beyond the first year post-stroke. Higher education was associated with better outcome on all auditory comprehension tasks. Age and gender were not associated with outcome or recovery slopes. Conclusions: The current findings suggest a critical role for the posterior left middle temporal gyrus in the recovery of auditory comprehension following stroke, and that spontaneous recovery of auditory comprehension can continue well beyond the first year post-stroke.

Proactive interference in working memory refers to the fact that memory of past experiences can interfere with the ability to hold new information in working memory. The left inferior frontal gyrus (LIFG) has been proposed to play an important role in resolving proactive interference in working memory. However, the role of white matter pathways and other cortical regions has been less investigated. Here we investigated proactive interference in working memory using the Recent Probes Test (RPT) in 15 stroke patients with unilateral chronic lesions in left (n = 7) or right (n = 2) prefrontal cortex (PFC), or left temporal cortex (n = 6). We examined the impact of lesions in both gray and white matter regions on the size of the proactive interference effect. We found that patients with left PFC lesions performed worse overall, but the proactive interference effect in this patient group was comparable to that of patients with right PFC lesions, temporal lobe lesions, and controls. Interestingly, the size of the interference effect was significantly correlated with the degree of damage in the extreme/external capsule and marginally correlated with the degree of damage in the inferior frontal occipital fasciculus (IFOF). These findings suggests that ventral white matter pathways connecting the LIFG to left posterior regions play a role in resolving proactive interference in working memory. This effect was particularly evident in one patient with a very large interference effect (>3 SDs above controls) who had mostly spared LIFG, but virtually absent ventral white matter pathways (i.e., passing through the extreme/external capsules and IFOF). This case study further supports the idea that the role of the LIFG in resolving interference in working memory is dependent on connectivity with posterior regions via ventral white matter pathways.

Research providing an evidence-base for autistic adult services is sparse. The Autism Spectrum Disorders in the European Union (ASDEU) network implemented an on-line survey to determine gaps in autistic adult diagnostic evaluation and post-diagnostic support services. More than 55% in all groups experienced most of the recommended features for diagnostic evaluation for autistic adults. In contrast, < 2% of adults or carers, and < 21% of professionals experienced each of the recommended features for post-diagnostic support. In contrast to 61% of professionals, only about 30% of autistic adults and carers had knowledge of good local services models for autism diagnosis in adulthood. There are major differences between good practice guidelines for diagnostic and post-diagnostic care for autistic adults, and what is actually experienced by services users and professionals.

This study aimed to investigate factors associated with a delayed autism spectrum (ASD) diagnosis when compared to children with either no or early ASD diagnosis. Among 893 children assessed for ASD before age 8, 39% had no ASD at baseline, of which 21% received a later ASD diagnosis. Autism symptoms, diagnostic history of other developmental disorders, cognitive ability, and socioeconomic factors were associated with delayed ASD. Autism Diagnostic Observation Schedule (ADOS) scores in delayed ASD fell between early and no ASD. Other developmental disorders, time and clinical trends like ADOS use and low parental education distinguished delayed and early ASD, whereas higher frequency of IQ < 70 at baseline and a diagnosis of emotional disorders during follow-up distinguished delayed and no ASD.