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Episodic counterfactual thoughts (eCFT) consist of imagining alternative outcomes to past experiences. A common sub-class of eCFT— upward eCFT—involves imagining how past negative experiences could have been better , either because one could have done something differently (internal) or because something about the circumstances could have been different (external). Although previous neuroimaging research has shown that the brain's default mode network (DMN) supports upward eCFT, it is unclear how it is differentially recruited during internal versus external upward eCFT. We collected functional magnetic resonance imaging data while participants remembered negative autobiographical memories, generated either internal or external upward eCFT for the memory, and then rated the plausibility, perceived control and difficulty of eCFT generation. Both internal and external eCFT engaged midline regions of cingulate cortex, a central node of the DMN. Most activity differentiating eCFT, however, occurred outside the DMN. External eCFT engaged cuneus, angular gyrus and precuneus, whereas internal eCFT engaged posterior cingulate and precentral gyrus. Angular gyrus and precuneus were additionally sensitive to perceived plausibility of external eCFT, while postcentral gyrus and insula activity scaled with perceived plausibility of internal eCFT. These results highlight the key brain regions that might be involved in cases of maladaptive mental simulations. This article is part of the theme issue ‘Thinking about possibilities: mechanisms, ontogeny, functions and phylogeny’.

Consider the trilinear form for twisted convolution on R 2 d \mathbb {R}^{2d} : T t ( f ) ≔ ∬ f 1 ( x ) f 2 ( y ) f 3 ( x + y ) e i t σ ( x , y ) d x d y , \begin{equation*} \mathcal {T}_t(\mathbf {f})≔\iint f_1(x)f_2(y)f_3(x+y)e^{it\sigma (x,y)}dxdy, \end{equation*} where σ \sigma is a symplectic form and t t is a real-valued parameter. It is known that in the case t ≠ 0 t\neq 0 the optimal constant for twisted convolution is the same as that for convolution, though no extremizers exist. Expanding about the manifold of triples of maximizers and t = 0 t=0 we prove a sharpened inequality for twisted convolution with an arbitrary antisymmetric form in place of σ \sigma .

Supplementary Figure 1 showing 1H-NMR spectra of Calix, TMZ and TMZ@Calix complex

The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumor in adults. However, its poor stability and unfavorable pharmacokinetic profile limit its clinical efficacy. There is an unmet need to tailor the therapeutic window of TMZ, either through complex derivatization or by utilizing pharmaceutical excipients. To enhance stability and aqueous solubility, we encapsulated TMZ in a p-sulphonatocalix[4]arene (Calix) nanocapsule and used 1H-NMR, LC-MS, and UV–Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and European Medicines Agency guidelines. LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix in vivo. The therapeutic efficacy of TMZ@Calix was compared with that of unbound TMZ in GBM cell lines and patient-derived primary cells with known O6-methylguanine-DNA methyltransferase (MGMT) expression status and in vivo in an intracranial U87 xenograft mouse model. Encapsulation significantly enhanced the stability of TMZ in all conditions tested. TMZ@Calix was more potent than native TMZ at inhibiting the growth of established GBM cell lines and patient-derived primary lines expressing MGMT and highly resistant to TMZ. In vivo, native TMZ was rapidly degraded in mouse plasma, whereas the stability of TMZ@Calix was enhanced threefold with increased therapeutic efficacy in an orthotopic model. In the absence of new effective therapies, this novel formulation is of clinical importance, serving as an inexpensive and highly efficient treatment that could be made readily available to patients with GBM and warrants further preclinical and clinical evaluation.

Effects of ADI-PEG20 on the folate pathway

Kaplan Meier plots for PFS and OS

Purpose:Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed.Patients and Methods:We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16–06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy.Results:Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti–ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5–20.8) and overall survival was 6.3 months (95% CI, 1.8–9.7).Conclusions:In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

ASS1 immunohistochemistry

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT

We investigated whether prestimulus alpha-band oscillatory activity and stimulus-elicited recurrent processing interact to facilitate conscious visual perception. Participants tried to perceive a visual stimulus that was perceptually masked through object substitution masking (OSM). We showed that attenuated prestimulus alpha power was associated with greater negative-polarity stimulus-evoked ERP activity that resembled the visual awareness negativity (VAN), previously argued to reflect recurrent processing related to conscious perception. This effect, however, was not associated with better perception. Instead, when prestimulus alpha power was elevated, a preferred prestimulus alpha phase was associated with a greater VAN-like negativity, which was then associated with better cue perception. Cue perception was worse when prestimulus alpha power was elevated but the stimulus occurred at a nonoptimal prestimulus alpha phase and the VAN-like negativity was low. Our findings suggest that prestimulus alpha activity at a specific phase enables temporally selective recurrent processing that facilitates conscious perception in OSM.

Moral Foundations Theory (MFT) posits that the human mind contains modules (or "foundations") that are functionally specialized to moralize unique dimensions of the social world: Authority, Loyalty, Purity, Harm, Fairness, and Liberty. Despite this strong claim about cognitive architecture, it is unclear whether neural activity during moral reasoning exhibits this modular structure. Here, we use spatiotemporal partial least squares correlation (PLSC) analyses of fMRI data collected during judgments of foundation-specific violations to investigate whether MFT's cognitive modularity claim extends to the neural level. A mean-centered PLSC analysis returned two latent variables that differentiated between social norm and moral foundation violations, functionally segregated Purity, Loyalty, Physical Harm, and Fairness from the other foundations, and suggested that Authority has a different neural basis than other binding foundations. Non-rotated PLSC analyses confirmed that neural activity distinguished social norm from moral foundation violations, and distinguished individualizing and binding moral foundations if Authority is dropped from the binding foundations. Purity violations were persistently associated with amygdala activity, whereas moral foundation violations more broadly tended to engage the default network. Our results constitute partial evidence for neural modularity and motivate further research on the novel groupings identified by the PLSC analyses.

People more frequently select norm-violating factors, relative to norm-conforming ones, as the cause of some outcome. Until recently, this abnormal-selection effect has been studied using retrospective vignette-based paradigms. We use a novel set of video stimuli to investigate this effect for prospective causal judgments—i.e., judgments about the cause of some future outcome. Four experiments show that people more frequently select norm-violating factors, relative to norm-conforming ones, as the cause of some future outcome. We show that the abnormal-selection effects are not primarily explained by the perception of agency (Experiment 4). We discuss these results in relation to recent efforts to model causal judgment.

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.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT 2 R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT 2 R. We repurposed EMA401, an AT 2 R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT 2 R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT 2 R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT 2 R differ drastically from complexes of AT 2 R 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.

An interactive version of the game Tetris based on the Meta-T game is presented. In this version, a human plays the standard Tetrix game while an AI algorithm attempts to determine the player’s skill and dynamically alter the game difficulty to match it. The AI determines which Tetris piece (called zoid) to give to the human by analyzing for each zoid every possible placement position on the current board state, and then ordering the zoids from easiest to hardest. An empirical study pitching this adaptive condition against easy and hard conditions show that the adaptive condition had a positive effect on a composite criterion made of 60% performance and 40% flow. Arguably, this is a realistic criterion for many human performance domains. The adaptive condition, powered by the AI algorithm, does well on this composite criterion because it avoids the pitfalls of the easy and hard conditions: the easy condition hurts performance while the hard condition hurts flow.

We describe an in vitro test for detection of glial malignancies (GLI-M) based on enrichment and immunostaining of Circulating Glial Cells (CGCs) from peripheral blood sample. Extensive analytical validation studies using U87MG reference cell lines spiked into blood established the analytical performance characteristics of the test. The ability of the test to detect and differentiate GLI-M from non-malignant brain tumors (NBT), non glial type central nervous system (CNS) malignancies (NGCM), brain metastases from primary epithelial malignancies in other organs and healthy individuals were evaluated in four studies. The cumulative performance metrics of the test across all 4 clinical studies were 99.35% Sensitivity (95%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 ICSOL.

Groups of people often find it challenging to coordinate on a single choice or option. Even when coordination is achieved, it may be inefficient because better outcomes were possible. Numerous rese...

BACKGROUND The identification of intrinsic brain tumours’ boundaries and their anatomical relationship with eloquent connectomes is one of the main challenges in neurosurgery. Several new intra-operative spectroscopic technologies have been recently investigated for this purpose. Multispectral imaging (MSI) analysis is based on analysis of reflected light, divided in specific wavelengths ranges across the electromagnetic spectrum. By doing so, it can identify wavelengths invisible to the naked eye, and make them visible by applying specific filters. METHODS We have used MSI to acquire intraoperative images during brain tumours surgeries. The MSI camera has been adapted to be connected to the intra-operative microscope and acquire a stack of images of different spectra to be analysed on a separate time. The focus of the images acquisition includes tumour structure, its margins, and eloquent connectomes during awake surgery or neurostimulation to analyse the possibility of different perfusion signal during activation. Image segmentation using K-mean clustering has been used to detect structural information and identify tumour’s area and tumour’s margins, while oxygen maps have been created using linear least squares regression to detect areas of metabolic activity. RESULTS Twenty-three patients have been enrolled in the current study at the time of this submission. We have analysed the intra-operative acquisition using intra-operative microscope picture, pre- and post-operative MRI scan, and neurophysiological findings as ground truth. Our preliminary results show that MSI is a potential additional technology to visually show tumour core, margins, and different degree of perfusions on the tissues analysed during tumour surgery. Although on a very limited subgroup of patients, MSI seems to be reliable in identify eloquent areas activation during awake surgery. These results are promising and warrant more data acquisition to be confirmed.

There is a lack of psychological, neuroscientific, and philosophical consensus regarding how people evaluate causal relationships: do people just consider what actually happened or do they also consider what could have counterfactually happened? We used eye tracking and Gaussian Process modeling to investigate how people mentally simulated a recent event to judge what caused the outcome to occur. Participants played a virtual ball-shooting game by selecting how to move, encoding the outcome, and—while looking at a blank screen—mentally simulating (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. Further, when simulating what caused the outcome to occur, participants moved their eyes in fixation patterns consistent with mental simulations of counterfactual possibilities. These results favor counterfactual theories of causal reasoning, demonstrate how eye movements can reflect visual mental simulation during this reasoning, and provide a novel approach in eye tracking for investigating retrospective causal reasoning and counterfactual thinking.

The class of Hölder–Brascamp–Lieb inequalities is a collection of multilinear inequalities generalizing a convolution inequality of Young and the Loomis–Whitney inequalities. The full range of exponents was classified in a paper of Bennett, Carbery, Christ, and Tao [Math. Res. Lett. 17 (2010), no. 4, 647–666]. In a setting similar to that of Ivanisvili and Volberg [J. Lond. Mat. Sci (2) (2015), no. 3, 657–674], we introduce a notion of size for these inequalities which generalizes L p L^p norms. Under this new setup, we then determine necessary and sufficient conditions for a generalized Hölder–Brascamp–Lieb-type inequality to hold and establish sufficient conditions for maximizers to exist when the underlying linear maps match those of the convolution inequality of Young.

Objectives A common finding in the mind-wandering literature is that older adults (OAs) tend to mind-wander less frequently than young adults (YAs). Here, we sought to determine whether this age-related difference in mind-wandering is attributable to age-related differences in motivation. Method YAs and OAs completed an attention task during which they responded to thought probes that assessed rates of mind-wandering, and they provided self-reports of task-based motivation before and after completion of the attention task. Results Age-related differences in mind-wandering are partially explained by differences in motivation, and motivating YAs via incentive diminishes mind-wandering differences across these groups. Discussion We consider these results in the context of theories on age-related differences in mind wandering, with a specific focus on their relevance to the recently proposed motivational account of such age-related differences.

Mike accidentally knocked against a bottle. Seeing that the bottle was about to fall, Jack was just about to catch it when Peter accidentally knocked against him, making Jack unable to catch it. Jack did not grab the bottle, and it fell to the ground and spilled. In double-prevention cases like these, philosophers and non-philosophers alike tend to judge that Mike knocking into the bottle caused the beer to spill and that Peter knocking into Jack did not cause the beer to spill. This difference in causal judgment is a difficult puzzle for counterfactual theories of causal judgment; if each event had not happened, the outcome would not have, yet there is a difference in people’s causal judgments. In four experiments and three supplemental experiments, we confirm this difference in causal judgments. We also show that differences in people’s counterfactual thinking can explain this difference in their causal judgments and that recent counterfactual models of causal judgment can account for these patterns. We discuss these results in relation to work on counterfactual thinking and causal modeling.

The human capacity for causal judgment has long been thought to depend on an ability to consider counterfactual alternatives: the lightning strike caused the forest fire because had it not struck, the forest fire would not have ensued. To accommodate psychological effects on causal judgment, a range of recent accounts of causal judgment have proposed that people probabilistically sample counterfactual alternatives from which they compute a graded index of causal strength. While such models have had success in describing the influence of probability on causal judgments, among other effects, we show that these models make further untested predictions: probability should also influence people's metacognitive confidence in their causal judgments. In a large (N=3020) sample of participants in a causal judgment task, we found evidence that normality indeed influences people's confidence in their causal judgments and that these influences were predicted by a counterfactual sampling model. We take this result as supporting evidence for existing Bayesian accounts of causal judgment.

Glioblastoma (GBM) is a primary brain tumour with poor prognosis and limited treatment options. We previously demonstrated that arginine deprivation by ADI-PEG20 is effective in GBM tumors which are auxotrophic for arginine. We also reported that ADI-PEG20 has efficacy in arginine non-auxotrophic GBM when combined with radiation in the presence of an immune competent environment. Here, we present detailed mechanistic insight into our latter findings using multiplex Imaging Mass Cytometry (Fluidigm) and Spatial Transcriptomics (10x Genomics) of tumor samples treated with ADI-PEG20. ADI-PEG20 enhanced the expression on MHC class II on infiltrating CD11c+ dendritic cells and these cells colocalised specifically with CD4+ T cells. We also observed changes in the expression of PD-1/PD-L1 with ADI-PEG20 and this was further enhanced when ADI-PEG20 was combined with radiation. Moreover, combination therapy increased the expression of chemokines involved in immune cell recruitment and activation. Our findings demonstrate that arginine deprivation restores immune function in the tumor microenvironment of arginine non-auxotrophic GBM tumors and suggests that combinations with immunotherapies will further enhance efficacy for GBM tumors.

Symptomatic presentation of patients with intra-cranial malignancy is frequently non-specific and differentiating such patients from those with benign conditions is challenging. Accordingly, GBM presents as a medical emergency more frequently than any other common cancer, implying that effective strategies for rapid and simple diagnostic stratification of such patients are urgently required. Here we describe the detection of glial malignancies based on the enrichment and identification of Circulating Glial Cells (CGCs) in peripheral blood. The first case controlled study included blood from 189 participants split into discrete training and test sets (145 GBM, 44 benign CNS conditions). The second case controlled study included 40 cases of glial malignancies, 22 benign CNS conditions, 24 solid tumors with brain metastases, and 500 healthy individuals with no prior diagnosis of cancer and no current suspicion of cancer. A third prospective study was also carried out in 68 individuals with radiologically evident intracranial space-occupying lesion suspected of glial malignancies. Blood specimens were blindly evaluated for detection of CGCs through TruBlood assay to determine clinical sensitivity and specificity. 98% sensitivity and specificity was observed in detecting glial malignancies and differentiating them from benign CNS conditions in both case controlled studies. We detected and differentiated glial malignancies from benign CNS, healthy samples, and brain metastases. In the prospective study, 56 were positive for CGS, and 12 were negative for CGCs. All CGC positive specimens were confirmed glial malignancies and all CGC negative specimens benign CNS conditions. We present a non-invasive approach to the diagnostic stratification of patients presenting with suspicious but non-specific neurocognitive symptoms and hence early detection of glial malignancies. Moreover, immunocytochemistry facilitates the differentiation of GBM from metastatic intra-cranial epithelial cancers.

Glioblastoma (GBM) is the most aggressive and prevalent primary brain malignancy with an average life expectancy of 18 months despite the standard of care which includes resection, temozolomide and radiotherapy. Thirty percent of GBMs show transcriptional loss of arginosuccinate synthetase 1 (ASS1), displaying arginine auxotrophy and hence, are amenable to arginine deprivation therapy by ADI-PEG20. Moreover, these tumours are more aggressive than their non-arginine auxotrophic counterparts. In this study we demonstrate that this may lie in part due to their enhanced ability to repair damaged DNA. ADI-PEG20 significantly altered the expression of DNA repair genes in vitro and in vivo. We observed downregulation of PCNA, ATR (p=0.0063) and CHEK1 (p=0.0150) and upregulation of CHEK2 (p=0.0033) and RAD51 (p=0.0230). PARP1 was also downregulated, albeit not statistically significant. Addition of ADI-PEG20 to temozolomide and radiation also caused significant downregulation of BRCA1 (p=0.0340) . With DNA repair gene upregulation contributing to treatment resistance and DDR inhibitors shown to potentiate current therapies in the literature, not only do our results help elucidate the mechanisms of radiosensitisation with ADI-PEG20, targeting this pathway with DDR inhibitors alongside the pleiotropic effects of ADI-PEG20 may provide a novel therapeutic combination for ASS1 negative GBM.

Glioblastoma (GBM) is a primary malignant brain tumor with poor clinical outcomes. Standard of care consists of surgical debulking followed by radiation and temozolomide, but the tumor invariably recurs, and median survival is only ~18 months. Repurposing drugs used for the treatment of other diseases is a promising avenue to identify novel treatments for this highly aggressive form of cancer. One such class of compounds is angiotensin II (AngII) receptor blockers, commonly used to control blood pressure. We show that ~80% of primary human GBM express the angiotensin II type 2 receptor (AT2R). In the presence of AngII, inhibition of AT2R using either PD123319 or EMA401 significantly inhibits GBM proliferation. This effect was lost in GBM cells with CRISPR/Cas9 mediated knockdown of AT2R. EMA401 inhibited invasion, angiogenesis, reduced GBM spheroid growth and induced apoptosis through caspase 3/7 activation. Furthermore, EMA401 induced changes in a number of growth regulatory pathways including apoptosis, DNA replication and focal adhesion. The crystal structure of AT2R bound to EMA401 revealed the receptor to be in an active-like conformation with helix-VIII blocking G protein or β-arrestin recruitment. We demonstrate that the architecture and interaction of EMA401 with AT2R differs drastically from complexes of AT2R with other compounds. Conjugation of EMA401 to angiopep-2 enhanced its blood brain barrier passage and reduced tumor volume in an orthotopic xenograft model of GBM. Targeting AT2R is a novel therapeutic strategy to treat GBM that should be explored in patients.

In this paper, I map out broad aims, challenges, predictions, and implica- tions for the resulting intersection of singular causal judgment and metacognition that I (tentatively) call causal metacognition. First, I will overview research on sin- gular causal judgment, focusing on popular counterfactual theories that provide a formal framework for evaluating dependency relationships, as well as several compet- ing definitions of singular causal strength. Next, I will provide relevant background in the literature on metacognition for perception and decision-making, discussing major computational theories of metacognitive judgments. After covering the small amount of work on uncertainty in causal judgments, I will then argue that although singular causal judgments pose a particular problem for some theories of metacognition, coun- terfactual theories of singular causal judgment already provide testable predictions for confidence in causal judgments and can be extended to account for a wide range of patterns in confidence in singular causal judgments. Finally, I will summarize why we need a study of causal metacognition, and what empirical and theoretical advancements in that field might look like.

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.

The comprehensive examination is a customary, yet relatively unexamined, requirement in North American doctoral education. This case study explored the purpose of a comprehensive examination as per...

This paper provides teachers and teacher educators with food for thought by developing a broad, contemporary re-evaluation of the often-used analogy between teaching and the theatre. It does so by ...

Aims Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumour, with a median survival of 12-14 months after diagnosis. Although GBM has been extensively characterised on the molecular level during the past decades, many targeted therapies have been proved ineffective due, in part, to high heterogeneity of GBM. Thus, novel therapies targeting the altered metabolism which is exhibited by all cancer cells have gained much attention. The therapeutic ketogenic diet (KD) is a high fat, low carbohydrate and adequate protein diet. It has been recognized as a treatment for refractory paediatric epilepsy for decades. Recent studies have shown that a KD reduced tumour growth and potentiated the effects of therapy in some glioma animal models. However, the underlying mechanism(s) is still unclear. Thus, the aim of this study was to understand the mechanism of action behind the KD’s effects in inhibiting tumour growth and potentiating chemotherapy and radiotherapy. Method To unravel the mechanism of action, we analyzed the expression of genes encoding chromatin modifying enzymes in brain tumour samples from mice fed either a KD or standard diet (SD), using the Mouse Epigenetic Chromatin Modification Enzyme PCR Array (Qiagen, Germany). The expression of genes of interest selected from the array were validated by qRT-PCR. Human GBM cell lines and primary cells from GBMs were used to validate the results of the GBM mouse model. Beta-hydroxybutyrate, the main physiological ketone body found in the circulation of patients during KD, was used in in vitro experiments to mimic the in vivo physiological effect of a KD. The effect of protein arginine methyltransferase 8 (PRMT8) overexpression in GBM cells was studied using a lentiviral system. Cell proliferation was measured by Sulforhodamine B assay (Sigma, USA). Spheroid growth and invasion was measured in GBM spheroids cultured in Matrigel matrix (Corning, USA). Results Our results highlighted changes in the expression of a number of key chromatin modifying enzymes in mice fed a KD compared to those fed a SD. PRMT8, a gene highly downregulated in GBM, was upregulated in tumors from mice fed a KD, with corresponding downregulation of its target genes, dihydrofolate reductase (DHFR) and C-X-C chemokine receptor type 4 (CXCR4). Our results also showed that overexpression of PRMT8 in GBM cells reduced cell proliferation and invasiveness. Conclusion PRMT8, DHFR and CXCR4 have been shown to play key roles in tumour growth, invasion, migration and chemo/radio-resistance. Moreover, therapeutic strategies to downregulate these genes have been investigated in the form of methotrexate for DHFR inhibition and small molecule inhibitors of CXCR4. Thus, our results suggest that one mechanism through which the KD exerts its therapeutic effects may be through altering the expression of chromatin modifying enzymes. This provides additional support for the use of a KD as an adjuvant in combination with existing therapeutic approaches.

Histone deacetylase 6 (HDAC6) inhibition is a potential treatment of a wide range of cancer types via the acetylation of diverse proteins in the cytoplasm. However, the regulation of histone acetylation and the maintenance of higher-order chromatin structure remains unidentified. Here, we investigated the effect of selective inhibition of HDAC6 by histone acetylation, chromatin relaxation assays, co-immunoprecipitation, acetylome peptide array and in vivo RNA microarray. Our data shows that nuclear HDAC6 physically interacts with the Histone 4 lysine 12 residue, and that HDAC6 inhibition increases acetylation specifically at this residue in several cancer types. Inhibition induces major chromatin structure modulation, but has no equivalent effect on knockout HDAC6-/- MEF cells. We identified several novel HDAC6-deacetylated substrates and high expression of HDAC6 in colorectal cancer (CRC) tissue association with reduced levels of H4K12ac and independent of the key CRC driver mutations, but positively associated with EGFR expression. Furthermore, in vivo HDAC6 inhibition induces significant tumor regression in a CRC xenograft mice model with significant changes in the expression of functional nuclear genes. We also demonstrated that a DNA damaging agent in combination with selective HDAC6 inhibition is effective and acts synergistically, inducing chromatin relaxation and increased cell death in CRC cells. CRC tissues (Normal versus tumor; n=58 matched pairs) together with TCGA data analysis of 467 CRC patients showed that high HDAC6 expression is associated with metastasis, overall and disease-free survival, and is an independent risk factor of CRC stage progression. Our findings designate a new role for nuclear HDAC6 both in cancer prognosis and as a new therapeutic target for CRC and other types of cancer.HighlightHistone deacetylases 6 activity; Chromatin relaxation; Histone modifications; Gene array; DOX: doxorubicin; OXA: oxaliplatin; 5-FU: fluorouracil; Ac: acetylation; MNase: Micrococal nuclease.

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1-positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials., This work was supported by the Brain Tumour Research Campaign (BTRC), Brain Tumour Research (BTR) CRUK Convergence Science Centre at The Institute of Cancer Research, London, and Imperial College London (C309/A31316) and the European Regional Development Fund (ERDF) under the Operational Program Epirus 2014-2020, NSRF 2014-2020 (project code 5033092, BIOPREDICTOR) and by the Hellenic Foundation for Research and Innovation (HFRI) under the “First call for HFRI research projects to support faculty members and researchers and the procurement of high-cost research equipment grant” (project code: 991, PROTECT). This research was also funded from grants by the Spanish Ministerio de Ciencia, Innovación y Universidades/FEDER/UE RTI2018-098645-B-100) and from Consejería de Economía y Conocimiento of Junta de Andalucía/FEDER/UE P18-RT-1372 and US-1264806. BTRC and BTR grants were awarded to NS and KON. JS was a recipient of CRUK Clinical Academic Training Programme. ADI-PEG20 was a gift from Polaris Pharmaceuticals Inc.

Visual practices of representing fossil fuel projects are entangled in diverse values and relations that often go underexplored. In Canada, visual media campaigns to aggressively push forward the fossil fuel industry not only relegate to obscurity indigenous values but mask evidence on health impacts as well as the aspirations of those most affected, including indigenous communities whose food sovereignty and stewardship relationship to the land continues to be affronted by oil pipeline expansion. The Tsleil-Waututh Nation, based at the terminal of the Trans Mountain Pipeline in Canada, has been at the forefront of struggles against the pipeline expansion. Contributing to geographical, environmental studies, and public health research grappling with the performativity of images, this article explores stories conveying health, environmental, and intergenerational justice concerns on indigenous territory. Adapting photovoice techniques, elders and youth illustrated how the environment has changed over time, impacts on sovereignty&mdash, both food sovereignty and more broadly, concepts of health, well-being and deep cultural connection with water, and visions for future relationships. We explore the importance of an intergenerational lens of connectedness to nature and sustainability, discussing visual storytelling not just as visual counter-narrative (to neocolonial extractivism) but also as an invitation into fundamentally different ways of seeing and interacting.

This case study of one urban school district in British Columbia, Canada, examines technology-related disruptions to the teaching plans of seven midcareer elementary school teachers over a ...

The cellular and molecular basis of choline uptake on PET imaging and MRS-visible choline-containing compounds is not well understood. Choline kinase alpha (ChoK&alpha, ) is an enzyme that phosphorylates choline, an essential step in membrane synthesis. We investigate choline metabolism through 18F-fluoromethylcholine (18F-FMC) PET, MRS, and tissue ChoK&alpha, in human glioma. Fourteen patients with a suspected diffuse glioma underwent multimodal 3T MRI and dynamic 18F-FMC PET/CT prior to surgery. Co-registered PET and MRI data were used to target biopsies to regions of high and low choline signal, and immunohistochemistry for ChoK&alpha, expression was performed. The 18F-FMC/PET differentiated WHO (World Health Organization) grade IV from grade II and III tumours, whereas MRS differentiated grade III/IV from grade II tumours. Tumoural 18F-FMC/PET uptake was higher than in normal-appearing white matter across all grades and markedly elevated within regions of contrast enhancement. The 18F-FMC/PET correlated weakly with MRS Cho ratios. ChoK&alpha, expression on IHC was negative or weak in all but one glioblastoma sample, and did not correlate with tumour grade or imaging choline markers. MRS and 18F-FMC/PET provide complimentary information on glioma choline metabolism. Tracer uptake is, however, potentially confounded by blood&ndash, brain barrier permeability. ChoK&alpha, overexpression does not appear to be a common feature in diffuse glioma.

Reflective learning has been considered an important learning experience in higher education because of its value for personal and professional self. Despite the potential benefits, there is diverse interpretation of the meaning and process of reflective learning. Theoretical frameworks and models that purport to explain what it entails abound; however, there is a dearth of research that explores conceptions from the perspective of instructors. This study examined university instructors’ conceptions of reflective learning in the context of education courses. Semi-structured interviews were employed to collect data from 32 instructors who consented to participate. The interviews were transcribed, segmented, coded and compared. Our phenomenographic analysis resulted in four qualitatively different conceptions of reflective learning: critical engagement with content, improving professional practice, identity development, and developing critical consciousness. The study has implications for faculty development and research on reflective learning.

We introduce a frequency-domain electromagnetic induction (EMI) instrument for detection and classification of objects with either high ( $\sigma > 10^{5}~\textrm {S/m}$ ) or intermediate ( $1 ) electrical conductivity. While high conductivity metallic targets exhibit a quadrature peak response for frequencies in a traditional EMI regime under 100 kHz, the response of intermediate conductivity objects manifests at higher frequencies, between 100 kHz and 15 MHz. Materials such as carbon fiber or conducting salt solutions exhibit conductivities in this intermediate range and are undetectable by traditional low-frequency EMI instruments. To detect these intermediate conductivity targets, we developed a high-frequency EMI (HFEMI) instrument with a frequency range extended to 15 MHz. The HFEMI instrument requires novel hardware considerations, coil design, and data processing schemes. Most importantly, the wire lengths of transmit and receive coils are shorter than those of traditional frequency EMI sensors, so that the phase on the transmit and receive coils is nearly constant. We present the hardware and software aspects of the HFEMI instrument along with preliminary data, demonstrating its ability to detect intermediate conductive objects.

The U.S. military has developed and currently uses composite material munitions. These composite munitions are typically comprised of carbon fiber and, because of their low electrical conductivity, have a much lower electromagnetic induction signature, which makes them difficult to detect using traditional metal detecting methods. The term intermediate electrically conductive (IEC) is used to describe these lower conductivity materials, with conductivity, σ, typically in the range 10 < σ < 105 S/m. The electromagnetic induction (EMI) relaxation response of carbon fiber munitions peaks in the low megaHertz range (

Team-based projects are widely used in both traditional face-to-face and online programs in higher education. To date, the teamwork experiences of students in each modality have been documented primarily through evaluative research conducted over short spans of time and limited by a priori frameworks. The literature also reflects a lack of agreement about what constitutes the phenomenon of teamwork in each modality. In order to address these limitations, we conducted a phenomenological study examining the lived experiences of teamwork among students in both face-to-face and online MBA programs in Iran. Our analysis revealed striking commonalities in the experiences of both groups, including a shared desire for effective leadership to alleviate the problem of free riders, as well as substantial time and effort invested in retaining reliable teammates from one team project to another. In other respects, face-to-face and online students’ experience differed strongly. For example, while face-to-face participants pursued teammates with similar beliefs about how teamwork should be accomplished, online participants found themselves pre-occupied with staying connected with their teammates and struggled to establish common communication channels with each and every team member. Overall, our findings suggest that while training and support for student teamwork can partly build on the shared needs among students in both modalities, the nature of the experience in each modality may be so different in vital respects that engaging in one mode of teamwork does not necessarily prepare students to participate well in the other mode. Other implications and limitations of the research are discussed.

Expansion joints are important components of bridges that accommodate the movements between deck spans that result from thermal loads, traffic loads, and other environmental factors. Experience shows that joints undergo premature deterioration on a regular basis, which leads to unexpected problems caused by leakage of water and other corrosive chemicals over the components of the superstructure and substructure, which in turn leads to premature deterioration of those components. The Virginia Department of Transportation (DOT) has spent millions of dollars over more than 50 years for repair and replacement of joints. Several types of closed joints have been developed and installed in the past three decades to combat this problem. Jointless details at piers and abutments have also been developed and installed in the past three decades to eliminate the need for joints and the associated deterioration. However, the issue persists. The Virginia DOT’s Structure and Bridge Division has developed a new design for a flexible joint system with bonded and debonded zones. An elastomeric concrete material acts as the load-bearing surface as well as the component that allows free expansion and contraction. This joint system has been installed in selected pilot bridges on secondary roads for observation. The performance of this joint system and the challenges faced in its development are discussed.

We present data showing the impact of unmanned aerial systems (UAS) propeller motors electrical noise on the acquisition of electromagnetic induction (EMI) signals. Multiple motor speeds and standoff distances are evaluated. Results indicate an optimum EMI sensor standoff distance from operating UAS motors.