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Imagining future events conveys adaptive benefits, yet recurrent simulations of feared situations may help to maintain anxiety. In two studies, we tested the hypothesis that people can attenuate future fears by suppressing anticipatory simulations of dreaded events. Participants repeatedly imagined upsetting episodes that they feared might happen to them and suppressed imaginings of other such events. Suppressing imagination engaged the right dorsolateral prefrontal cortex, which modulated activation in the hippocampus and in the ventromedial prefrontal cortex (vmPFC). Consistent with the role of the vmPFC in providing access to details that are typical for an event, stronger inhibition of this region was associated with greater forgetting of such details. Suppression further hindered participants’ ability to later freely envision suppressed episodes. Critically, it also reduced feelings of apprehensiveness about the feared scenario, and individuals who were particularly successful at down-regulating fears were also less trait-anxious. Attenuating apprehensiveness by suppressing simulations of feared events may thus be an effective coping strategy, suggesting that a deficiency in this mechanism could contribute to the development of anxiety.

Psychotic phenomena manifest in healthy and clinical populations as complex patterns of aberrant perceptions (hallucinations) and tenacious, irrational beliefs ( delusions). According to predictive processing accounts, hallucinations and delusions arise from atypicalities in the integration of prior knowledge with incoming sensory information. However, the computational details of these atypicalities and their specific phenomenological manifestations are not well characterized. We tested the hypothesis that hallucination-proneness arises from increased reliance on overly general application of prior knowledge in perceptual inference, generating percepts that readily capture the gist of the environment but inaccurately render its details. We separately probed the use of prior knowledge to perceive the gist vs the details of ambiguous images in a healthy population with varying degrees of hallucination- and delusion-proneness. We found that the use of prior knowledge varied with psychotic phenomena and their composition in terms of aberrant percepts vs aberrant beliefs. Consistent with previous findings, hallucination-proneness conferred an advantage using prior knowledge to perceive image gist but, contrary to predictions, did not confer disadvantage perceiving image details. Predominant hallucination-proneness actually conferred advantages perceiving both image gist and details, consistent with reliance on highly detailed perceptual knowledge. Delusion-proneness, and especially predominance of delusion-proneness over hallucination-proneness, conferred disadvantage perceiving image details but not image gist, though evidence of specific impairment of detail perception was preliminary. We suggest this is consistent with reliance on abstract, belief-like knowledge. We posit that phenomenological variability in psychotic experiences may be driven by variability in the type of knowledge observers rely upon to resolve perceptual ambiguity.

This study compared knowledge attainment and student enjoyment and engagement between clinical case vignette, patient-testimony videos and mixed reality (MR) teaching via the Microsoft HoloLens 2, all delivered remotely to third year medical students. The feasibility of conducting MR teaching on a large scale was also assessed. Medical students in Year 3 at Imperial College London participated in three online teaching sessions, one in each format. All students were expected to attend these scheduled teaching sessions and to complete the formative assessment. Inclusion of their data used as part of the research trial was optional. The primary outcome measure was performance on a formative assessment, which served to compare knowledge attainment between three forms of online learning. Moreover, we aimed to explore student engagement with each form of learning via a questionnaire, and also feasibility of applying MR as a teaching tool on a large scale. Comparisons between performances on the formative assessment between the three groups were investigated using a repeated measures two-way ANOVA. Engagement and enjoyment were also analysed in the same manner. A total of 252 students participated in the study. Knowledge attainment of students using MR was comparable with the other two methods. Participants reported higher enjoyment and engagement (p<0.001) for the case vignette method, compared with MR and video-based teaching. There was no difference in enjoyment or engagement ratings between MR and the video-based methods. This study demonstrated that the implementation of MR is an effective, acceptable, and feasible way of teaching clinical medicine to undergraduate students on a large scale. However, case-based tutorials were found to be favoured most by students. Future work could further explore the best uses for MR teaching within the medical curriculum.

This collection of essays written by biblical scholars from around the world attempts to probe the relationship between the Bible and the world. It reflects modern social, political and hermeneutical issues, including liberation concerns. These themes echo John Rogerson's commitment to relate his research and the Bible to contemporary issues - a commitment visible both in his publications and in his religious and political activities. This book is an expression of appreciation of John Rogerson by former and current colleagues, former students, and other biblical scholars.

In the last decade since their emergence, brain organoids have offered an increasingly popular and powerful model for the study of early development and disease in humans. These 3D stem cell-derived models exist in a newer space at the intersection of in vivo and 2D in vitro models. Functional benchmarking has so far remained largely uncharacterised however, leaving the extent to which these models may accurately portray in vivo processes still yet to be fully realised. Here we present a standardised unguided protocol to generate brain organoids from mice, the most commonly-used in vivo mammalian model; and in parallel establish a guided protocol for generating region-specific choroid plexus mouse organoids. Both unguided and guided mouse organoids progress through neurodevelopmental stages with an in vivo-like tempo and recapitulate species-specific characteristics of neural and choroid plexus development, respectively. Neuroepithelial cells generate neural progenitors that give rise to different neural subtypes including deep-layer neurons, upper-layer neurons, and glial cells. We further adapted protocols to prolong mouse cerebral organoid (CO) cultures as slices at the air-liquid interface (ALI), enhancing accessibility for long-term studies and functional investigations. In mature mouse ALI-COs, we observed mature glia, as well as synaptic structures and long-range axon tracts projecting to distant regions, suggesting an establishment and maturation of neural circuitry. Indeed, functional analyses with high-density multi-electrode arrays (HD-MEAs) indicate comparable activity to ex vivo organotypic mouse brain slices. Having established protocols for both region-specific and unpatterned mouse brain organoids, we demonstrate that their neurodevelopmental trajectories, and resultant mature features, closely mimic the in vivo models to which they are benchmarked across multiple biochemical, morphological, and functional read-outs. We propose that mouse brain organoids are a valuable model for functional studies, and provide insight into how closely brain organoids of other species, such as human, may recapitulate their own respective in vivo development.Competing Interest StatementMAL and LP are inventors on patents describing organoid methods, MAL is co-founder and advisory board member of a:head bio.Footnotes* Author order has been updated on the bioRxiv system to match the PDF of the paper. No other changes to the manuscript have been made.

The considerably slow pace of human brain development correlates with an evolutionary increase in brain size, cell numbers, and expansion of neuronal structures, with axon tracts undergoing an even greater evolutionary increase than other neuronal domains. However, whether tempo is responsible for these differences in magnitude, and how, remains to be determined. Here, we used brain organoids to investigate this and observed that human axon tracts spend more time growing and extend farther compared to those of mice, independent of their tissue environment. Single cell RNA sequencing analysis pointed to a subset of calcium-permeable ion channels expressed throughout neuron development, including during axon tract outgrowth. Calcium imaging during early neuron development consistently revealed a reduced calcium influx in human neurons compared to mouse neurons. Stimulating calcium influx and increasing cAMP levels resulted in premature halting of axon tract outgrowth and shorter axon tracts, mimicking the mouse phenotype, while abrogating calcium influx led to an even longer phase of axon tract outgrowth and longer axon tracts in humans. Thus, evolutionary differences in calcium regulation set the tempo of neuronal development, by extending the time window to foster the more elaborated human neuron morphology.Competing Interest StatementMAL is an inventor on patents covering cerebral organoids, and is co-founder and advisory board member of a:head bio.Footnotes* Authorship adjusted with addition of two authors.

Synapses are essential for neuronal function and are central to numerous neurological disorders including developmental and neurodegenerative diseases. Synapses structurally constitute a very small proportion of a neuron, and their protein content is difficult to study using whole tissue preparations. Especially studying synapses on the functional level is challenging. To overcome this limitation, synapses can be captured as synaptosomes generated through enrichment of isolated nerve terminals. Such synaptosomes have a re-sealed plasma membrane and can regenerate their membrane potential and perform physiological function, for example neurotransmitter release. Synaptosomes are traditionally enriched from rodent or postmortem human brain tissue, but rodent models lack human-specific synaptic features, and the functionality of synaptosomes from postmortem tissues is limited by the postmortem interval and often only show disease endpoints. Furthermore, due to ethical issues and availability, only a few studies have been conducted on human samples. However, neural organoids (NOs) have emerged as a possible new source for isolation of intact and live human nerve terminals to study human-specific aspects of synaptic transmission. Further, the enrichment of synaptosomes is usually performed using density gradient centrifugation, which requires a lot of starting material. In the present study we developed a method for the enrichment of synaptic structures from human NOs applying a differential centrifugation protocol. We then used mass spectrometry-based quantitative proteomics to document the enrichment of synapse and growth cone specific proteins, and quantitative phosphoproteomics upon KCl stimulation to demonstrate viability and physiological function of the derived synaptic structures.Competing Interest StatementThe authors have declared no competing interest.

Slowly clearing infections in the pleural space are a source of substantial morbidity. This study showed that instillation of recombinant DNase and tissue plasminogen activator (t-PA) is more effective than placebo in clearing radiographic pleural effusions. Pleural infection affects more than 65,000 patients each year in the United States and the United Kingdom, 1 and the incidence is increasing in both countries — in both children 2 – 4 and adults. 5 , 6 The mortality rate from pleural infection is between 10% and 20%, 5 , 7 – 9 and drainage through a chest tube and administration of antibiotics fail in approximately one third of patients, who then require surgical drainage. 5 , 9 The median duration of the hospital stay for these patients is 12 to 15 days, 5 , 6 , 8 , 9 with 25% hospitalized for more than a month. Care of each patient costs . . .

Background: Although the health benefits of regular physical activity and exercise are well established and have been incorporated into national public health recommendations, there is a relative lack of understanding pertaining to the harmful effects of physical inactivity. Experimental paradigms including complete immobilization and bed rest are not physiologically representative of sedentary living. A useful ‘real-world’ approach to contextualize the physiology of societal downward shifts in physical activity patterns is that of short-term daily step reduction. Results: Step-reduction studies have largely focused on musculoskeletal and metabolic health parameters, providing relevant disease models for metabolic syndrome, type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), sarcopenia and osteopenia/osteoporosis. In untrained individuals, even a short-term reduction in physical activity has a significant impact on skeletal muscle protein and carbohydrate metabolism, causing anabolic resistance and peripheral insulin resistance, respectively. From a metabolic perspective, short-term inactivity-induced peripheral insulin resistance in skeletal muscle and adipose tissue, with consequent liver triglyceride accumulation, leads to hepatic insulin resistance and a characteristic dyslipidaemia. Concomitantly, various inactivity-related factors contribute to a decline in function; a reduction in cardiorespiratory fitness, muscle mass and muscle strength. Conclusions: Physical inactivity maybe particularly deleterious in certain patient populations, such as those at high risk of T2D or in the elderly, considering concomitant sarcopenia or osteoporosis. The effects of short-term physical inactivity (with step reduction) are reversible on resumption of habitual physical activity in younger people, but less so in older adults. Nutritional interventions and resistance training offer potential strategies to prevent these deleterious metabolic and musculoskeletal effects. Impact: Individuals at high risk of/with cardiometabolic disease and older adults may be more prone to these acute periods of inactivity due to acute illness or hospitalization. Understanding the risks is paramount to implementing countermeasures.

IntroductionThe emergence of the novel respiratory SARS-CoV-2 and subsequent COVID-19 pandemic have required rapid assimilation of population-level data to understand and control the spread of infection in the general and vulnerable populations. Rapid analyses are needed to inform policy development and target interventions to at-risk groups to prevent serious health outcomes. We aim to provide an accessible research platform to determine demographic, socioeconomic and clinical risk factors for infection, morbidity and mortality of COVID-19, to measure the impact of COVID-19 on healthcare utilisation and long-term health, and to enable the evaluation of natural experiments of policy interventions.Methods and analysisTwo privacy-protecting population-level cohorts have been created and derived from multisourced demographic and healthcare data. The C20 cohort consists of 3.2 million people in Wales on the 1 January 2020 with follow-up until 31 May 2020. The complete cohort dataset will be updated monthly with some individual datasets available daily. The C16 cohort consists of 3 million people in Wales on the 1 January 2016 with follow-up to 31 December 2019. C16 is designed as a counterfactual cohort to provide contextual comparative population data on disease, health service utilisation and mortality. Study outcomes will: (a) characterise the epidemiology of COVID-19, (b) assess socioeconomic and demographic influences on infection and outcomes, (c) measure the impact of COVID-19 on short -term and longer-term population outcomes and (d) undertake studies on the transmission and spatial spread of infection.Ethics and disseminationThe Secure Anonymised Information Linkage-independent Information Governance Review Panel has approved this study. The study findings will be presented to policy groups, public meetings, national and international conferences, and published in peer-reviewed journals.