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Constrained confabulation: Comment on "The paradox of the self-studying brain" by Battaglia, Servajean, and Friston.

Asia's Wolves and Synergies With Big Cats

In Asia, carnivore conservation is often focused on charismatic big cats. Opportunities to conserve the entire carnivore guild are frequently overlooked by channeling conservation and mitigation efforts into single-species conservation. We synthesize experiences across Asia to explore these challenges and propose mitigations to maximize conservation benefits for the entire carnivore guild. Seven challenges for wolves (Canis lupus) in Asia are highlighted: wolves (1) have been neglected over decades of single-species conservation, (2) receive less cultural appreciation in many regions, (3) are subject to lax legislation and law enforcement, (4) are often blamed disproportionately for livestock depredation, (5) are often considered more abundant than they are, (6), receive disproportionately little attention from the scientific and conservation communities relative to their ecological importance, and (7) are threatened ecologically and genetically by increasing feral dog populations. As a result, the status of wolves across Asia is poorly documented, there is an enhanced risk of losing significant evolutionary lineages, and it detracts from research and conservation opportunities to preserve the entire carnivore guild. We propose various remedies, such as widening the scope of existing conservation programs, building awareness and knowledge of communities and law enforcement agencies, and more research to inform conservation and legislation.

Correction to: Identifying remnant biodiversity hotspots in Southern Asia reveals disequilibrium in mammalian communities (Biodiversity and Conservation, (2024), 33, 11, (3057-3074), 10.1007/s10531-024-02902-0)

In this article, Susana Rostro-García at affiliation “Wildlife Conservation Research Unit, Department of Biology, The Recanati-Kaplan Centre, University of Oxford, Tubney House, Tubney, Oxon, OX13 5QL, UK” was missing from the author’s list. The original article has been corrected.

Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia.

INTRODUCTION: Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females. METHODS: We included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex. RESULTS: Females with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe. DISCUSSION: Females with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation. HIGHLIGHTS: Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.

Neural dynamics of reselecting visual and motor contents in working memory after external interference.

In everyday tasks, we must often shift our focus away from internal representations held in working memory to engage with perceptual events in the external world. Here, we investigated how our internal focus is reestablished following an interrupting task by tracking the reselection of visual representations and their associated action plans in working memory. Specifically, we ask whether reselection occurs for both visual and motor memory attributes and when this reselection occurs. We developed a visual-motor working-memory task in which participants were retrospectively cued to select one of two memory items before being interrupted by a perceptual discrimination task. To determine what information was reselected, the memory items had distinct visual and motor attributes. To determine when internal representations were reselected, the interrupting task was presented at one of three distinct time points following the retro-cue. We employed electroencephalography time-frequency analyses to track the initial selection and later reselection of visual and motor representations, as operationalized through modulations of posterior alpha (8-12 Hz) activity relative to the memorized item location (visual) and of central beta (13-30 Hz) activity relative to the required response hand (motor). Our results showed that internal visual and motor contents were concurrently reselected immediately after completing the interrupting task, rather than only when internal information was required for memory-guided behavior. Thus, following interruption, we swiftly resume our internal focus in working memory through the simultaneous reselection of memorized visual representations and their associated action plans, thereby restoring internal contents to a ready-to-use state.Significance statement A key challenge for working memory is to maintain past visual representations and their associated actions while engaging with the external environment. Our cognitive system must, therefore, often juggle multiple tasks within a common time frame. Despite the ubiquity of multi-task situations in everyday life, working memory has predominantly been studied devoid of additional perceptual, attentional, and response demands during the retention interval. Here, we investigate the neural dynamics of returning to internal contents following task-relevant interruptions. Particularly, we identify which attributes of internal representations are reselected and when this reselection occurs. Our findings demonstrate that both visual and motor contents are reselected immediately and in tandem after completion of an external, interrupting task.

Integrative role of CTPS cytoophidia in polyploid tissue growth and nutrient adaptation

Tissue growth and development are fundamental to organismal survival, requiring precise coordination of metabolic processes, nutrient availability, and signaling pathways. Cytidine triphosphate synthase (CTPS) is a rate-limiting enzyme in nucleotide biosynthesis and assembles filamentous cytoophidia, conserved across species. Despite increasing interest in cytoophidia, how CTPS filaments integrate metabolic and signaling cues to drive cell size and tissue growth remains incompletely understood. Using RNA interference and clustered regularly interspaces short palindromic repeats (CRISPR) / CRISPR-associate nuclease 9 gene editing, we generated CTPS-knockdown and point-mutated mutants to investigate the role of cytoophidia in cell growth. Specifically, we introduced the H355A mutation, which disrupts CTPS filament formation without affecting its enzymatic activity. Our findings revealed that CTPS depletion or filament disruption significantly impairs growth in polyploid organs, such as the fat body and salivary glands, underscoring the pivotal role of CTPS cytoophidia in cell growth regulation. Mutants lacking cytoophidia exhibited reduced DNA replication activity and smaller cell sizes compared to wild-type controls. Mechanistically, we found that nutrient-sensing pathways, particularly insulin-PI3K-Akt signaling pathway, regulate CTPS expression and cytoophidia formation in response to nutrient availability. Activation of the sterol regulatory element-binding protein partially rescued the growth defects caused by CTPS depletion. These findings provide new insights into the molecular mechanisms of the regulation of CTPS filaments, highlighting their role as critical mediators of tissue growth by integrating environmental demands, metabolism, and signaling pathways to regulate cell size and nutrient adaptation.

Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.

We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

In Vivo Quantification of Creatine Kinase Kinetics in Mouse Brain Using 31P-MRS at 7 T

31P-MRS is a method of choice for studying neuroenergetics in vivo, but its application in the mouse brain has been limited, often restricted to ultrahigh field (> 7 T) MRI scanners. Establishing its feasibility on more readily available preclinical 7-T scanners would create new opportunities to study metabolism and physiology in murine models of brain disorders. Here, we demonstrate that the apparent forward rate constant (kf) of creatine kinase (CK) can be accurately quantified using a progressive saturation-transfer approach in the mouse brain at 7 T. We also find that a 20% reduction in respiration of anesthetized mice can lead to 36% increase in kf attributable to a drop in cellular pH and mitochondrial ATP production. To achieve this, we used a test–retest analysis to assess the reliability and repeatability of 31P-MRS acquisition, analysis, and experimental design protocols. We report that many 31P-containing metabolites can be reliably measured using a localized 3D-ISIS sequence, which showed highest SNR amplitude, SNR consistency, and minimal T2 relaxation signal loss. Our study identifies key physiological factors influencing mouse brain energy homeostasis in vivo and provides a methodological basis to guide future studies interested in implementing 31P-MRS on preclinical 7-T scanners.

Rapid identification of bacterial isolates using microfluidic adaptive channels and multiplexed fluorescence microscopy.

We demonstrate the rapid capture, enrichment, and identification of bacterial pathogens using Adaptive Channel Bacterial Capture (ACBC) devices. Using controlled tuning of device backpressure in polydimethylsiloxane (PDMS) devices, we enable the controlled formation of capture regions capable of trapping bacteria from low cell density samples with near 100% capture efficiency. The technical demands to prepare such devices are much lower compared to conventional methods for bacterial trapping and can be achieved with simple benchtop fabrication methods. We demonstrate the capture and identification of seven species of bacteria with bacterial concentrations lower than 1000 cells per mL, including common Gram-negative and Gram-positive pathogens such as Escherichia coli and Staphylococcus aureus. We further demonstrate that species identification of the trapped bacteria can be undertaken in the order of one-hour using multiplexed 16S rRNA-FISH with identification accuracies of 70-98% with unsupervised classification methods across 7 species of bacteria. Finally, by using the bacterial capture capabilities of the ACBC chip with an ultra-rapid antimicrobial susceptibility testing method employing fluorescence imaging and convolutional neural network (CNN) classification, we demonstrate that we can use the ACBC chip as an imaging flow cytometer that can predict the antibiotic susceptibility of E. coli cells after identification.

Infection Inspection: using the power of citizen science for image-based prediction of antibiotic resistance in Escherichia coli treated with ciprofloxacin.

Antibiotic resistance is an urgent global health challenge, necessitating rapid diagnostic tools to combat its threat. This study uses citizen science and image feature analysis to profile the cellular features associated with antibiotic resistance in Escherichia coli. Between February and April 2023, we conducted the Infection Inspection project, in which 5273 volunteers made 1,045,199 classifications of single-cell images from five E. coli strains, labelling them as antibiotic-sensitive or antibiotic-resistant based on their response to the antibiotic ciprofloxacin. User accuracy in image classification reached 66.8 ± 0.1%, lower than our deep learning model's performance at 75.3 ± 0.4%, but both users and the model were more accurate when classifying cells treated at a concentration greater than the strain's own minimum inhibitory concentration. We used the users' classifications to elucidate which visual features influence classification decisions, most importantly the degree of DNA compaction and heterogeneity. We paired our classification data with an image feature analysis which showed that most of the incorrect classifications happened when cellular features varied from the expected response. This understanding informs ongoing efforts to enhance the robustness of our diagnostic methodology. Infection Inspection is another demonstration of the potential for public participation in research, specifically increasing public awareness of antibiotic resistance.

A first report of the detection of Avipoxvirus genomic sequences in louse flies (Diptera: Hippoboscidae).

Contributed Talks I: Detecting and characterising microsaccades from AOSLO images of the photoreceptor mosaic using computer vision.

Fixational eye movements (FEMs), especially microsaccades (MS), are promising biomarkers of neurodegenerative disease. In vivo images of the photoreceptor mosaic acquired using an Adaptive Optics Scanning Laser Ophthalmoscope (AOSLO) are systematically distorted by eye motion. Most methods to extract FEMs from AOSLO data rely on comparison to a motion-free reference, giving eye-position as a function of time. MS are subsequently identified using adaptive velocity thresholds (Engbert & Kliegl, 2003). We use computer vision and machine learning (ML) for detection and characterisation of MS directly from raw AOSLO images. For training and validation, we use Emulated Retinal Image CApture (ERICA), an open-source tool to generate synthetic AOSLO datasets of retinal images and ground-truth velocity profiles (Young & Smithson, 2021). To classify regions of AOSLO images that contain a MS, images were divided into a grid of 32-by-32-pixel sub-images. Predictions from rows of sub-images aligned with the fast-scan of the AOSLO were combined, giving 1ms resolution. Model performance was high (F1 scores >0.92) across plausible MS displacement magnitudes and angles, with most errors close to the velocity threshold for classification. Direct velocity predictions were also derived from regression ML models. We show that ML models can be systematically adapted for generalisation to real in vivo images, allowing characterisation of MS at much finer spatial scales than video-based eye-trackers.

Investigating the association between recorded smoking cessation interventions and smoking cessation in people living with cardiovascular disease using UK general practice data.

BACKGROUND: Smoking significantly increases the risk of cardiovascular diseases (CVD), yet quitting smoking after diagnosis of CVD can mitigate further negative impacts. However, encouraging smoking cessation remains a challenge for General Practitioners (GPs) with concerns regarding mental health. Since 2004, the UK's Quality and Outcomes Framework (QOF) incentivises GP smoking cessation support. Despite this, a significant proportion of individuals diagnosed with CVD continue to smoke after diagnosis. This study aims to investigate the frequencies and types of smoking cessation interventions offered to people with CVD (defined as coronary heart disease (CHD) and stroke), with and without mental illness, and assess their association with successful cessation. METHODS: This retrospective cohort study examined adults diagnosed with CHD or stroke using the QResearch general practice records database (1996-2019). We evaluated the frequency and types of smoking cessation interventions documented in patients' records, including education, brief interventions, pharmacological support, referrals, and counselling. Logistic regression assessed the relationship between recorded interventions and smoking abstinence rates within the one-year post-index event, considering QOF incentives and mental illness presence. RESULTS: While smoking cessation education was common in general practice settings, prescriptions for nicotine replacement therapy or other evidence-based interventions were comparatively low. CHD and stroke populations showed a significant association between any intervention and smoking cessation within one year (CHD: OR 1.41, 95% CI 1.36-1.45; stroke: OR 1.49, 95% CI 1.43-1.55). Education consistently correlated with higher cessation likelihoods, while other interventions were linked to lower rates. Individuals with common and serious mental illness were less likely to quit, irrespective of intervention. QOF implementation led to increased documentation of advice but not intensive support or treatment, with pre-QOF interventions associated with significantly increased abstinence likelihoods (CHD: OR 5.09, 95% CI 4.84-5.35; stroke: OR 4.44, 95% CI 4.07-4.86). CONCLUSIONS: Financial incentives for GP smoking cessation support outlined in QOF may not suffice to enhance methods that are more efficacious or improve cessation rates, especially among people with mental illness. Practical strategies that provide tangible support and treatment are needed for CVD patients, including those with mental illness, to facilitate successful cessation.

A single dose of lamotrigine induces a positive memory bias in healthy volunteers.

BACKGROUND: Lamotrigine has been shown to be effective in the long-term treatment and relapse prevention of depression in bipolar disorder. However, the neuropsychological mechanisms underlying these effects are unclear. We investigated the effects of lamotrigine on a battery of emotional processing tasks in healthy volunteers, previously shown to be sensitive to antidepressant drug action in similar experimental designs. METHODS: Healthy volunteers (n = 36) were randomized in a double-blind design to receive a single dose of placebo or 300 mg lamotrigine. Mood and subjective effects were monitored throughout the study period, and emotional processing was assessed using the Oxford Emotional Test Battery (ETB) 3 hours post-administration. RESULTS: Participants receiving lamotrigine showed increased accurate recall of positive versus negative self-descriptors, compared to those in the placebo group. There were no other significant effects on emotional processing in the ETB, and lamotrigine did not affect ratings of mood or subjective experience. CONCLUSIONS: Lamotrigine did not induce widespread changes in emotional processing. However, there was increased positive bias in emotional memory, similar to the effects of antidepressants reported in previous studies. Further work is needed to assess whether similar effects are seen in the clinical treatment of patients with bipolar disorder and the extent to which this is associated with its clinical action in relapse prevention.

Sleep-related hypermotor epilepsy in a patient with myelin-oligodendrocyte-glycoprotein antibody disease.

Unusual seizure phenotypes in myelin-oligodendrocyte-glycoprotein (MOG) seropositive patients have previously been reported, although so far, no cases of sleep-related hypermotor epilepsy (SHE). In our case, a patient with a diagnosis of MOG antibody-associated disease (MOGAD) began reporting unusual sleep disturbances; video-audio documentation was in keeping with the clinical diagnosis of SHE. MRI brain was normal at the time of the assessment for seizures. Symptoms responded to antiepileptic drugs (AEDs). These unusual seizure events were thought to be indicative of the underlying autoimmune condition, suggesting that the clinical spectrum of MOGAD is wider than previously thought.

Future directions for brain health clinics.

Brain Health Services are second-generation memory clinics that aim to reduce the risk of progression to dementia in at-risk individuals. We describe the rationale for such a service, and comment on its novel implementation by Venkataraman and colleagues that integrates digital technologies and biomarker testing. We describe the advantages and possible limitations of such an approach, then investigate areas for further work - namely, the need to account for multiple pathologies in biomarker testing and to formulate standards for genetic counselling.

Dorsomedial and ventromedial prefrontal cortex lesions differentially impact social influence and temporal discounting.

The medial prefrontal cortex (mPFC) has long been associated with economic and social decision-making in neuroimaging studies. Several debates question whether different ventral mPFC (vmPFC) and dorsal mPFC (dmPFC) regions have specific functions or whether there is a gradient supporting social and nonsocial cognition. Here, we tested an unusually large sample of rare participants with focal damage to the mPFC (N = 33), individuals with lesions elsewhere (N = 17), and healthy controls (N = 71) (total N = 121). Participants completed a temporal discounting task to estimate their baseline discounting preferences before learning the preferences of two other people, one who was more temporally impulsive and one more patient. We used Bayesian computational models to estimate baseline discounting and susceptibility to social influence after learning others' economic preferences. mPFC damage increased susceptibility to impulsive social influence compared to healthy controls and increased overall susceptibility to social influence compared to those with lesions elsewhere. Importantly, voxel-based lesion-symptom mapping (VLSM) of computational parameters showed that this heightened susceptibility to social influence was attributed specifically to damage to the dmPFC (area 9; permutation-based threshold-free cluster enhancement (TFCE) p < 0.025). In contrast, lesions in the vmPFC (areas 13 and 25) and ventral striatum were associated with a preference for seeking more immediate rewards (permutation-based TFCE p < 0.05). We show that the dmPFC is causally implicated in susceptibility to social influence, with distinct ventral portions of mPFC involved in temporal discounting. These findings provide causal evidence for sub-regions of the mPFC underpinning fundamental social and cognitive processes.

Reproductive output of old males is limited by seminal fluid, not sperm number.

Male reproductive senescence is typically characterized by a decline in the number of sperm produced and transferred by old males, a phenomenon that may be exacerbated in polygynous species where males mate multiply. However, males also transfer seminal fluid to females, and little is known about its role in modulating male reproductive senescence. Here, we explore the contributions of sperm and seminal fluid towards male reproductive senescence in a series of sequential matings, using Drosophila melanogaster. As expected, old males produce fewer offspring than young males. However, this pattern is not driven by sperm limitation: old males have more sperm and transfer similar numbers to females, compared to young males. Instead, females storing fewer sperm of old males compared to that of young males, over a long term, drives male reproductive senescence. We are able to mitigate the age-related decline in male reproductive output by supplementing females with the seminal fluid of a young male, before she mates with an old male. Similarly, we alleviate the reduction in reproductive output across sequential matings by supplementing females with seminal fluid. Our findings highlight that seminal fluid, rather than sperm number, limits reproductive success in old or multiply mating males, highlighting its underappreciated role in reproductive aging.

Engineering of extracellular vesicles for efficient intracellular delivery of multimodal therapeutics including genome editors.

Intracellular delivery of protein and RNA therapeutics represents a major challenge. Here, we develop highly potent engineered extracellular vesicles (EVs) by incorporating bio-inspired attributes required for effective delivery. These comprise an engineered mini-intein protein with self-cleavage activity for active cargo loading and release, and fusogenic VSV-G protein for endosomal escape. Combining these components allows high efficiency recombination and genome editing in vitro following EV-mediated delivery of Cre recombinase and Cas9/sgRNA RNP cargoes, respectively. In vivo, infusion of a single dose Cre loaded EVs into the lateral ventricle in brain of Cre-LoxP R26-LSL-tdTomato reporter mice results in greater than 40% and 30% recombined cells in hippocampus and cortex respectively. In addition, we demonstrate therapeutic potential of this platform by showing inhibition of LPS-induced systemic inflammation via delivery of a super-repressor of NF-ĸB activity. Our data establish these engineered EVs as a platform for effective delivery of multimodal therapeutic cargoes, including for efficient genome editing.

Evaluation of an adaptation to the Oxford Cognitive Screen for reduced visual acuity: a cohort study.

BACKGROUND: The Oxford Cognitive Screen (OCS) was specifically designed for acute stroke survivors and to be inclusive of aphasia, neglect, motor impairments. However, reduced visual acuity (VA), including lack of access to required reading glasses, can impact completion rates and performance. The aim of the study was to evaluate contrast enhanced OCS-tasks for completion rates and equivalence to the original version. METHODS: Adult stroke survivors were asked to complete two versions (standard and adapted) of two tasks (broken hearts cancellation and trails) in a randomized order, to determine relative completion rates and equivalency. A bedside vision assessment, completed by an orthoptist was collected, including near and distance VA with required refractive correction if available. Two groups were created based on near VA; normal near VA (≥0.2LogMAR) and reduced near VA (<0.2LogMAR). RESULTS: Five hundred participants were recruited, 56.8% male, mean age 70.62 years. Mean near VA was 0.278 (SD0.277) LogMAR. The broken hearts and trails tasks were completed by 2.2% (p=0.041) and 0.4% (p=0.791) more participants respectively with the adapted version. Participants completing both versions with good near VA were used to analyze equivalence. All the lower and upper bounds of the two one-sided test of equivalence fell within the range of 0.5SD for all scores, indicating that the means are equivalent. Analysis of impairment detection revealed fair to good agreement. CONCLUSION: The adapted version is suitable for stroke survivors with reduced near VA to complete the assessment. In the presence of good VA, the tasks were deemed to be equivalent.