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Background Functional cognitive disorder (FCD) may be common after a concussion, and no evidence-based treatment options are available. The current study evaluated the feasibility of a novel cognitive–behavioural therapy (CBT) protocol tailored to FCD after concussion.Methods Participants were randomised to CBT (n=11) or the current standard of care, cognitive rehabilitation (n=13). Both interventions consisted of eleven 50 min manualised videoconference sessions. CBT involved cognitive reappraisal and exposure-based strategies. Cognitive rehabilitation involved traditional memory compensation strategy training. Prespecified feasibility criteria were set for recruitment, perceived credibility, patient adherence, therapist protocol compliance and retention. The primary efficacy outcome was the Multifactorial Memory Questionnaire-Satisfaction (MMQ-S). The first five CBT completers completed a semistructured interview about their experience with the intervention.Results Most feasibility benchmarks were met, as 86% of invited patients consented, 96% of participants rated their intervention as credible, participants attended 96% of sessions, therapists covered all essential content in 94% of sessions and 100% of participants completed the post-treatment evaluation. Both groups improved on the MMQ-S. Post-treatment MMQ-S scores were similar between groups (Cohen’s d=−0.05 (95% CI [−0.86, 0.75])). Two themes resulted from the qualitative data analysis, which highlighted aspects of the CBT interventions that participants valued.Implications This pilot trial supports the feasibility of CBT tailored to FCD after concussion and suggests that patients with FCD may benefit from either CBT or standard cognitive rehabilitation. A larger trial is needed to evaluate the efficacy of these interventions for FCD after concussion and potentially FCD in other clinical contexts.Trial registration number NCT05581810.

There has been a significant increase in the consumption of cannabis for both recreational and medicinal purposes in recent years, and its use can have long-term consequences on cognitive functions, including memory. Here, we review the immediate and long-term effects of cannabis and its derivatives on glutamatergic neurotransmission, with a focus on both the presynaptic and postsynaptic alterations. Several factors can influence cannabinoid-mediated changes in glutamatergic neurotransmission, including dosage, sex, age, and frequency of use. Acute exposure to cannabis typically inhibits glutamate release, whereas chronic use tends to increase glutamate release. Conversely, the postsynaptic alterations are more complicated than the presynaptic effects, as cannabis can affect the glutamate receptor expression and the downstream signaling of glutamate. All these effects ultimately influence cognitive functions, particularly memory. This review will cover the current research on glutamate–cannabis interactions, as well as the future directions of research needed to understand cannabis-related health effects and neurological and psychological aspects of cannabis use.

Demetra Georgiou,1 Laura Monje-Garcia,2,3 Tracie Miles,4 Kevin Monahan,2,5 Neil AJ Ryan6,7 1Genomics and Personalised Medicine Service, Charing Cross Hospital, London, UK; 2The St Mark’s Centre for Familial Intestinal Cancer Polyposis, St Mark’s Hospital, London, UK; 3School of Public Health, Imperial College, London, UK; 4South West Genomics Medicine Service Alliance, Bristol, UK; 5Department of Gastroenterology, Imperial College, London, UK; 6Department of Gynaecological Oncology, Royal Infirmary of Edinburgh, Edinburgh, UK; 7The College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UKCorrespondence: Neil AJ Ryan, Department of Gynaecology Oncology, Royal Infirmary of Edinburgh, Edinburgh, UK, Email neilryan@nhs.netAbstract: Lynch syndrome (LS) is an autosomal dominant condition that increases an individual’s risk of a constellation of cancers. LS is defined when an individual has inherited pathogenic variants in the mismatch repair genes. Currently, most people with LS are undiagnosed. Early detection of LS is vital as those with LS can be enrolled in cancer reduction strategies through chemoprophylaxis, risk reducing surgery and cancer surveillance. However, these interventions are often invasive and require refinement. Furthermore, not all LS associated cancers are currently amenable to surveillance. Historically only those with a strong family history suggestive of LS were offered testing; this has proved far too restrictive. New criteria for testing have recently been introduced including the universal screening for LS in associated cancers. This has increased the number of people being diagnosed with LS but has also brought about unique challenges such as when to consent for germline testing and questions over how and who should carry out the consent. The results of germline testing for LS can be complicated and the diagnostic pathway is not always clear. Furthermore, by testing only those with cancer for LS we fail to identify these individuals before they develop potentially fatal pathology. This review will outline these challenges and explore solutions. Furthermore, we consider the potential future of LS care and the related treatments and interventions which are the current focus of research.Keywords: genetic counselling, Lynch syndrome, mainstreaming

Abstract Background During range expansion in spatially distributed habitats, organisms differ from one another in terms of their patterns of localization versus propagation. To exploit locations or explore the landscape? This is the competition-colonization trade-off, a dichotomy at the core of ecological succession. In bacterial communities, this trade-off is a fundamental mechanism towards understanding spatio-temporal fluxes in microbiome composition. Results Using microfluidics devices as structured bacterial habitats, we show that, in a synthetic two-species community of motile strains, Escherichia coli is a fugitive species, whereas Pseudomonas aeruginosa is a slower colonizer but superior competitor. We provide evidence highlighting the role of succession and the relevance of this trade-off in the community assembly of bacteria in spatially distributed patchy landscapes. Furthermore, aggregation-dependent priority effects enhance coexistence which is not possible in well-mixed environments. Conclusions Our findings underscore the interplay between micron-scale landscape structure and dispersal in shaping biodiversity patterns in microbial ecosystems. Understanding this interplay is key to unleash the technological revolution of microbiome applications.

Background: Tissue fibrosis is a major healthcare burden that affects various organs in the body for which no effective treatments exist. An underlying, emerging theme across organs and tissue types at early stages of fibrosis is the activation of pericytes and/or fibroblasts in the perivascular space. In hepatic tissue, it is well known that liver sinusoidal endothelial cells (EC) help maintain the quiescence of stellate cells, but whether this phenomenon holds true for other endothelial and perivascular cell types is not well studied.Methods: The goal of this work was to develop an organ-on-chip microvascular model to study the effect of EC co-culture on the activation of perivascular cells perturbed by the pro-fibrotic factor TGFβ1. A high-throughput microfluidic platform, PREDICT96, that was capable of imparting physiologically relevant fluid shear stress on the cultured endothelium was utilized.Results: We first studied the activation response of several perivascular cell types and selected a cell source, human dermal fibroblasts, that exhibited medium-level activation in response to TGFβ1. We also demonstrated that the PREDICT96 high flow pump triggered changes in select shear-responsive factors in human EC. We then found that the activation response of fibroblasts was significantly blunted in co-culture with EC compared to fibroblast mono-cultures. Subsequent studies with conditioned media demonstrated that EC-secreted factors play at least a partial role in suppressing the activation response. A Luminex panel and single cell RNA-sequencing study provided additional insight into potential EC-derived factors that could influence fibroblast activation.Conclusion: Overall, our findings showed that EC can reduce myofibroblast activation of perivascular cells in response to TGFβ1. Further exploration of EC-derived factors as potential therapeutic targets in fibrosis is warranted.

Abstract Microphysiological organ-on-chip models offer the potential to improve the prediction of drug safety and efficacy through recapitulation of human physiological responses. The importance of including multiple cell types within tissue models has been well documented. However, the study of cell interactions in vitro can be limited by complexity of the tissue model and throughput of current culture systems. Here, we describe the development of a co-culture microvascular model and relevant assays in a high-throughput thermoplastic organ-on-chip platform, PREDICT96. The system consists of 96 arrayed bilayer microfluidic devices containing retinal microvascular endothelial cells and pericytes cultured on opposing sides of a microporous membrane. Compatibility of the PREDICT96 platform with a variety of quantifiable and scalable assays, including macromolecular permeability, image-based screening, Luminex, and qPCR, is demonstrated. In addition, the bilayer design of the devices allows for channel- or cell type-specific readouts, such as cytokine profiles and gene expression. The microvascular model was responsive to perturbations including barrier disruption, inflammatory stimulation, and fluid shear stress, and our results corroborated the improved robustness of co-culture over endothelial mono-cultures. We anticipate the PREDICT96 platform and adapted assays will be suitable for other complex tissues, including applications to disease models and drug discovery.

Understanding mechanisms shaping distributions and interactions of soil microbes is essential for determining their impact on large scale ecosystem services, such as carbon sequestration, climate regulation, waste decomposition, and nutrient cycling. As the functional unit of soil ecosystems, we focus our attention on the spatial structure of soil macroaggregates. Emulating this complex physico-chemical environment as a patchy habitat landscape we investigate on-chip the effect of changing the connectivity features of this landscape as Escherichia coli forms a metapopulation. We analyze the distributions of E. coli occupancy using Taylor's law, an empirical law in ecology which asserts that the fluctuations in populations is a power law function of the mean. We provide experimental evidence that bacterial metapopulations in patchy habitat landscapes on microchips follow this law. Furthermore, we find that increased variance of patch-corridor connectivity leads to a qualitative transition in the fluctuation scaling. We discuss these results in the context of the spatial ecology of microbes in soil.

Spatiotemporal structures and heterogeneities are common in natural habitats, yet their role in the evolution of antibiotic resistance is still to be uncovered. We applied a microfluidic gradient generator device to study the emergence of resistant bacteria in spatial ciprofloxacin gradients. We observed biofilm formation in regions with sub-inhibitory concentrations of antibiotics, which quickly expanded into the high antibiotic regions. In the absence of an explicit structure of the habitat, this multicellular formation led to a spatial structure of the population with local competition and limited migration. Therefore, such structures can function as amplifiers of selection and aid the spread of beneficial mutations. We found that the physical environment itself induces stress-related mutations that later prove beneficial when cells are exposed to antibiotics. This shift in function suggests that exaptation occurs in such experimental scenarios. The above two processes pave the way for the subsequent emergence of highly resistant specific mutations.

Although the U.S. Supreme Court goes to great lengths to avoid the “political thicket,” it is sometimes unwittingly pulled in. We employ several experimental treatments—each of which is composed of real behaviors that took place during the Trump impeachment trial—to understand the impact of the trial on attitudes about the Court. We find that Chief Justice Roberts’ presence and behaviors during the trial failed to legitimize the proceeding and may have even harmed views of the Court. Treatments involving Roberts’ actions decreased willingness to accept Court decisions and, in some cases, negatively impacted perceived legitimacy. We also find that criticisms of the Chief Justice by Senators decreased decision acceptance. These findings clarify both the bounds of the institution’s legitimizing power and the tenuous nature of public support in times of greater Court politicization by outside actors.

Background The loss of endothelial integrity increases the risk of intracerebral hemorrhage during ischemic stroke. Adjunct therapeutic targets for reperfusion in ischemic stroke are in need to prevent blood‐brain barrier disruption. Recently, we have shown that endothelial permeability is mediated by lysophosphatidic acid (LPA), but the role of autotaxin, which produces LPA, remains unclear in stroke. We investigate whether autotaxin/LPA axis regulates blood‐brain barrier integrity after cerebral ischemia. Methods and Results Ischemic stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by 24‐hour reperfusion. The therapeutic efficacy of autotaxin/LPA receptor blockade was evaluated using triphenyl tetrazolium chloride staining, Evans blue permeability, infrared imaging, mass spectrometry, and XF24 analyzer to evaluate blood‐brain barrier integrity, autotaxin activity, and mitochondrial bioenergetics. In our mouse model of ischemic stroke, the mRNA levels of autotaxin were elevated 1.7‐fold following the cerebral ischemia and reperfusion (I/R) group compared with the sham. The enzymatic activity of autotaxin was augmented by 4‐fold in the I/R group compared with the sham. Plasma and brain tissues in I/R group showed elevated LPA levels. The I/R group also demonstrated mitochondrial dysfunction, as evidenced by decreased (P

Detailed knowledge of jet plume development in the near-field (the first 10–15 nozzle exit diameters for a round jet) is important in aero-engine propulsion system design, e.g., for jet noise and plume infrared (IR) signature assessment. Nozzle exit Mach numbers are often high subsonic but improperly expanded (e.g., shock-containing) plumes also occur; high Reynolds numbers (O (106)) are typical. The near-field is obviously influenced by nozzle exit conditions (velocity/turbulence profiles) so knowledge of exit boundary layer characteristics is desirable. Therefore, an experimental study was carried out to provide detailed data on nozzle inlet and exit conditions and near-field development for convergent round nozzles operated at Nozzle Pressure Ratios (NPRs) corresponding to high subsonic and supersonic (underexpanded) jet plumes. Both pneumatic probe and Laser Doppler Anemometry (LDA) measurements were made. The data revealed that internal nozzle acceleration led to a dramatic reduction in wall boundary layer thickness and a more laminar-like profile shape. The addition of a parallel wall extension to the end of the nozzle allowed the boundary layer to return to a turbulent state, increasing its thickness, and removing vena contracta effects. Differences in nozzle exit boundary layers exerted a noticeable influence but only in the first few diameters of plume development. The addition of the exit extension removed the vena contracta effects of the convergence only design. At underexpanded NPRs, this change to nozzle geometry modified the shock cell pattern and shortened the potential core length of the jet.

Yersinia pestis, the causative agent of bubonic and pneumonic plague, is typically a zoonotic vector-borne disease of wild rodents. Bacterial biofilm formation in the proventriculus of the flea contributes to chronic infection of fleas and facilitates efficient disease transmission. However prior to biofilm formation, ingested bacteria must survive within the flea midgut, and yet little is known about vector-pathogen interactions that are required for flea gut colonization. Here we establish a Drosophila melanogaster model system to gain insight into Y. pestis colonization of the insect vector. We show that Y. pestis establishes a stable infection in the anterior midgut of fly larvae, and we used this model system to study the roles of genes involved in biofilm production and/or resistance to gut immunity stressors. We find that PhoP and GmhA both contribute to colonization and resistance to antimicrobial peptides in flies, and furthermore, the data suggest biofilm formation may afford protection against antimicrobial peptides. Production of reactive oxygen species in the fly gut, as in fleas, also serves to limit bacterial infection, and OxyR mediates Y. pestis survival in both insect models. Overall, our data establish the fruit fly as an informative model to elucidate the relationship between Y. pestis and its flea vector.

There has been a significant increase in the consumption of cannabis for both recreational and medicinal purposes in recent years, and its use can have long-term consequences on cognitive functions, including memory. Here, we review the immediate and long-term effects of cannabis and its derivatives on glutamatergic neurotransmission, with a focus on both the presynaptic and postsynaptic alterations. Several factors can influence cannabinoid-mediated changes in glutamatergic neurotransmission, including dosage, sex, age, and frequency of use. Acute exposure to cannabis typically inhibits glutamate release, whereas chronic use tends to increase glutamate release. Conversely, the postsynaptic alterations are more complicated than the presynaptic effects, as cannabis can affect the glutamate receptor expression and the downstream signaling of glutamate. All these effects ultimately influence cognitive functions, particularly memory. This review will cover the current research on glutamate–cannabis interactions, as well as the future directions of research needed to understand cannabis-related health effects and neurological and psychological aspects of cannabis use. [ABSTRACT FROM AUTHOR]

The last few years have witnessed an increase in democratic "backsliding" in the United States—a decline in the quality of democracy, typically accompanied by an influx of non-normative behavior, such as political violence. Despite the real consequences of support for violence, fairly little is known about such an extremist attitude outside studies of terrorism or aggression. Using a unique survey containing many psychological, political, and social characteristics, we find that perceived victimhood, authoritarianism, populism, and white identity are the most powerful predictors of support for violence, though military service, conspiratorial thinking, anxiety, and feelings of powerlessness are also related. These patterns suggest that subjective feelings about being unjustly victimized—irrespective of the truth of the matter—and the psychological baggage that accompanies such feelings lie at the heart of support for violence. We use these results to build a profile of characteristics that explain support for violence; the predictive validity of this profile is then tested by examining its relationship with support for the January 6, 2021, U.S. Capitol riot, with which it is strongly associated, even accounting for support for Donald Trump. Our findings have implications for the detection of extremist attitudes and our understanding of the non-partisan/ideological foundations of anti-social political behavior. [ABSTRACT FROM AUTHOR]