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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

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.

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

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.

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.