Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis.

Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAPon and YAPoff classes. These transcriptional coactivators are oncogenic in YAPon cancers. In contrast, YAP/TAZ are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAPoff cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/ß5, independent of the integrin-binding RGD ligand. Other effectors of this anticancer YAP function are unknown. Here, using clustered regularly interspaced short palindromic repeats (CRISPR) screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAPoff cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks, whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAPoff cancers. Netrins are considered protumorigenic, but knockout and peptide/decoy receptor blocking assays reveal that in YAPoff cancers, UNC5B and Netrin-1 can cooperate with integrin-αV/ß5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/ß5 axis as a critical effector of YAP tumor suppressor activity. SIGNIFICANCE: Netrins are widely perceived as procancer proteins; however, we uncover an anticancer function for Netrin-1 and its receptor UNC5B.

A healthy breakfast each and every day is important for students' motivation and achievement.

Breakfast is often cited as the most important meal of the day and vital for students' academic functioning at school. Although much research has linked students' breakfast consumption to better achievement, there has been debate about why and how breakfast has academic benefits. The present study of 648 Australian high school students investigated (a) the role of breakfast consumption and breakfast quality in students' self-reported motivation and their achievement in a science test, (b) the role of motivation in mediating the link between breakfast consumption and quality and students' achievement, and (c) the extent to which breakfast consumption effects are moderated by the quality of breakfast (e.g., more vegetables, fruit, dairy/protein, wholegrains, cereals, water; less sugary drinks, processed meat, fast take-away, unhealthy snack foods). Findings indicated that beyond the effects of personal, home, and classroom factors, breakfast consumption predicted higher adaptive motivation (p < .05), breakfast quality predicted lower maladaptive motivation (p < .05), and in turn, students' adaptive (positively, p < .01) and maladaptive (negatively, p < .01) motivation predicted their achievement. Moreover, adaptive motivation significantly mediated the relationship between breakfast consumption and achievement (p < .05). The effect of breakfast consumption was moderated by the quality of breakfast such that consuming a high-quality breakfast in the morning was associated with the highest levels of adaptive motivation (p < .01) and achievement (p < .05) later in the day. Findings have implications for educational practice and policy seeking to promote a healthy start to the school day to optimize students' motivation and achievement.

Slower but more accurate mental rotation performance in aphantasia linked to differences in cognitive strategies.

Mental rotation tasks are frequently used as standard measures of mental imagery. However, aphantasia research has brought such use into question. Here, we assessed a large group of individuals who lack visual imagery (aphantasia) on two mental rotation tasks: a three-dimensional block-shape, and a human manikin rotation task. In both tasks, those with aphantasia had slower, but more accurate responses than controls. Both groups demonstrated classic linear increases in response time and error-rate as functions of angular disparity. In the three-dimensional block-shape rotation task, a within-group speed-accuracy trade-off was found in controls, whereas faster individuals in the aphantasia group were also more accurate. Control participants generally favoured using object-based mental rotation strategies, whereas those with aphantasia favoured analytic strategies. These results suggest that visual imagery is not crucial for successful performance in classical mental rotation tasks, as alternative strategies can be effectively utilised in the absence of holistic mental representations.

Revisiting the blind mind: Still no evidence for sensory visual imagery in individuals with aphantasia.

The inability to visualise was given the name aphantasia in 2015 by Zeman and colleagues. In 2018 we published research showing that fifteen individuals who self-identified as having aphantasia also demonstrated a lack of sensory visual imagery when undergoing the binocular rivalry imagery paradigm, suggesting more than just a metacognitive difference. Here we update these findings with over fifty participants with aphantasia and show that there is evidence for a lack of sensory imagery in aphantasia. How the binocular rivalry paradigm scores relate to the vividness of visual imagery questionnaire (VVIQ) and how aphantasia can be confirmed is discussed.

Multisensory subtypes of aphantasia: Mental imagery as supramodal perception in reverse.

Cognitive neuroscience research on mental imagery has largely focused on the visual imagery modality in unimodal task contexts. Recent studies have uncovered striking individual differences in visual imagery capacity, with some individuals reporting a subjective absence of conscious visual imagery ability altogether ("aphantasia"). However, naturalistic mental imagery is often multi-sensory, and preliminary findings suggest that many individuals with aphantasia also report a subjective lack of mental imagery in other sensory domains (such as auditory or olfactory imagery). In this paper, we perform a series of cluster analyses on the multi-sensory imagery questionnaire scores of two large groups of aphantasic subjects, defining latent sub-groups in this sample population. We demonstrate that aphantasia is a heterogenous phenomenon characterised by dominant sub-groups of individuals with visual aphantasia (those who report selective visual imagery absence) and multi-sensory aphantasia (those who report an inability to generate conscious mental imagery in any sensory modality). We replicate our findings in a second large sample and show that more unique aphantasia sub-types also exist, such as individuals with selectively preserved mental imagery in only one sensory modality (e.g. intact auditory imagery). We outline the implications of our findings for network theories of mental imagery, discussing how unique aphantasia aetiologies with distinct self-report patterns might reveal alterations to various levels of the sensory processing hierarchy implicated in mental imagery.

Different Mechanisms for Supporting Mental Imagery and Perceptual Representations: Modulation Versus Excitation.

Recent research suggests imagery is functionally equivalent to a weak form of visual perception. Here we report evidence across five independent experiments on adults that perception and imagery are supported by fundamentally different mechanisms: Whereas perceptual representations are largely formed via increases in excitatory activity, imagery representations are largely supported by modulating nonimagined content. We developed two behavioral techniques that allowed us to first put the visual system into a state of adaptation and then probe the additivity of perception and imagery. If imagery drives similar excitatory visual activity to perception, pairing imagery with perceptual adapters should increase the state of adaptation. Whereas pairing weak perception with adapters increased measures of adaptation, pairing imagery reversed their effects. Further experiments demonstrated that these nonadditive effects were due to imagery weakening representations of nonimagined content. Together these data provide empirical evidence that the brain uses categorically different mechanisms to represent imagery and perception.

Deneddylation of ribosomal proteins promotes synergy between MLN4924 and chemotherapy to elicit complete therapeutic responses.

The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but the contribution of non-CRL targets is unknown. Here, CRISPR screens map MLN4924-monotherapy sensitivity in retinoblastoma to a classic DNA damage-induced p53/E2F3/BAX-dependent death effector network, which synergizes with Nutlin3a or Navitoclax. In monotherapy-resistant cells, MLN4924 plus standard-of-care topotecan overcomes resistance, but reduces DNA damage, instead harnessing ribosomal protein nucleolar-expulsion to engage an RPL11/p21/MYCN/E2F3/p53/BAX synergy network that exhibits extensive cross-regulation. Strikingly, unneddylatable RPL11 substitutes for MLN4924 to perturb nucleolar function and enhance topotecan efficacy. Orthotopic tumors exhibit complete responses while preserving visual function. Moreover, MLN4924 plus melphalan deploy this DNA damage-independent strategy to synergistically kill multiple myeloma cells. Thus, MLN4924 synergizes with standard-of-care drugs to unlock a nucleolar death effector network across cancer types implying broad therapeutic relevance.

Implicit bias training can remove bias from subliminal stimuli, restoring choice divergence: A proof-of-concept study.

Subliminal information can influence our conscious life. Subliminal stimuli can influence cognitive tasks, while endogenous subliminal neural information can sway decisions before volition. Are decisions inextricably biased towards subliminal information? Or can they diverge away from subliminal biases via training? We report that implicit bias training can remove biases from subliminal sensory primes. We first show that subliminal stimuli biased an imagery-content decision task. Participants (n = 17) had to choose one of two different patterns to subsequently imagine. Subliminal primes significantly biased decisions towards imagining the primed option. Then, we trained participants (n = 7) to choose the non-primed option, via post choice feedback. This training was successful despite participants being unaware of the purpose or structure of the reward schedule. This implicit bias training persisted up to one week later. Our proof-of-concept study indicates that decisions might not always have to be biased towards non-conscious information, but instead can diverge from subliminal primes through training.

Translational feasibility and efficacy of nasal photodynamic disinfection of SARS-CoV-2.

The lack of therapeutic options to fight Covid-19 has contributed to the current global pandemic. Despite the emergence of effective vaccines, development of broad-spectrum antiviral treatment remains a significant challenge, in which antimicrobial photodynamic therapy (aPDT) may play a role, especially at early stages of infection. aPDT of the nares with methylene blue (MB) and non-thermal light has been successfully utilized to inactivate both bacterial and viral pathogens in the perioperative setting. Here, we investigated the effect of MB-aPDT to inactivate human betacoronavirus OC43 and SARS-CoV-2 in vitro and in a proof-of-principle COVID-19 clinical trial to test, in a variety of settings, the practicality, technical feasibility, and short-term efficacy of the method. aPDT yielded inactivation of up to 6-Logs in vitro, as measured by RT-qPCR and infectivity assay. From a photo-physics perspective, the in vitro results suggest that the response is not dependent on the virus itself, motivating potential use of aPDT for local destruction of SARS-CoV-2 and its variants. In the clinical trial we observed variable effects on viral RNA in nasal-swab samples as assessed by RT-qPCR attributed to aPDT-induced RNA fragmentation causing falsely-elevated counts. However, the viral infectivity in clinical nares swabs was reduced in 90% of samples and undetectable in 70% of samples. This is the first demonstration based on quantitative clinical viral infectivity measurements that MB-aPDT is a safe, easily delivered and effective front-line technique that can reduce local SARS-CoV-2 viral load.

Memories with a blind mind: Remembering the past and imagining the future with aphantasia.

Our capacity to re-experience the past and simulate the future is thought to depend heavily on visual imagery, which allows us to construct complex sensory representations in the absence of sensory stimulation. There are large individual differences in visual imagery ability, but their impact on autobiographical memory and future prospection remains poorly understood. Research in this field assumes the normative use of visual imagery as a cognitive tool to simulate the past and future, however some individuals lack the ability to visualise altogether (a condition termed "aphantasia"). Aphantasia represents a rare and naturally occurring knock-out model for examining the role of visual imagery in episodic memory recall. Here, we assessed individuals with aphantasia on an adapted form of the Autobiographical Interview, a behavioural measure of the specificity and richness of episodic details underpinning the memory of events. Aphantasic participants generated significantly fewer episodic details than controls for both past and future events. This effect was most pronounced for novel future events, driven by selective reductions in visual detail retrieval, accompanied by comparatively reduced ratings of the phenomenological richness of simulated events, and paralleled by quantitative linguistic markers of reduced perceptual language use in aphantasic participants compared to those with visual imagery. Our findings represent the first systematic evidence (using combined objective and subjective data streams) that aphantasia is associated with a diminished ability to re-experience the past and simulate the future, indicating that visual imagery is an important cognitive tool for the dynamic retrieval and recombination of episodic details during mental simulation.

Multicenter international assessment of a SARS-CoV-2 RT-LAMP test for point of care clinical application.

Continued waves, new variants, and limited vaccine deployment mean that SARS-CoV-2 tests remain vital to constrain the coronavirus disease 2019 (COVID-19) pandemic. Affordable, point-of-care (PoC) tests allow rapid screening in non-medical settings. Reverse-transcription loop-mediated isothermal amplification (RT-LAMP) is an appealing approach. A crucial step is to optimize testing in low/medium resource settings. Here, we optimized RT-LAMP for SARS-CoV-2 and human ß-actin, and tested clinical samples in multiple countries. "TTTT" linker primers did not improve performance, and while guanidine hydrochloride, betaine and/or Igepal-CA-630 enhanced detection of synthetic RNA, only the latter two improved direct assays on nasopharygeal samples. With extracted clinical RNA, a 20 min RT-LAMP assay was essentially as sensitive as RT-PCR. With raw Canadian nasopharygeal samples, sensitivity was 100% (95% CI: 67.6% - 100%) for those with RT-qPCR Ct values ≤ 25, and 80% (95% CI: 58.4% - 91.9%) for those with 25 < Ct ≤ 27.2. Highly infectious, high titer cases were also detected in Colombian and Ecuadorian labs. We further demonstrate the utility of replacing thermocyclers with a portable PoC device (FluoroPLUM). These combined PoC molecular and hardware tools may help to limit community transmission of SARS-CoV-2.

Mapping transgene insertion sites reveals the α-Cre transgene expression in both developing retina and olfactory neurons.

The Tg(Pax6-cre,GFP)2Pgr (α-Cre) mouse is a commonly used Cre line thought to be retinal-specific. Using targeted locus amplification (TLA), we mapped the insertion site of the transgene, and defined primers useful to deduce zygosity. Further analyses revealed four tandem copies of the transgene. The insertion site mapped to clusters of vomeronasal and olfactory receptor genes. Using R26R and Ai14 Cre reporter mice, we confirmed retinal Cre activity, but also detected expression in Gα0+ olfactory neurons. Most α-Cre+ olfactory neurons do not express Pax6, implicating the influence of neighboring regulatory elements. RT-PCR and buried food pellet test did not detect any effects of the transgene on flanking genes in the nasal mucosa and retina. Together, these data precisely map α-Cre, show that it does not affect surrounding loci, but reveal previously unanticipated transgene expression in olfactory neurons. The α-Cre mouse can be a valuable tool in both retinal and olfactory research.

Aphantasia, dysikonesia, anauralia: call for a single term for the lack of mental imagery-Commentary on Dance et al. (2021) and Hinwar and Lambert (2021).

Recently, the term 'aphantasia' has become current in scientific and public discourse to denote the absence of mental imagery. However, new terms for aphantasia or its subgroups have recently been proposed, e.g., 'dysikonesia' or 'anauralia', which complicates the literature, research communication and understanding for the general public. Before further terms emerge, we advocate the consistent use of the term 'aphantasia' as it can be used flexibly and precisely, and is already widely known in the scientific community and among the general public.

The pupillary light response as a physiological index of aphantasia, sensory and phenomenological imagery strength.

The pupillary light response is an important automatic physiological response which optimizes light reaching the retina. Recent work has shown that the pupil also adjusts in response to illusory brightness and a range of cognitive functions, however, it remains unclear what exactly drives these endogenous changes. Here, we show that the imagery pupillary light response correlates with objective measures of sensory imagery strength. Further, the trial-by-trial phenomenological vividness of visual imagery is tracked by the imagery pupillary light response. We also demonstrated that a group of individuals without visual imagery (aphantasia) do not show any significant evidence of an imagery pupillary light response, however they do show perceptual pupil light responses and pupil dilation with larger cognitive load. Our results provide evidence that the pupillary light response indexes the sensory strength of visual imagery. This work also provides the first physiological validation of aphantasia.

CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.

Progression through G1/S phase of the cell cycle is coordinated by cyclin-dependent kinase (CDK) activities. Here, we find that the requirement for different CDK activities and cyclins in driving cancer cell cycles is highly heterogeneous. The differential gene requirements associate with tumor origin and genetic alterations. We define multiple mechanisms for G1/S progression in RB-proficient models, which are CDK4/6 independent and elicit resistance to FDA-approved inhibitors. Conversely, RB-deficient models are intrinsically CDK4/6 independent, but exhibit differential requirements for cyclin E. These dependencies for CDK and cyclins associate with gene expression programs that denote intrinsically different cell-cycle states. Mining therapeutic sensitivities shows that there are reciprocal vulnerabilities associated with RB1 or CCND1 expression versus CCNE1 or CDKN2A. Together, these findings illustrate the complex nature of cancer cell cycles and the relevance for precision therapeutic intervention.

Targeting the Ubiquitin-Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer.

PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with an overall 5-year survival rate of less than 10%. Treatment for SCLC with cisplatin/etoposide chemotherapy (C/E) ± radiotherapy has changed modestly over several decades. The ubiquitin-proteasome system is an underexplored therapeutic target for SCLC. We preclinically evaluated TAK-243, a first-in-class small molecule E1 inhibitor against UBA1. EXPERIMENTAL DESIGN: We assessed TAK-243 in 26 SCLC cell-lines as monotherapy and combined with C/E, the PARP-inhibitor, olaparib, and with radiation using cell viability assays. We interrogated TAK-243 response with gene expression to identify candidate biomarkers. We evaluated TAK-243 alone and in combination with olaparib or radiotherapy with SCLC patient-derived xenografts (PDX). RESULTS: Most SCLC cell lines were sensitive to TAK-243 monotherapy (EC50 median 15.8 nmol/L; range 10.2 nmol/L-367.3 nmol/L). TAK-243 sensitivity was associated with gene-sets involving the cell cycle, DNA and chromatin organization, and DNA damage repair, while resistance associated with cellular respiration, translation, and neurodevelopment. These associations were also observed in SCLC PDXs. TAK-243 synergized with C/E and olaparib in vitro across sensitive and resistant SCLC cell lines. Considerable TAK-243-olaparib synergy was observed in an SCLC PDX resistant to both drugs individually. TAK-243 radiosensitization was also observed in an SCLC PDX. CONCLUSIONS: TAK-243 displays efficacy in SCLC preclinical models. Enrichment of gene sets is associated with TAK-243 sensitivity and resistance. TAK-243 exhibits synergy when combined with genotoxic therapies in cell lines and PDXs. TAK-243 is a potential therapeutic strategy to improve SCLC patient outcomes, both as a single agent and in combination with existing therapies.

Simplifying cancer: binary pan-cancer superclasses stratified by opposite YAP/TEAD effects.

The inherent complexity of cancer complicates treatment. Identifying higher-order principles that govern cancer biology can circumvent this problem and pinpoint broadly applicable treatment options. We recently found that opposite expression and pro- versus anti-cancer activity of a single transcriptional complex functionally stratifies cancer into binary superclasses.