Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.

Profiling of circulating glial cells for accurate blood-based diagnosis of glial malignancies.

Here, we describe a blood test for the detection of glial malignancies (GLI-M) based on the identification of circulating glial cells (CGCs). The test is highly specific for GLI-M and can detect multiple grades (II-IV) and subtypes including gliomas, astrocytomas, oligodendrogliomas, oligoastrocytomas and glioblastomas, irrespective of gender and age. Analytical validation of the test was performed as per Clinical and Laboratory Standards Institute (CLSI) guidelines. Real-world performance characteristics of the test were evaluated in four clinical (observational) studies. The test has high analytical sensitivity (95%), specificity (100%) and precision (coefficient of variation [CV] = 13.7% for repeatability and CV = 23.5% for within laboratory precision, both at the detection threshold) and is not prone to interference from common drugs and serum factors. The ability of the test to detect and differentiate GLI-M from non-malignant brain tumours (NBT), brain metastases from primary epithelial malignancies (EPI-M) and healthy individual donors (HD) was evaluated in four clinical cohorts. Across these clinical studies, the test showed 99.35% sensitivity (95% confidence interval [CI]: 96.44%-99.98%) and 100% specificity (95% CI: 99.37%-100%). The performance characteristics of this test support its clinical utility for diagnostic triaging of individuals presenting with intracranial space-occupying lesions (ICSOL).

Challenges with segmenting intraoperative ultrasound for brain tumours.

Objective - Addressing the challenges that come with identifying and delineating brain tumours in intraoperative ultrasound. Our goal is to both qualitatively and quantitatively assess the interobserver variation, amongst experienced neuro-oncological intraoperative ultrasound users (neurosurgeons and neuroradiologists), in detecting and segmenting brain tumours on ultrasound. We then propose that, due to the inherent challenges of this task, annotation by localisation of the entire tumour mass with a bounding box could serve as an ancillary solution to segmentation for clinical training, encompassing margin uncertainty and the curation of large datasets. Methods - 30 ultrasound images of brain lesions in 30 patients were annotated by 4 annotators - 1 neuroradiologist and 3 neurosurgeons. The annotation variation of the 3 neurosurgeons was first measured, and then the annotations of each neurosurgeon were individually compared to the neuroradiologist's, which served as a reference standard as their segmentations were further refined by cross-reference to the preoperative magnetic resonance imaging (MRI). The following statistical metrics were used: Intersection Over Union (IoU), Sørensen-Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD). These annotations were then converted into bounding boxes for the same evaluation. Results - There was a moderate level of interobserver variance between the neurosurgeons [ I o U : 0.789 , D S C : 0.876 , H D : 103.227 ] and a larger level of variance when compared against the MRI-informed reference standard annotations by the neuroradiologist, mean across annotators [ I o U : 0.723 , D S C : 0.813 , H D : 115.675 ] . After converting the segments to bounding boxes, all metrics improve, most significantly, the interquartile range drops by [ I o U : 37 % , D S C : 41 % , H D : 54 % ] . Conclusion - This study highlights the current challenges with detecting and defining tumour boundaries in neuro-oncological intraoperative brain ultrasound. We then show that bounding box annotation could serve as a useful complementary approach for both clinical and technical reasons.

Feasibility of [18F]fluoropivalate hybrid PET/MRI for imaging lower and higher grade glioma: a prospective first-in-patient pilot study.

PURPOSE: MRI and PET are used in neuro-oncology for the detection and characterisation of lesions for malignancy to target surgical biopsy and to plan surgical resections or stereotactic radiosurgery. The critical role of short-chain fatty acids (SCFAs) in brain tumour biology has come to the forefront. The non-metabolised SCFA radiotracer, [18F]fluoropivalate (FPIA), shows low background signal in most tissues except eliminating organs and has appropriate human dosimetry. Tumour uptake of the radiotracer is, however, unknown. We investigated the uptake characteristics of FPIA in this pilot PET/MRI study. METHODS: Ten adult glioma subjects were identified based on radiological features using standard-of-care MRI prior to any surgical intervention, with subsequent histopathological confirmation of glioma subtype and grade (lower-grade - LGG - and higher-grade - HGG - patients). FPIA was injected as an intravenous bolus injection (range 342-368 MBq), and dynamic PET and MRI data were acquired simultaneously over 66 min. RESULTS: All patients tolerated the PET/MRI protocol. Three patients were reclassified following resection and histology. Tumour maximum standardised uptake value (SUVmax,60) increased in the order LGG (WHO grade 2) < HGG (WHO grade 3) < HGG (WHO grade 4). The net irreversible solute transfer, Ki, and influx rate constant, K1, were significantly higher in HGG (p < 0.05). Of the MRI variables studied, DCE-MRI-derived extravascular-and-extracellular volume fraction (ve) was high in tumours of WHO grade 4 compared with other grades (p < 0.05). SLC25A20 protein expression was higher in HGG compared with LGG. CONCLUSION: Tumoural FPIA PET uptake is higher in HGG compared to LGG. This study supports further investigation of FPIA PET/MRI for brain tumour imaging in a larger patient population. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04097535.

Effect of temperature on the post-diapause developmental rate, survival, and body mass of the solitary wasp Isodontia elegans: Implications for rearing of trap-nesting Hymenoptera.

We examined the relationship of post-diapause rearing temperature to developmental rate, survival, and adult body mass of the solitary wasp Isodontia elegans using prepupae from trap-nests. Isodontia elegans is a member of a genus often found in trap-nests in North America and Europe. Trap-nests are commonly used tools for studying cavity-nesting solitary wasps and bees. In temperate zones, progeny in nests usually overwinter as prepupae before pupating and emerging as adults. An important aspect of properly using trap-nests is determining temperatures that affect survival and health of developing offspring. After overwintering >600 cocoons containing prepupae after the summers of 2015 and 2016, we placed cocoons on a laboratory thermal gradient where offspring experienced one of 19 constant temperatures from 6 to 43 °C; emergence of adults was monitored for 100 days. Our conservative estimate for the critical thermal minimum for development is 14 °C, whereas that for the critical maximum is ∼33 °C. Prepupae transitioned to adults most rapidly at 29-33 °C, but developmental rate was lower for some progeny exposed to temperatures ≥30 °C. Offspring successfully reached the adult stage in <100 days at of temperatures of ∼19-33 °C. Adults from cocoons reared at lower temperatures weighed on average 6-10% more than expected based on their head widths, whereas those reared at higher temperatures weighed 4-10% less than expected. The difference may be due to greater rates of water loss and lipid metabolism during development at higher temperatures. Pre-overwintering cocoon mass was a significant predictor of relative adult body mass, indicating that adult health is partly related to their condition before overwintering. The trends we observed were similar to those for the bee Megachile rotundata, which we previously studied on the same gradient apparatus. However, data is needed on many other species of wasps and bees from a diversity of environments.

Effects of category learning strategies on recognition memory.

Extant research has shown that previously acquired categorical knowledge affects recognition memory, and that differences in category learning strategies impact classification accuracy. However, it is unknown whether different learning strategies also have downstream effects on subsequent recognition memory. The present study investigates the effect of two unidimensional rule-based category learning strategies - learning (a) with or without explicit instruction, and (b) with or without supervision - on subsequent recognition memory. Our findings suggest that acquiring categorical knowledge increased both hits (Experiments 1 and 2) and false-alarms (Experiment 1) for category-congruent items regardless of the particular strategy employed in initially learning these categories. There were, however, small processing speed advantages during recognition memory for both explicit instruction and supervised practice relative to neither (Experiment 2). We discuss these findings in the context of how prior knowledge influences recognition memory, and in relation to similar findings showing schematic effects on episodic memory.

Dissociating the freely-moving thought dimension of mind-wandering from the intentionality and task-unrelated thought dimensions.

The recently forwarded family-resemblances framework of mind-wandering argues that mind-wandering is a multidimensional construct consisting of a variety of exemplars. On this view, membership in the mind-wandering family is graded along various dimensions that define more or less prototypical instances of mind-wandering. In recent work, three dimensions that have played a prominent role in defining prototypicality within the mind-wandering family include: (a) task-relatedness (i.e., how related the content of a thought is to an ongoing task), (b) intentionality (i.e., whether thought is deliberately or spontaneously engaged), and (c) thought constraint (i.e., how much attention constrains thought dynamics). One concern, however, is that these dimensions may be redundant with each other. The utility of distinguishing among these different dimensions of mind-wandering rests upon a demonstration that they are dissociable. To shed light on this issue, we indexed the task-relatedness, intentionality, and constraint dimensions of thought during the completion of a laboratory task to evaluate how these dimensions relate to each other. We found that 56% of unconstrained thoughts were "on-task" and that 23% of constrained thoughts were "off-task." Moreover, we found that rates of off-task thought, but not "freely-moving" (i.e., unconstrained) thought, varied as a function of expected changes in task demands, confirming that task-relatedness and thought constraint are separable dimensions. Participants also reported 21% of intentional off-task thoughts that were freely moving and 9% of unintentional off-task thoughts that were constrained. Finally, off-task thoughts were more likely to be freely-moving than unintentional. Taken together, the results suggest that these three dimensions of mind-wandering are not redundant with one another.

Modeling undergraduates' selection of course modality: A large sample, multi-discipline study.

Scholarly understanding is limited with regard to what influences students' choice to take a particular course fully online or in-person. We surveyed 650 undergraduates at a public Canadian university who were enrolled in courses that were offered in both modalities during the same semester, for roughly the same tuition cost. The courses spanned a wide range of disciplines, from archaeology to computing science. Twenty-five variables were gauged, covering areas including students' personal circumstances, their competence in the language of instruction, previous experience with online courses, grade expectations, and psychological variables including their regulation of their time and study environment, work avoidance and social goal orientation. Two logistic regression models (of modality of enrolment and modality of preference) both had good fit to the data, each correctly classifying roughly 75% of cases using different variables. Implications for instructional design and enrolment management are discussed.

Two challenges for a dual system approach to temporal cognition.

Hoerl & McCormack (H&M) propose a two-system account of temporal cognition. We suggest that, following other classic proposals where cognitive systems are putatively independent, H&M's two-system hypothesis should, at a minimum, involve (1) a difference in the nature of the representations upon which each system operates, and (2) a difference in the computations they carry out. In this comment we offer two challenges aimed at showing that H&M's proposal does not meet the minimal requirements (1) and (2).

Looking at Mental Images: Eye-Tracking Mental Simulation During Retrospective Causal Judgment.

How do people evaluate causal relationships? Do they just consider what actually happened, or do they also consider what could have counterfactually happened? Using eye tracking and Gaussian process modeling, we investigated how people mentally simulated past events to judge what caused the outcomes to occur. Participants played a virtual ball-shooting game and then-while looking at a blank screen-mentally simulated (a) what actually happened, (b) what counterfactually could have happened, or (c) what caused the outcome to happen. Our findings showed that participants moved their eyes in patterns consistent with the actual or counterfactual events that they mentally simulated. When simulating what caused the outcome to occur, participants moved their eyes consistent with simulations of counterfactual possibilities. These results favor counterfactual theories of causal reasoning, demonstrate how eye movements can reflect simulation during this reasoning and provide a novel approach for investigating retrospective causal reasoning and counterfactual thinking.

Hyperspectral and multispectral imaging in neurosurgery: a systematic literature review and meta-analysis.

INTRODUCTION: The neuro-surgical community is witnessing a rising interest for surgical application of multispectral/hyperspectral imaging. Several potential technical applications of this optical imaging are reported, but the set-up is variable and so are the processing methods. We present a systematic review of the relevant literature on the topic. MATERIALS AND METHODS: A literature search based on the PRISMA principles was performed on PubMed, SCOPUS, and Web of Science, using MESH terms and Boolean operators. Papers regarding intra-operative in-vivo application of multispectral and/or hyperspectral imaging in humans during neurosurgical procedures were included. Papers reporting technologies related to radiological applications were excluded. A meta-analysis on the performance metrics was also conducted. RESULTS: Our search string retrieved 20 papers. The main applications of optical imaging during neurosurgery concern tumour detection and improvement of the extent of resection (15 papers) or visualization of perfusion changes during neuro-oncology or neuro-vascular surgery (5 papers). All the retrieved articles were pilot studies, proof of concepts, or case reports, with limited number of patients recruited. Sensitivity, specificity, and accuracy were promising in most of the reports, but the metanalysis showed heterogeneous approaches and results among studies. CONCLUSIONS: The present review shows that several approaches are currently being tested to integrate hyperspectral imaging in neurosurgery, but most of the studies reported a limited pool of patients, with different approaches to data collection and analysis. Further studies on larger cohorts of patients are therefore desirable to fully explore the potential of this imaging technique.

Modeling confidence in causal judgments.

Counterfactual theories propose that people's capacity for causal judgment depends on their ability to consider alternative possibilities: The lightning strike caused the forest fire because had it not struck, the forest fire would not have ensued. To accommodate a variety of psychological effects on causal judgment, a range of recent accounts have proposed that people probabilistically sample counterfactual alternatives from which they compute a graded measure of causal strength. While such models successfully describe the influence of the statistical normality (i.e., the base rate) of the candidate and alternate causes on causal judgments, we show that they make further untested predictions about how normality influences people's confidence in their causal judgments. In a large (N = 3,020) sample of participants in a causal judgment task, we found that normality indeed influences people's confidence in their causal judgments and that these influences were predicted by a counterfactual sampling model in which people are more confident in a causal relationship when the effect of the cause is less variable among imagined counterfactual possibilities. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Peer-Assisted Learning Is More Effective at Higher Task Complexity and Difficulty.

This paper presents two studies in which a peer-assisted learning condition was compared to an individual learning condition. The first study used the paired-associates learning task and the second study used an incrementally more complex task-the remote associate test. Participants in the peer-assisted learning condition worked in groups of four. They had to solve a given problem individually and give a first answer before being able to request to see their peers' solutions; then, a second answer was issued. After six sessions of peer-assisted practice, a final individual test was administered. Peer interaction was found to benefit learning in both studies but the benefit transferred to the final test only in the second study. Fine-grained behavioral analyses and computational modeling suggested that the benefits of peer interaction were (partially) offset by its costs, particularly increased cognitive load and error exposure. Overall, the superiority of peer-assisted learning over individual learning was more pronounced in the more complex task and for the more difficult problems in that task.

Distinct Capabilities in NAD Metabolism Mediate Resistance to NAMPT Inhibition in Glioblastoma.

Glioblastoma (GBM) cells require high levels of nicotinamide adenine dinucleotide (NAD) to fuel metabolic reactions, regulate their cell cycle and support DNA repair in response to chemotherapy and radiation. Inhibition of a key enzyme in NAD biosynthesis, NAMPT, has demonstrated significant anti-neoplastic activity. Here, we sought to characterise NAD biosynthetic pathways in GBM to determine resistance mechanisms to NAD inhibitors. GBM cells were treated with the NAMPT inhibitor FK866 with and without NAD precursors, and were analysed by qPCR, Western blot and proliferation assays (monolayer and spheroid). We also measured changes in the cell cycle, apoptosis, NAD/NADH levels and energy production. We performed orthoptic xenograft experiments in athymic nude mice to test the efficacy of FK866 in combination with temozolomide (TMZ). We show that the expression of key genes involved in NAD biosynthesis is highly variable across GBM tumours. FK866 inhibits proliferation, reduces NAD levels and limits oxidative metabolism, leading to G2/M cell cycle arrest; however, this can be reversed by supplementation with specific NAD precursors. Furthermore, FK866 potentiates the effects of radiation and TMZ in vitro and in vivo. NAMPT inhibitors should be considered for the treatment of GBM, with patients stratified based on their expression of key enzymes in other NAD biosynthetic pathways.

A computational modeling approach to investigating mind wandering-related adjustments to gaze behavior during scene viewing.

Research on gaze control has long shown that increased visual-cognitive processing demands in scene viewing are associated with longer fixation durations. More recently, though, longer durations have also been linked to mind wandering, a perceptually decoupled state of attention marked by decreased visual-cognitive processing. Toward better understanding the relationship between fixation durations and visual-cognitive processing, we ran simulations using an established random-walk model for saccade timing and programming and assessed which model parameters best predicted modulations in fixation durations associated with mind wandering compared to attentive viewing. Mind wandering-related fixation durations were best described as an increase in the variability of the fixation-generating process, leading to more variable-sometimes very long-durations. In contrast, past research showed that increased processing demands increased the mean duration of the fixation-generating process. The findings thus illustrate that mind wandering and processing demands modulate fixation durations through different mechanisms in scene viewing. This suggests that processing demands cannot be inferred from changes in fixation durations without understanding the underlying mechanism by which these changes were generated.

Comparison of commercial real-time reverse transcription-PCR assays for reliable, early, and rapid detection of heterologous strains of porcine reproductive and respiratory syndrome virus in experimentally infected or noninfected boars by use of different sample types.

The aims of this study were to compare three commercial porcine reproductive and respiratory syndrome virus (PRRSV) real-time reverse transcription-PCR (RT-PCR) assays for detection of genetically diverse PRRSV isolates in serum, semen, blood swabs, and oral fluids collected from experimentally infected boars and to evaluate the effects of sample pooling. Six groups of three boars negative for PRRSV were each inoculated with one of six PRRSV isolates (sharing 55 to 99% nucleotide sequence identity in ORF5). Samples were collected on days -2, 1, 3, 5, 7, 14, and 21 postinoculation (p.i.) and tested by one of three commercially available real-time RT-PCR assays (VetMax from Applied Biosystems, Foster City, CA [abbreviated AB]; VetAlert from Tetracore, Rockville, MD [TC]; and AcuPig from AnDiaTec GmbH, Kornwestheim, Germany [AD]). At day 1 p.i., all assays detected at least one positive sample in each group. The highest detection rates were on days 3 and 5 p.i. Between days 1 and 7 p.i., serum samples had the highest detection rate (90%) with 100% agreement between tests, followed by blood swabs (kappa value of 0.97) and semen (kappa value of 0.80). Oral fluids had the lowest detection rates (AB, 55%; TC, 41%; AD, 46%) and the highest disagreement between kits (kappa value of 0.63). Pools of five samples did not reduce the detection rates if there was one positive sample with a large amount (cycle threshold, <30) of viral RNA in the pool. Serum and blood swab samples had shorter turnaround times for RNA extraction. The AB assay had a 1.6-times-shorter PCR time. In summary, serum and blood swabs had the best performance with highest detection rates and agreement between assays and the shortest turnaround times.

Evaluation of the impact of the Canadian subarachnoid haemorrhage clinical decision rules on British practice.

INTRODUCTION: Acute headache is among the commonest presenting complaints to emergency departments. While it is estimated that only 1-3% result from subarachnoid haemorrhage (SAH), because the disease carries such significant morbidity and mortality if missed, most clinicians have a low threshold for investigation. A recent prospective cohort study in Canada determined a number of high-risk clinical characteristics for SAH in patients with acute headache. We investigated the potential impact of incorporating the Canadian clinical decision rules on British practice. METHODS: A retrospective case note review on all adult patients presenting to our emergency department with acute headache between August and October 2011 was conducted. The Canadian decision rules for SAH were applied retrospectively to the cases identified, and the sensitivity, specificity and negative predictive values calculated. The two-tailed McNemar test was used to evaluate differences between proportions of patients undergoing investigations using the clinical decision rules against current practice. RESULTS: In all, 112 patients met the inclusion criteria in a 3-month period, of which 41 patients (36.6%) underwent unenhanced computed tomography and 4 (3.6%) were found to have SAH. Nine patients subsequently had a lumbar puncture and none demonstrated xanthochromia. None of the patients who were not fully investigated were readmitted to the regional neurosurgical centre within 6 months of discharge with missed SAH. Application of the Canadian clinical decision rules would have led to an investigation rate between 59% and 74%, compared to an actual rate of 37% (p < 0.05). CONCLUSION: The present study shows that application of the Canadian clinical decision rules for SAH would lead to more patients with acute headache being investigated than current British practice. However, much larger prospective studies are required to determine whether such clinical decision rules may identify patients at risk who would otherwise have been missed.

Diversity and distribution of orchid bees (Hymenoptera: Apidae, Euglossini) in Belize.

Background: Orchid bees are abundant and widespread in the Neotropics, where males are important pollinators of orchids they visit to collect fragrant chemicals later used to court females. Assemblages of orchid bees have been intensively surveyed in parts of Central America, but less so in Belize, where we studied them during the late-wet and early-dry seasons of 2015-2020. Methods: Using bottle-traps baited with chemicals known to attract a variety of orchid bee species, we conducted surveys at sites varying in latitude, historical annual precipitation, elevation, and the presence of nearby agricultural activities. Each sample during each survey period consisted of the same number of traps and the same set of chemical baits, their positions randomized along transects. Results: In 86 samples, we collected 24 species in four genera: Euglossa (16 species), Eulaema (3), Eufriesea (3), and Exaerete (2). During our most extensive sampling (December 2016-February 2017), species diversity was not correlated with latitude, precipitation, or elevation; species richness was correlated only with precipitation (positively). However, a canonical correspondence analysis indicated that species composition of assemblages varied across all three environmental gradients, with species like Eufriesea concava, Euglossa imperialis, and Euglossa viridissima most common in the drier north, and Euglossa ignita, Euglossa purpurea, and Eulaema meriana more so in the wetter southeast. Other species, such as Euglossa tridentata and Eulaema cingulata, were common throughout the area sampled. Mean species diversity was higher at sites with agricultural activities than at sites separated from agricultural areas. A Chao1 analysis suggests that other species should yet be found at our sites, a conclusion supported by records from adjacent countries, as well as the fact that we often added new species with repeated surveys of the same sites up through early 2020, and with the use of alternative baits. Additional species may be especially likely if sampling occurs outside of the months/seasons that we have sampled so far.

Designing higher surface area metal-organic frameworks: are triple bonds better than phenyls?

We have synthesized, characterized, and computationally validated the high Brunauer-Emmett-Teller surface area and hydrogen uptake of a new, noncatenating metal-organic framework (MOF) material, NU-111. Our results imply that replacing the phenyl spacers of organic linkers with triple-bond spacers is an effective strategy for boosting molecule-accessible gravimetric surface areas of MOFs and related high-porosity materials.