PREVALENCE OF ATOPIC DISORDERS AMONG PEDIATRIC PATIENTS WITH PULMONARY AND DISSEMINATED COCCIDIOIDOMYCOSIS.

Type 2 inflammatory responses are associated with worse prognosis in coccidioidomycosis. It is unclear whether patients with preexisting type 2 inflammation and atopic disorders are predisposed to disseminated coccidioidomycosis. A retrospective analysis of pediatric patients with disseminated coccidioidomycosis revealed no significant difference in the history of atopic disorders or eosinophilia as compared to those with isolated pulmonary disease. Tissue-specific type 2 responses may still play a role in coccidioidomycosis immune dysregulation, and further investigation is needed.

Genome-wide CRISPR/Cas9 screen shows that loss of GET4 increases mitochondria-endoplasmic reticulum contact sites and is neuroprotective.

Organelles form membrane contact sites between each other, allowing for the transfer of molecules and signals. Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are cellular subdomains characterized by close apposition of mitochondria and ER membranes. They have been implicated in many diseases, including neurodegenerative, metabolic, and cardiac diseases. Although MERCS have been extensively studied, much remains to be explored. To uncover novel regulators of MERCS, we conducted a genome-wide, flow cytometry-based screen using an engineered MERCS reporter cell line. We found 410 genes whose downregulation promotes MERCS and 230 genes whose downregulation decreases MERCS. From these, 29 genes were selected from each population for arrayed screening and 25 were validated from the high population and 13 from the low population. GET4 and BAG6 were highlighted as the top 2 genes that upon suppression increased MERCS from both the pooled and arrayed screens, and these were subjected to further investigation. Multiple microscopy analyses confirmed that loss of GET4 or BAG6 increased MERCS. GET4 and BAG6 were also observed to interact with the known MERCS proteins, inositol 1,4,5-trisphosphate receptors (IP3R) and glucose-regulated protein 75 (GRP75). In addition, we found that loss of GET4 increased mitochondrial calcium uptake upon ER-Ca2+ release and mitochondrial respiration. Finally, we show that loss of GET4 rescues motor ability, improves lifespan and prevents neurodegeneration in a Drosophila model of Alzheimer's disease (Aß42Arc). Together, these results suggest that GET4 is involved in decreasing MERCS and that its loss is neuroprotective.

Head Exposure to Acceleration Database in Sport (HEADSport): a kinematic signal processing method to enable instrumented mouthguard (iMG) field-based inter-study comparisons.

Objective: Instrumented mouthguard (iMG) systems use different signal processing approaches limiting field-based inter-study comparisons, especially when artefacts are present in the signal. The objective of this study was to assess the frequency content and characteristics of head kinematic signals from head impact reconstruction laboratory and field-based environments to develop an artefact attenuation filtering method (HEADSport filter method). Methods: Laboratory impacts (n=72) on a test-dummy headform ranging from 25 to 150 g were conducted and 126 rugby union players were equipped with iMGs for 209 player-matches. Power spectral density (PSD) characteristics of the laboratory impacts and on-field head acceleration events (HAEs) (n=5694) such as the 95th percentile cumulative sum PSD frequency were used to develop the HEADSport method. The HEADSport filter method was compared with two other common filtering approaches (Butterworth-200Hz and CFC180 filter) through signal-to-noise ratio (SNR) and mixed linear effects models for laboratory and on-field events, respectively. Results: The HEADSport filter method produced marginally higher SNR than the Butterworth-200Hz and CFC180 filter and on-field peak linear acceleration (PLA) and peak angular acceleration (PAA) values within the magnitude range tested in the laboratory. Median PLA and PAA (and outlier values) were higher for the CFC180 filter than the Butterworth-200Hz and HEADSport filter method (p<0.01). Conclusion: The HEADSport filter method could enable iMG field-based inter-study comparisons and is openly available at https://github.com/GTBiomech/HEADSport-Filter-Method.

Instrumented Mouthguards in Elite-Level Men's and Women's Rugby Union: The Incidence and Propensity of Head Acceleration Events in Matches.

OBJECTIVES: The aim of this study was to examine head acceleration event (HAE) propensity and incidence during elite-level men's and women's rugby union matches. METHODS: Instrumented mouthguards (iMGs) were fitted in 92 male and 72 female players from nine elite-level clubs and three international teams. Data were collected during 406 player matches (239 male, 167 female) using iMGs and video analysis. Incidence was calculated as the number of HAEs per player hour and propensity as the proportion of contact events resulting in an HAE at a range of linear and angular thresholds. RESULTS: HAE incidence above 10 g was 22.7 and 13.2 per hour in men's forwards and backs and 11.8 and 7.2 per hour in women's forwards and backs, respectively. Propensity varied by contact event, with 35.6% and 35.4% of men's tackles and carries and 23.1% and 19.6% of women's tackles and carries producing HAEs above 1.0 krad/s2. Tackles produced significantly more HAEs than carries, and incidence was greater in forwards compared with backs for both sexes and in men compared with women. Women's forwards were 1.6 times more likely to experience a medium-magnitude HAE from a carry than women's backs. Propensity was similar from tackles and carries, and between positional groups, while significantly higher in men than women. The initial collision stage of the tackle had a higher propensity than other stages. CONCLUSION: This study quantifies HAE exposures in elite rugby union players using iMGs. Most contact events in rugby union resulted in lower-magnitude HAEs, while higher-magnitude HAEs were comparatively rare. An HAE above 40 g occurred once every 60-100 min in men and 200-300 min in women. Future research on mechanisms for HAEs may inform strategies aimed at reducing HAEs.

Polygene risk scores and randomized experiments.

We explore Madole & Harden's (2022) suggestion that single-nucleotide polymorphism (SNP)/trait correlations are analogous to randomized experiments and thus can be given a causal interpretation.

Exploring the Application of Peer-Assisted Learning in Practical Neuroanatomy Classes: A Cohort Comparison Within a Medical Curriculum.

Despite well-documented benefits, the effectiveness of some aspects of near-peer (NP) teaching in medical education within anatomy curricula remains unclear. Here, we explored the impact of various permutations of staff/student laboratory-based co-teaching in neuroanatomy by determining the optimal staff and student teaching combination. We assessed student perceptions and knowledge acquisition using three different co-teaching strategies. Second-year medical students at the University of Southampton were co-taught neuroanatomy by faculty staff and third-year medical students (NP teachers). Three cohorts, 2016/2017, 2017/2018, and 2018/2019, were included in the study. Subsequent cohorts experienced increasingly structured NP teaching with more NP teachers. Students completed evaluations for anatomy sessions, which were statistically compared. The 2017/2018 and 2018/2019 cohorts completed lunchtime quizzes matched to the learning outcomes of each practical session, which were analysed. A focus group involving six students was transcribed and thematically analysed. Anatomy practical ratings were significantly higher when both session structure and NP teacher numbers increased from 3 to 5-6 (p = 0.0010) and from 3 to 7-8 (p = 0.0020). There were no significant differences in anatomy practical ratings using 5-6 and 7-8 NP teachers (p > 0.9999). There were no significant differences between the knowledge scores of students who experienced 5-6 and 7-8 NP teachers. Themes detailing the benefits of NP teaching and the importance of faculty involvement were identified, demonstrating that students appreciated NP teaching within a co-teaching environment. Therefore, increased NP teaching may augment students' perceptions and knowledge acquisition. In this context, the optimal number of NP teachers may sit between 5 and 8.

Seronegative Mediastinal Coccidioidomycosis as a Novel Presentation of CTPS1 Combined Immunodeficiency.

Inborn errors of immunity may present with susceptibility to coccidioidomycosis. This is especially so in disorders impairing the interferon-γ and interleukin 12 signaling axis. We describe the first case of cytidine nucleotide triphosphate synthetase 1 (CTPS1) deficiency, a combined immunodeficiency impairing lymphocyte proliferation, presenting with coccidioidomycosis.

Top-down causation in psychiatric disorders: a clinical-philosophical inquiry.

Psychiatry has long debated whether the causes of mental illness can be better explained by reductionist or pluralistic accounts. Although the former relies on commonsense scientific bottom-up causal models, the latter (which typically include environmental, psychological, and/or socio-cultural risk factors) requires top-down causal processes often viewed with skepticism, especially by neuroscientists. We begin with four clinical vignettes which illustrate self-interventions wherein high-order psychological processes (e.g. religious beliefs or deep interpersonal commitments) appear to causally impact the risk for or the course of psychiatric/behavioral disorders. We then propose a model for how to understand this sort of top-down self-causation. Our model relies centrally on the concept of a control variable which, like a radio tuning dial, can implement a series of typically unknown physical processes to obtain the desired ends. We set this control variable in the context of an interventionist account of causation that assumes that a cause (C) produces an effect (E) when intervening on C (by manipulating it) is associated with a change in E. We extend this framework by arguing that certain psychological changes can result from individuals intervening on their own mental states and/or selection of environments. This in turn requires a conception of the self that contains mental capacities that are at least partially independent of one another. Although human beings cannot directly intervene on the neurobiological systems which instantiate risk for psychiatric illness, they can, via control variables at the psychological level, and/or by self-selection into protective environments, substantially alter their own risk.

Causal Responsibility and Robust Causation.

How do people judge the degree of causal responsibility that an agent has for the outcomes of her actions? We show that a relatively unexplored factor - the robustness (or stability) of the causal chain linking the agent's action and the outcome - influences judgments of causal responsibility of the agent. In three experiments, we vary robustness by manipulating the number of background circumstances under which the action causes the effect, and find that causal responsibility judgments increase with robustness. In the first experiment, the robustness manipulation also raises the probability of the effect given the action. Experiments 2 and 3 control for probability-raising, and show that robustness still affects judgments of causal responsibility. In particular, Experiment 3 introduces an Ellsberg type of scenario to manipulate robustness, while keeping the conditional probability and the skill deployed in the action fixed. Experiment 4, replicates the results of Experiment 3, while contrasting between judgments of causal strength and of causal responsibility. The results show that in all cases, the perceived degree of responsibility (but not of causal strength) increases with the robustness of the action-outcome causal chain.

Flagellum Removal by a Nectar Metabolite Inhibits Infectivity of a Bumblebee Parasite.

Plant phytochemicals can act as natural "medicines" for animals against parasites [1-3]. Some nectar metabolites, for example, reduce parasite infections in bees [4-7]. Declining plant diversity through anthropogenic landscape change [8-11] could reduce the availability of medicinal nectar plants for pollinators, exacerbating their decline [12]. Existing studies are, however, limited by (1) a lack of mechanistic insights into how phytochemicals affect pollinator diseases and (2) the restriction to few, commercially available chemicals, thereby potentially neglecting plants with the biggest antiparasitic effects. To rapidly identify plants with the greatest potential as natural bee medicines, we developed a bioactivity-directed fractionation assay for nectar metabolites. We evaluated 17 important nectar plants against the bumblebee pathogen Crithidia bombi (Trypanosomatidae) [13-17]. The most bioactive species was heather (Calluna vulgaris), the second most productive UK nectar plant [10]. We identified 4-(3-oxobut-1-enylidene)-3,5,5-trimethylcyclohex-2-en-1-one (callunene) from heather nectar as a potent inhibitor of C. bombi. Wild bumblebees (Bombus terrestris) foraging on heather ingest callunene at concentrations causing complete C. bombi inhibition. Feeding on callunene was prophylactic against infections. We show that C. bombi establishes infections by flagellar anchoring to the ileum epithelium. Short-term callunene exposure induced flagellum loss in C. bombi choanomastigotes, resulting in a loss of infectivity. We conclude that plant secondary metabolites can disrupt parasite flagellum attachment, revealing a mechanism behind their prophylactic effects. The decline of heathlands [18-21] reduces the availability of natural bee "medicine" and could exacerbate the contribution of diseases to pollinator declines. VIDEO ABSTRACT.

Koch's postulates: An interventionist perspective.

We argue that Koch's postulates are best understood within an interventionist account of causation, in the sense described in Woodward (2003). We show how this treatment helps to resolve interpretive puzzles associated with Koch's work and how it clarifies the different roles the postulates play in providing useful, yet not universal criteria for disease causation. Our paper is an effort at rational reconstruction; we attempt to show how Koch's postulates and reasoning make sense and are normatively justified within an interventionist framework and more difficult to understand within alternative frameworks for thinking about causation.

Emotional and Utilitarian Appraisals of Moral Dilemmas Are Encoded in Separate Areas and Integrated in Ventromedial Prefrontal Cortex.

Moral judgment often requires making difficult tradeoffs (e.g., is it appropriate to torture to save the lives of innocents at risk?). Previous research suggests that both emotional appraisals and more deliberative utilitarian appraisals influence such judgments and that these appraisals often conflict. However, it is unclear how these different types of appraisals are represented in the brain, or how they are integrated into an overall moral judgment. We addressed these questions using an fMRI paradigm in which human subjects provide separate emotional and utilitarian appraisals for different potential actions, and then make difficult moral judgments constructed from combinations of these actions. We found that anterior cingulate, insula, and superior temporal gyrus correlated with emotional appraisals, whereas temporoparietal junction and dorsomedial prefrontal cortex correlated with utilitarian appraisals. Overall moral value judgments were represented in an anterior portion of the ventromedial prefrontal cortex. Critically, the pattern of responses and functional interactions between these three sets of regions are consistent with a model in which emotional and utilitarian appraisals are computed independently and in parallel, and passed to the ventromedial prefrontal cortex where they are integrated into an overall moral value judgment. Significance statement: Popular accounts of moral judgment often describe it as a battle for control between two systems, one intuitive and emotional, the other rational and utilitarian, engaged in winner-take-all inhibitory competition. Using a novel fMRI paradigm, we identified distinct neural signatures of emotional and utilitarian appraisals and used them to test different models of how they compete for the control of moral behavior. Importantly, we find little support for competitive inhibition accounts. Instead, moral judgments resembled the architecture of simple economic choices: distinct regions represented emotional and utilitarian appraisals independently and passed this information to the ventromedial prefrontal cortex for integration into an overall moral value signal.

Deep Panning: steps towards probing the IgOme.

BACKGROUND: Polyclonal serum consists of vast collections of antibodies, products of differentiated B-cells. The spectrum of antibody specificities is dynamic and varies with age, physiology, and exposure to pathological insults. The complete repertoire of antibody specificities in blood, the IgOme, is therefore an extraordinarily rich source of information-a molecular record of previous encounters as well as a status report of current immune activity. The ability to profile antibody specificities of polyclonal serum at exceptionally high resolution has been an important and serious challenge which can now be overcome. METHODOLOGY/PRINCIPAL FINDINGS: Here we illustrate the application of Deep Panning, a method that combines the flexibility of combinatorial phage display of random peptides with the power of high-throughput deep sequencing. Deep Panning is first applied to evaluate the quality and diversity of naïve random peptide libraries. The production of very large data sets, hundreds of thousands of peptides, has revealed unexpected properties of combinatorial random peptide libraries and indicates correctives to ensure the quality of the libraries generated. Next, Deep Panning is used to analyze a model monoclonal antibody in addition to allowing one to follow the dynamics of biopanning and peptide selection. Finally Deep Panning is applied to profile polyclonal sera derived from HIV infected individuals. CONCLUSIONS/SIGNIFICANCE: The ability to generate and characterize hundreds of thousands of affinity-selected peptides creates an effective means towards the interrogation of the IgOme and understanding of the humoral response to disease. Deep Panning should open the door to new possibilities for serological diagnostics, vaccine design and the discovery of the correlates of immunity to emerging infectious agents.

Just do it? Investigating the gap between prediction and action in toddlers' causal inferences.

Adults' causal representations integrate information about predictive relations and the possibility of effective intervention; if one event reliably predicts another, adults can represent the possibility that acting to bring about the first event might generate the second. Here we show that although toddlers (mean age: 24 months) readily learn predictive relationships between physically connected events, they do not spontaneously initiate one event to try to generate the second (although older children, mean age: 47 months, do; Experiments 1 and 2). Toddlers succeed only when the events are initiated by a dispositional agent (Experiment 3), when the events involve direct contact between objects (Experiment 4), or when the events are described using causal language (Experiment 5). This suggests that causal language may help children extend their initial causal representations beyond agent-initiated and direct contact events.

Moral intuition: its neural substrates and normative significance.

Philosophers use the phrase "moral intuition" to describe the appearance in consciousness of moral judgments or assessments without any awareness of having gone through a conscious reasoning process that produces this assessment. This paper investigates the neural substrates of moral intuition. We propose that moral intuitions are part of a larger set of social intuitions that guide us through complex, highly uncertain and rapidly changing social interactions. Such intuitions are shaped by learning. The neural substrates for moral intuition include fronto-insular, cingulate, and orbito-frontal cortices and associated subcortical structure such as the septum, basil ganglia and amygdala. Understanding the role of these structures undercuts many philosophical doctrines concerning the status of moral intuitions, but vindicates the claim that they can sometimes play a legitimate role in moral decision-making.