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A new clinical trial is testing a virtual reality (VR) based psychological therapy for people with severe mental health difficulties. gameChange is the largest ever clinical trial of virtual reality for a mental health disorder. Automated delivery of therapy using VR has potential to transform NHS provision of psychological therapy.
GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy.
Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.
Associations Between Trust in Healthcare Professionals and Perceptions of Modifiability of Dementia and Stroke Risks Through Maintaining or Changing Lifestyle Habits
Purpose: To investigate the trust levels in health information sources from a United States (U.S.) sample, and to examine the relationships between trust in healthcare professionals (HCPs) and perceptions of modifiability of dementia and stroke risks through maintaining or changing lifestyle habits. Design: Cross-sectional. Setting: A survey distributed via the vendor platform Prolific to a sample of the U.S. population. Participants: Data included on U.S. adults (n = 1478) in 2023. Measures: Outcome variables were perceiving that dementia and stroke risk can be modified through maintaining or changing lifestyle habits. Independent variables were trust levels in HCPs. Analysis: Descriptive analysis was performed to assess levels of trust in information sources. Subsequently, we performed multivariable regression analyses between trust in HCPs and perceptions of risk modifiability in dementia and stroke. A hierarchal cluster analysis was conducted to characterize trust patterns in this cohort. Results: Participants with high trust in HCPs compared to those with low trust in HCPs were more likely to perceive that maintaining (adjusted odds ratio [aOR] = 1.57, 95% confidence interval [CI]:1.15-2.12) and changing lifestyle habits (aOR = 1.72, 95% CI: 1.26-2.33) could reduce risk of dementia. Similar associations were found for perceptions of stroke risk reduction through maintaining (aOR = 1.49, 95% CI: 1.07-2.04) and changing (aOR = 2.68, 95% CI: 1.72-4.12) lifestyle habits. Cluster analyses identified three trust patterns amongst the participants: (i) a generally trusting cluster, (ii) a trusting of “official” health sources only cluster, and (iii) a generally not trusting cluster. Conclusion: This study found statistically significant associations between trusting HCPs and the perceptions that maintaining or changing lifestyle habits can modify risks of dementia and stroke, highlighting the importance of trust when developing preventive strategies.
Origin and Evolution of Bacterial Periplasmic Force Transducers.
In double-membraned bacteria, non-equilibrium processes that occur at the outer membrane are typically coupled to the chemiosmotically energized inner membrane. TolA and TonB are homologous proteins which energetically couple inner membrane motor proteins to the essential processes of outer membrane stabilization and substrate import, respectively. The evolutionary trajectories of these proteins have been difficult to elucidate due to low-sequence conservation, yet they are thought to transduce force similarly. Here, this problem was addressed using structural prediction approaches to identify and annotate force transduction operons to trace their distribution and evolutionary origins. In the process, we identify a novel outer membrane-tethering system and a previously unknown family of monomeric force transducers. This approach revealed putative tolA genes, and thus the core organizational principles of the tol-pal operon throughout diverse bacterial taxa. We discovered that the α-helical structure of the periplasm-spanning domain II of TolA previously thought its hallmark, is anomalous amongst most Tol-Pal systems. This structure is mainly prevalent in γ-proteobacteria, likely in adaptation to their lifestyle. Comparison of Tol-Pal and Ton system distribution suggests that TolA emerged from a TonB paralogue and co-emerged with Pal, the outer membrane-tethering lipoprotein that functionalizes the Tol-Pal system. We also determined that TolB, the Pal-mobilizing protein, likely emerged from a family of outer membrane proteins; and CpoB, a periplasmic factor that coordinates peptidoglycan remodeling with cell division, was originally a lipoprotein present in the ancestral Tol-Pal system. The extensive conservation of the Tol-Pal system throughout Gracilicutes highlights its significance in bacterial cell biology.
miR-107 represses DMPK and is sequestered by CUG repeats triggering the MSI2/miR-7 pathogenesis axis in myotonic dystrophy
Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder characterized by muscle disease, including muscle atrophy partially originating from excessive autophagy. We have previously demonstrated that excessive Musashi-2 (MSI2) repressed the biogenesis of miR-7, which derepressed autophagy, ultimately contributing to muscle atrophy, but the root cause of MSI2 dysregulation is unknown. Herein, we investigate the intricate role of miR-107 in DM1 pathogenesis, focusing on its involvement in the MSI2>miR-7>autophagy axis as this microRNA (miRNA) directly regulates MSI2. We found that in DM1, miR-107 function is impaired because expanded CUG repeats sequester it, causing an increase in the expression of its targets, including MSI2. Through different experimental approaches, including luciferase reporter assays, differential scanning fluorimetry, and electrophoretic mobility shift assay (EMSA), we confirm that miR-107 directly binds to CUG repeats in mutant DMPK transcripts. DMPK posttranscriptional regulation by miR-107 was also demonstrated. Modulation of miR-107 in a DM1 cell model context significantly affects its downstream targets, MSI2 and miR-7, thus decreasing excessive autophagic markers and restoring pathological phenotypes such as ribonuclear foci and impaired fusion capacity. These findings underscore the critical role of miR-107 in regulating the MSI2>miR-7>autophagy axis and support this miRNA as a promising therapeutic target for correcting muscle dysfunction in DM1.
Exploring standard and low luminance visual acuity and the Moorfields Acuity Chart as outcome measures in inherited retinal disease.
INTRODUCTION: Standard visual acuity (VA) is often insensitive to subtle changes in vision that result from inherited retinal disease. Low luminance VA (LLVA) has grown in popularity as an alternative acuity measure. A new test, the Moorfields Acuity Chart (MAC) has been designed as a more sensitive and repeatable test for use in patients with age-related macular degeneration. The study explores the utility and repeatability of standard VA, LLVA and the MAC in a mixed cohort of patients with inherited retinal disease. METHODS: Participants were recruited as part of the visual function in retinal degeneration study (Ethics Reference 20/WM/0283). Standard VA was obtained using the Early Treatment of Diabetic Retinopathy study (ETDRS) chart placed at 4 m. LLVA was obtained using the same ETDRS chart with the addition of a 2.0-log unit neutral density filter. MAC VA was obtained using standard clinic room lighting. All participants completed repeated testing. RESULTS: Thirty-five patient participants and 36 healthy controls, with logMAR 1.00 (6/60) or better, completed testing. Both LLVA and MAC VA were reduced compared to standard VA in patient participants and healthy controls (linear mixed model: p
An Analysis of Scotopic Microperimetry in Healthy Adults
Purpose: Scotopic microperimetry measures retinal sensitivity under very low light and may be useful in conditions characterized by nyctalopia, such as retinitis pigmentosa and age-related macular degeneration. The Scotopic Macular Integrity Assessment device enables two-color perimetry to isolate rod and cone responses. This study assesses the reliability, test–retest repeatability, and sensitivity in healthy participants aiming to establish normative values. Methods: Scotopic microperimetry was performed using cyan and red stimuli on a 37-point radial grid after dark adaptation on control participants with no history of eye disease and visual acuity of 0.1 logarithm of the minimum angle of resolution or better. Fixation stability, fixation losses, and identification of the rod-free zone were used as reliability metrics. A subset underwent repeat testing within 4 weeks. Results: Thirty-nine participants (19 male and 20 female), median age 24 years (interquartile range, 9.5 years) and 23 years (interquartile range, 9 years) for the right and left eyes, respectively, completed testing. Overall 77 eyes underwent scotopic testing, with 82% meeting reliability criteria. Mean cyan and red sensitivities were 19.9 ± 1.1 dB and 20.9 ± 1.2 dB in right eyes, and 20.1 ± 1.4 dB and 21.3 ± 1.4 dB in left eyes, respectively. Volumetric cyan and red sensitivities were 2868 ± 157 dB.deg2 and 3077 ± 176 dB.deg2 in the right eyes, respectively, and 2892 ± 205 dB.deg2 and 3126 ± 207 dB.deg2 in the left eyes, respectively. Mean sensitivity coefficients of repeatability (CoR) were ± 1.4 dB (cyan) and ± 2.1 dB (red) while pointwise coefficients of repeatability were ± 7.2 dB (95% confidence interval, 6.5–7.6 dB) for cyan and ± 7.9 dB (95% confidence interval, 7.3–8.4 dB) for red, with no significant differences between eyes or genders. Fixation stability assessed using the 95% bivariate contour ellipse area for cyan was 2.9 ± 5.9 deg2 and 2.3 ± 2.2 deg2 for the right and left eyes, respectively, and for red were 0.7 ± 0.6 deg2 and 0.9 ± 0.8 deg2 for the right and left eyes, respectively. Again, there were no significant differences between cyan and red tests (Friedman test, bivariate contour ellipse area 63%, P = 0.455; bivariate contour ellipse area 95%, P = 0.432). Conclusions: Scotopic microperimetry using the Scotopic Macular Integrity Assessment device was feasible and well-tolerated. Repeatability metrics demonstrated limitations in fine spatial mapping of scotopic retinal sensitivity. Translational Relevance: This study highlights potential areas for future improvements in scotopic microperimetry before its use as an outcome measure in clinical trials for retinal disease.
Evidence that 5-HT2A receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non-psychedelic drugs.
BACKGROUND AND PURPOSE: Serotonergic psychedelic drugs are under investigation as therapies for various psychiatric disorders, including major depression. Although serotonergic psychedelic drugs are 5-HT2A receptor agonists, some such agonists are not psychedelic, potentially due to differences in 5-HT2A receptor ligand bias or signalling efficacy. Here, we investigated 5-HT2A receptor signalling properties of selected psychedelic and non-psychedelic drugs. EXPERIMENTAL APPROACH: Gq-coupled (Ca2+ and IP1) and β-arrestin2 signalling effects of six psychedelic drugs (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe and DOI) and three non-psychedelic drugs (lisuride, TBG and IHCH-7079) were characterised using SH-SY5Y cells expressing human 5-HT2A receptors. Ligand bias and signalling efficacy were measured using concentration-responses curves, compared with 5-HT. The generality of findings was tested using rat C6 cells which express endogenous 5-HT2A receptors. KEY RESULTS: In SH-SY5Y cells, all psychedelic drugs were partial agonists at both 5-HT2A receptor signalling pathways and none showed significant ligand bias. In comparison, the non-psychedelic drugs were not distinguishable from psychedelic drugs in terms of ligand bias properties but exhibited the lowest 5-HT2A receptor signalling efficacy of all drugs tested. The latter result was confirmed in C6 cells. CONCLUSION AND IMPLICATIONS: In summary, all psychedelic drugs tested were unbiased, partial 5-HT2A receptor agonists. Importantly, the non-psychedelic drugs lisuride, TBG and IHCH-7079 were discriminated from psychedelic drugs, not through ligand bias but rather by low efficacy. Therefore, low 5-HT2A receptor signalling efficacy may explain why some 5-HT2A receptor agonists are not psychedelic, although a larger panel of drugs should be tested to confirm this idea.
Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.
Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P
Neuroticism, omega-3 fatty acids, and risk of incident dementia.
BACKGROUND: High levels of neuroticism are associated with an increased risk of dementia, yet the underlying biological mechanisms remain poorly understood. Investigating the role of metabolites, the downstream products of metabolic processes, may offer valuable insights into this association. METHODS: In 215,624 dementia-free UK Biobank participants aged 40-69 years, we assessed neuroticism's associations with 249 nuclear magnetic resonance-measured metabolites using linear regression. Metabolites reaching Bonferroni-corrected significance were further tested for associations with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD) using Cox proportional-hazards regression, and with white matter hyperintensities volume using linear regression. Causality in significant observational relationships was evaluated through two-sample Mendelian randomization. RESULTS: Neuroticism was significantly associated with 119 out of 249 metabolites (Bonferroni-adjusted p
Germ cell cancers in adult males are associated with a history of infantile pyloric stenosis.
Germ cell cancers (GCT) are the most common cancers of young men and are curable in at least 90% of cases. A number of aetiological factors have been identified which predispose to the development of these cancers, such as cryptorchidism and hernia. We report the association of GCT with infantile pyloric stenosis (IPS). The case records from 542 adult males with germ cell cancer arising from any site were screened for a history of pyloric stenosis requiring surgical treatment. Nine cases were observed (expected number = 2.168; chi squared = 21.5 (P < 0.001), standardised ratio = 4.15; 95% confidence interval 1.9-7.88). The recognition of rare associations of germ cell tumours may lead to the identification of genetic and environmental factors involved in their aetiology.
Sites in human nuclei where damage induced by ultraviolet light is repaired: Localization relative to transcription sites and concentrations of proliferating cell nuclear antigen and the tumour suppressor protein, p53
The repair of damage induced in DNA by ultraviolet light involves excision of the damaged sequence and synthesis of new DNA to repair the gap. Sites of such repair synthesis were visualized by incubating permeabilized HeLa or MRC-5 cells with the DNA precursor, biotin-dUTP, in a physiological buffer; then incorporated biotin was immunolabelled with fluorescent antibodies. Repair did not take place at sites that reflected the DNA distribution; rather, sites were focally concentrated in a complex pattern. This pattern changed with time; initially intense repair took place at transcriptionally active sites but when transcription became inhibited it continued at sites with little transcription. Repair synthesis in vitro also occurred in the absence of transcription. Repair sites generally contained a high concentration of proliferating cell nuclear antigen but not the tumour-suppressor protein, p53.
A cognitive map for value-guided choice in the ventromedial prefrontal cortex.
The prefrontal cortex (PFC) is crucial for economic decision-making. However, how PFC value representations facilitate flexible decisions remains unknown. We reframe economic decision-making as a navigation process through a cognitive map of choice values. We found rhesus macaques represented choices as navigation trajectories in a value space using a grid-like code. This occurred in ventromedial PFC (vmPFC) local field potential theta frequency across two datasets. vmPFC neurons deployed the same grid-like code and encoded chosen value. However, both signals depended on theta phase: occurring on theta troughs but on separate theta cycles. Finally, we found sharp-wave ripples-a key signature of planning and flexible behavior-in vmPFC. Thus, vmPFC utilizes cognitive map-based computations to organize and compare values, suggesting an alternative architecture for economic choice in PFC.
Neural mechanisms of credit assignment for delayed outcomes during contingent learning.
Adaptive behavior in complex environments critically relies on the ability to appropriately link specific choices or actions to their outcomes. However, the neural mechanisms that support the ability to credit only those past choices believed to have caused the observed outcomes remain unclear. Here, we leverage multivariate pattern analyses of functional magnetic resonance imaging (fMRI) data and an adaptive learning task to shed light on the underlying neural mechanisms of such specific credit assignment. We find that the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) code for the causal choice identity when credit needs to be assigned for choices that are separated from outcomes by a long delay, even when this delayed transition is punctuated by interim decisions. Further, we show when interim decisions must be made, learning is additionally supported by lateral frontopolar cortex (lFPC). Our results indicate that lFPC holds previous causal choices in a 'pending' state until a relevant outcome is observed, and the fidelity of these representations predicts the fidelity of subsequent causal choice representations in lOFC and HC during credit assignment. Together, these results highlight the importance of the timely reinstatement of specific causes in lOFC and HC in learning choice-outcome relationships when delays and choices intervene, a critical component of real-world learning and decision making.
Constructing future behavior in the hippocampal formation through composition and replay.
The hippocampus is critical for memory, imagination and constructive reasoning. Recent models have suggested that its neuronal responses can be well explained by state spaces that model the transitions between experiences. Here we use simulations and hippocampal recordings to reconcile these views. We show that if state spaces are constructed compositionally from existing building blocks, or primitives, hippocampal responses can be interpreted as compositional memories, binding these primitives together. Critically, this enables agents to behave optimally in new environments with no new learning, inferring behavior directly from the composition. We predict a role for hippocampal replay in building and consolidating these compositional memories. We test these predictions in two datasets by showing that replay events from newly discovered landmarks induce and strengthen new remote firing fields. When the landmark is moved, replay builds a new firing field at the same vector to the new location. Together, these findings provide a framework for reasoning about compositional memories and demonstrate that such memories are formed in hippocampal replay.
A tale of two algorithms: Structured slots explain prefrontal sequence memory and are unified with hippocampal cognitive maps.
Remembering events is crucial to intelligent behavior. Flexible memory retrieval requires a cognitive map and is supported by two key brain systems: hippocampal episodic memory (EM) and prefrontal working memory (WM). Although an understanding of EM is emerging, little is understood of WM beyond simple memory retrieval. We develop a mathematical theory relating the algorithms and representations of EM and WM by unveiling a duality between storing memories in synapses versus neural activity. This results in a formalism of prefrontal WM as structured, controllable neural subspaces (activity slots) representing dynamic cognitive maps without synaptic plasticity. Using neural networks, we elucidate differences, similarities, and trade-offs between the hippocampal and prefrontal algorithms. Lastly, we show that prefrontal representations in tasks from list learning to cue-dependent recall are unified as controllable activity slots. Our results unify frontal and temporal representations of memory and offer a new understanding for dynamic prefrontal representations of WM.
Deep learning image enhancement algorithms in PET/CT imaging: a phantom and sarcoma patient radiomic evaluation.
PURPOSE: PET/CT imaging data contains a wealth of quantitative information that can provide valuable contributions to characterising tumours. A growing body of work focuses on the use of deep-learning (DL) techniques for denoising PET data. These models are clinically evaluated prior to use, however, quantitative image assessment provides potential for further evaluation. This work uses radiomic features to compare two manufacturer deep-learning (DL) image enhancement algorithms, one of which has been commercialised, against 'gold-standard' image reconstruction techniques in phantom data and a sarcoma patient data set (N=20). METHODS: All studies in the retrospective sarcoma clinical [ 18 F]FDG dataset were acquired on either a GE Discovery 690 or 710 PET/CT scanner with volumes segmented by an experienced nuclear medicine radiologist. The modular heterogeneous imaging phantom used in this work was filled with [ 18 F]FDG, and five repeat acquisitions of the phantom were acquired on a GE Discovery 710 PET/CT scanner. The DL-enhanced images were compared to 'gold-standard' images the algorithms were trained to emulate and input images. The difference between image sets was tested for significance in 93 international biomarker standardisation initiative (IBSI) standardised radiomic features. RESULTS: Comparing DL-enhanced images to the 'gold-standard', 4.0% and 9.7% radiomic features measured significantly different (pcritical < 0.0005) in the phantom and patient data respectively (averaged over the two DL algorithms). Larger differences were observed comparing DL-enhanced images to algorithm input images with 29.8% and 43.0% of radiomic features measuring significantly different in the phantom and patient data respectively (averaged over the two DL algorithms). CONCLUSION: DL-enhanced images were found to be similar to images generated using the 'gold-standard' target image reconstruction method with more than 80% of radiomic features not significantly different in all comparisons across unseen phantom and sarcoma patient data. This result offers insight into the performance of the DL algorithms, and demonstrate potential applications for DL algorithms in harmonisation for radiomics and for radiomic features in quantitative evaluation of DL algorithms.