Targeting TBK1 to overcome resistance to cancer immunotherapy.

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.

Annotation Query (AnnoQ): an integrated and interactive platform for large-scale genetic variant annotation.

The Annotation Query (AnnoQ) (http://annoq.org/) is designed to provide comprehensive and up-to-date functional annotations for human genetic variants. The system is supported by an annotation database with ∼39 million human variants from the Haplotype Reference Consortium (HRC) pre-annotated with sequence feature annotations by WGSA and functional annotations to Gene Ontology (GO) and pathways in PANTHER. The database operates on an optimized Elasticsearch framework to support real-time complex searches. This implementation enables users to annotate data with the most up-to-date functional annotations via simple queries instead of setting up individual tools. A web interface allows users to interactively browse the annotations, annotate variants and search variant data. Its easy-to-use interface and search capabilities are well-suited for scientists with fewer bioinformatics skills such as bench scientists and statisticians. AnnoQ also has an API for users to access and annotate the data programmatically. Packages for programming languages, such as the R package, are available for users to embed the annotation queries in their scripts. AnnoQ serves researchers with a wide range of backgrounds and research interests as an integrated annotation platform.

Distinct electrophysiological signatures of task-unrelated and dynamic thoughts.

Humans spend much of their lives engaging with their internal train of thoughts. Traditionally, research focused on whether or not these thoughts are related to ongoing tasks, and has identified reliable and distinct behavioral and neural correlates of task-unrelated and task-related thought. A recent theoretical framework highlighted a different aspect of thinking-how it dynamically moves between topics. However, the neural correlates of such thought dynamics are unknown. The current study aimed to determine the electrophysiological signatures of these dynamics by recording electroencephalogram (EEG) while participants performed an attention task and periodically answered thought-sampling questions about whether their thoughts were 1) task-unrelated, 2) freely moving, 3) deliberately constrained, and 4) automatically constrained. We examined three EEG measures across different time windows as a function of each thought type: stimulus-evoked P3 event-related potentials and non-stimulus-evoked alpha power and variability. Parietal P3 was larger for task-related relative to task-unrelated thoughts, whereas frontal P3 was increased for deliberately constrained compared with unconstrained thoughts. Frontal electrodes showed enhanced alpha power for freely moving thoughts relative to non-freely moving thoughts. Alpha-power variability was increased for task-unrelated, freely moving, and unconstrained thoughts. Our findings indicate distinct electrophysiological patterns associated with task-unrelated and dynamic thoughts, suggesting these neural measures capture the heterogeneity of our ongoing thoughts.

Sadness facilitates "deeper" reading comprehension: a behavioural and eye tracking study.

Reading is one of the most common everyday activities, yet research elucidating how affective influence reading processes and outcomes is sparse with inconsistent results. To investigate this question, we randomly assigned participants (N = 136) to happiness (positive affect), sadness (negative affect), and neutral video-induction conditions prior to engaging in self-paced reading of a long, complex science text. Participants completed assessments targeting multiple levels of comprehension (e.g. recognising factual information, integrating different textual components, and open-ended responses of concepts from memory) after reading and after a week-long delay. Results indicated that the Sadness (vs. Happiness) condition had higher comprehension scores, with the largest effects emerging for assessments targeting deeper levels comprehension immediately after reading. Eye-tracking analyses revealed that such benefits may be partly driven by sustained attentional focus over the 20-minute reading session. We discuss results with respect to theories on affect, cognition, and text comprehension.

Webcam-based eye tracking to detect mind wandering and comprehension errors.

Recent advances in computer vision have opened the door for scalable eye tracking using only a webcam. Such solutions are particularly useful for online educational technologies, in which a goal is to respond adaptively to students' ongoing experiences. We used WebGazer, a webcam-based eye-tracker, to automatically detect covert cognitive states during an online reading-comprehension task related to task-unrelated thought and comprehension. We present data from two studies using different populations: (1) a relatively homogenous sample of university students (N = 105), and (2) a more diverse sample from Prolific (N = 173, with < 20% White participants). Across both studies, the webcam-based eye-tracker provided sufficiently accurate and precise gaze measurements to predict both task-unrelated thought and reading comprehension from a single calibration. We also present initial evidence of predictive validity, including a positive correlation between predicted rates of task-unrelated thought and comprehension scores. Finally, we present slicing analyses to determine how performance changed under certain conditions (lighting, glasses, etc.) and generalizability of the results across the two datasets (e.g., training on the data Study 1 and testing on data from Study 2, and vice versa). We conclude by discussing results in the context of remote research and learning technologies.

Deceased organ and tissue donation after medical assistance in dying: 2023 updated guidance for policy.

BACKGROUND: Since Canadian Blood Services (CBS) developed policy guidance in 2019 for organ and tissue donation after medical assistance in dying (MAiD), the federal government has made changes to legislation related to MAiD. This document provides updated guidance for clinicians, organ donation organizations, end-of-life care experts, MAiD providers and policy-makers on the impact of these changes. METHODS: Canadian Blood Services assembled a group of 63 experts from critical care, organ and tissue donation, health care administration, MAiD, bioethics, law and research to review the legislative changes in the Organ and Tissue Donation After Medical Assistance in Dying - Guidance for Policy forum. Two patients who had requested and been found eligible for MAiD and 2 family members of patients who had donated organs after MAiD were also included as participants. In a series of 3 online meetings from June 2021 to April 2022, forum participants addressed a variety of topics in small and large groups. These discussions were informed by a comprehensive scoping review using JBI methodology. We used an adapted form of nominal group technique to develop the recommendations, which were approved by consensus of the participants. Management of competing interests was in accordance with Guideline International Network principles. RECOMMENDATIONS: Although many of the recommendations from the guidance developed in 2019 are still relevant, this guidance provides 2 updated recommendations and 8 new recommendations in the following areas: referral to an organ donation organization, consent, directed and conditional donation, MAiD procedures, determination of death, health care professionals and reporting. INTERPRETATION: Policies and practices for organ and tissue donation after MAiD in Canada should align with current Canadian legislation. This updated guidance will help clinicians navigate the medical, legal and ethical challenges that arise when they support patients pursuing donation after MAiD.

PANTHER version 16: a revised family classification, tree-based classification tool, enhancer regions and extensive API.

PANTHER (Protein Analysis Through Evolutionary Relationships, http://www.pantherdb.org) is a resource for the evolutionary and functional classification of protein-coding genes from all domains of life. The evolutionary classification is based on a library of over 15,000 phylogenetic trees, and the functional classifications include Gene Ontology terms and pathways. Here, we analyze the current coverage of genes from genomes in different taxonomic groups, so that users can better understand what to expect when analyzing a gene list using PANTHER tools. We also describe extensive improvements to PANTHER made in the past two years. The PANTHER Protein Class ontology has been completely refactored, and 6101 PANTHER families have been manually assigned to a Protein Class, providing a high level classification of protein families and their genes. Users can access the TreeGrafter tool to add their own protein sequences to the reference phylogenetic trees in PANTHER, to infer evolutionary context as well as fine-grained annotations. We have added human enhancer-gene links that associate non-coding regions with the annotated human genes in PANTHER. We have also expanded the available services for programmatic access to PANTHER tools and data via application programming interfaces (APIs). Other improvements include additional plant genomes and an updated PANTHER GO-slim.

Investigating the appraisal structure of spontaneous thoughts: evidence for differences among unexpected thought, involuntary autobiographical memories, and ruminative thought.

Involuntary thinking occurs when mental states arise without intention. Such thoughts can take different forms, such as involuntary autobiographical memories (IAM), ruminative thoughts, and unexpected thoughts-all of which are popular areas of study, albeit in somewhat disparate literatures. Despite these mental states sharing a common thread of feeling involuntary in nature, it is nevertheless unclear what separates them phenomenologically. We conducted a set of exploratory and confirmatory experiments to elucidate the appraisal dimensions behind these forms of involuntary thought, with a particular interest in understanding the phenomenology behind unexpected thoughts that are predicted to violate expectations of both timing and content. Across two experiments, we found that unexpected thoughts had unique appraisal structures compared to the other two forms of involuntary thought: they were less identifiably cued, more surprising in content and timing, and offered new information (i.e., insight). We discuss how these distinctions support recent theories regarding the nature of unexpected thought and its relation to other forms of involuntary thinking, namely IAM and ruminative thought, which are the more commonly studied forms of involuntary thinking.

A possible shared underlying mechanism among involuntary autobiographical memory and déjà vu.

We propose that IAM and déjà vu may not share a placement on the same gradient, per se, but the mechanism of cue familiarity detection, and a major differentiating factor between the two metacognitive experiences is whether the resulting inward directed search of memory yields retrieved content or not. Déjà vu may manifest when contentless familiarity detection is inexplicable by the experiencer.

Daily mindfulness training reduces negative impact of COVID-19 news exposure on affective well-being.

COVID-19 has led to mental health adversities worldwide. The current study examined whether daily practice of brief mindfulness training has a beneficial impact on affective well-being, and mitigates the negative impact of exposure to COVID-19 news during the pandemic. Participants were randomly assigned into a mindfulness training (MT) group or a waitlist control (WC) group. Participants in the MT group practiced guided mindfulness meditation for a minimum of 10 min each day for 10 days. Both groups completed questionnaires assessing well-being at baseline and after the 10-day period. We also included four ecological momentary assessments (EMA) interspersed throughout the day to measure fine-grained affective states and recent exposure to COVID-19-related news, which has been linked to negative affect. We observed an increase in positive affect in the MT group compared to the WC group in the post-training assessment. However, no group differences emerged in the other three post-training affective measures of negative affect, anxiety and depression. EMA revealed that the MT group also showed more positive affective valence than the WC group across the 10 days. Notably, the WC group reported more negative affective valence following COVID-19 news exposure, whereas the MT group was not impacted. Taken together, our study indicates brief sessions of guided mindfulness meditation during COVID-19 may boost positive affect and serve as a protective buffer against the negative impact of exposure to COVID-19-related news on affective well-being. These findings highlight the utility of mindfulness meditation as an accessible and cost-effective technique to elevate positive affect amidst the COVID-19 pandemic.

Enhanced capacity to switch but not to maintain: The basis of attentional bias to high calorie foods in restrained eaters.

It has been argued that high restrained eaters (i.e., people who fluctuate between restrictive food intake and overeating) are characterised by a heightened attentional bias to high calorie foods. However, the validity of this hypothesis has not yet been convincingly established. The current study sought to empirically evaluate this hypothesis using two directional measures of attentional bias: the well-established dot probe bias assessment task and the more novel Chase the Food bias assessment task. The latter attentional assessment approach has the capacity to differentiate between attentional switching and attentional maintenance within a complex and dynamic food environment. Participants (61 high restrained eaters and 38 low restrained eaters) completed the dot probe task and the Chase the Food task. Findings obtained on the dot probe task did not reveal a group difference in terms of biased attentional responding towards high calorie vs. low calorie food. Conversely, the two groups were found to differ on one of the measures obtained on the Chase the Food task. Specifically, high restrained eaters, as compared to low restrained eaters, demonstrated speeded attentional switching to high calorie foods, rather than a greater ability to maintain attention on high calorie foods when required to do so. These novel findings imply that high restrained eaters are potentially characterised by facilitated attentional switching towards high calorie foods. Implications are discussed including the possibility of targeting biased attentional switching using training variants of the Chase the Food task in interventions designed to reduce maladaptive eating behaviours.

Lung donation after medical assistance in dying at home.

Organ donation after medical assistance in dying (MAID) has only been possible for patients having the MAID procedure performed at a hospital facility due to prohibitive warm ischemic times. Herein, we describe a protocol for lung donation following MAID at home and demonstrate excellent postoperative outcomes. Lung donation following MAID at home is possible and should be considered by transplant programs.

More than off-task: Increased freely-moving thought in ADHD.

Off-task thought has been found to occur at high rates and is related to impairment in ADHD. However, off-task thought is heterogenous and it remains unclear which specific dimensions of off-task thought are more prevalent in this disorder. It is therefore important to dissociate different aspects of off-task thought in order to better understand the mechanisms underlying impairment. The current study focused on the dimension of constrained (focused) to freely moving off-task thought. Self-report and neurophysiological measures during a computerized attention tasks provided convergent evidence that individuals with ADHD not only have more off-task thought than those without, but also engaged in a greater proportion of freely moving off-task thought than non-ADHD controls. Overall, this work demonstrated differences in both the quantity and type of off-task thought in adults with ADHD. It provides novel insight into both the phenomenology of off-task thought, as well as potential mechanisms underlying impairment in ADHD.

Trends in anticoagulation management services following incorporation of direct oral anticoagulants at a large academic medical center.

The introduction of direct oral anticoagulants (DOACs) to the market has expanded anticoagulation options for outpatient use. Routine evaluation by health care professionals is recommended as it is with warfarin, therefore requiring adjustments in practices of anticoagulation management services (AMS). This study aims to describe trends that occurred following the incorporation of DOACs into AMS at a large academic medical center. A retrospective chart review of pharmacist-run AMS was used to compare patients on DOAC therapy versus other types of anticoagulation, including warfarin and parenteral agents. Primary outcomes included trends in the number of unique patients, management encounters, and telephone encounters throughout the study period. Secondary outcomes included trends in new encounters, and changes in patient characteristics, resources utilized, and patient satisfaction scores. A total of 2976 unique patients, 74,582 management encounters, and 13,282 telephone encounters were identified. From study beginning to end, results showed stable numbers of unique patients, an increase in management encounters for the DOAC group and decrease in the other anticoagulants group, and stable numbers of telephone encounters. Additionally, the number of new encounters for both groups increased. Throughout the study, pharmacy resources were reallocated within anticoagulation to adapt to the changing trends and patient satisfaction reached targets. Patients' characteristics remained stable, with the DOAC group having fewer comorbid conditions and concomitant medications that could increase bleed risk. This study showed that by reallocating resources within anticoagulation, AMS can maintain stable patient populations while continuing to expand access and satisfy patients following DOAC inclusion.

Heterogeneity within the frontoparietal control network and its relationship to the default and dorsal attention networks.

The frontoparietal control network (FPCN) plays a central role in executive control. It has been predominantly viewed as a unitary domain general system. Here, we examined patterns of FPCN functional connectivity (FC) across multiple conditions of varying cognitive demands, to test for FPCN heterogeneity. We identified two distinct subsystems within the FPCN based on hierarchical clustering and machine learning classification analyses of within-FPCN FC patterns. These two FPCN subsystems exhibited distinct patterns of FC with the default network (DN) and the dorsal attention network (DAN). FPCNA exhibited stronger connectivity with the DN than the DAN, whereas FPCNB exhibited the opposite pattern. This twofold FPCN differentiation was observed across four independent datasets, across nine different conditions (rest and eight tasks), at the level of individual-participant data, as well as in meta-analytic coactivation patterns. Notably, the extent of FPCN differentiation varied across conditions, suggesting flexible adaptation to task demands. Finally, we used meta-analytic tools to identify several functional domains associated with the DN and DAN that differentially predict activation in the FPCN subsystems. These findings reveal a flexible and heterogeneous FPCN organization that may in part emerge from separable DN and DAN processing streams. We propose that FPCNA may be preferentially involved in the regulation of introspective processes, whereas FPCNB may be preferentially involved in the regulation of visuospatial perceptual attention.

The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification.

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.

Updating the dynamic framework of thought: Creativity and psychedelics.

Contemporary investigations regard creativity as a dynamic form of cognition that involves movement between the dissociable stages of creative generation and creative evaluation. Our recently proposed Dynamic Framework of Thought (Christoff et al., 2016) offered a conceptualization of these stages in terms of an interplay between sources of constraint and variability on thought. This initial conceptualization, however, has yet to be fully explicated and given targeted discussion. Here, we refine this framework's account of creativity by highlighting the dynamic nature of creative thought, both within and between the stages of creative generation and evaluation. In particular, we emphasize that creative generation in particular is best regarded as a product of multiple, varying mental states, rather than being a singular mental state in and of itself. We also propose that the psychedelic state is a mental state with high potential for facilitating creative generation and update the Dynamic Framework of Thought to incorporate this state. This paper seeks to highlight the dynamic nature of the neurocognitive processes underlying creative thinking and to draw attention to the potential utility of psychedelic substances as experimental tools in the neuroscience of creativity.

Initial lung transplantation experience with uncontrolled donation after cardiac death in North America.

Uncontrolled donation after cardiac death (uDCD) has the potential to ameliorate the shortage of suitable lungs for transplant. To date, no lung transplant data from these donors are available from North America. We describe the successful use of these donors using a simple method of in situ lung inflation so that the organ can be protected from warm ischemic injury. Forty-four potential donors were approached, and family consent was obtained in 30 cases (68%). Of these, the lung transplant team evaluated 16 uDCDs on site, and 14 were considered for transplant pending ex vivo lung perfusion assessment. Five lungs were ultimately used for transplant (16.7% use rate from consented donors). The mean warm ischemic time was 2.8 hours. No primary graft dysfunction grade 3 was observed at 24, 48, or 72 hours after transplant. Median intensive care unit stay was 5 days (range: 2-78 days), and median hospital stay was 17 days (range: 8-100 days). The 30-day mortality was 0%. Four of 5 patients are alive at a median of 651 days (range: 121-1254 days) with preserved lung function. This study demonstrates the proof of concept and the potential for uDCD lung donation using a simple donor intervention.

Tendency to ruminate and anxiety are associated with altered alpha and beta oscillatory power dynamics during memory for contextual details.

Rumination occurs when an individual becomes mentally stuck and cannot redirect attention away from an unwanted thought demonstrating cognitive inflexibility. Cognitive flexibility is important for various cognitive functions, including episodic memory. Trait rumination is a partial mediator in the relationship between depression and overgeneral episodic memory, suggesting that rumination may negatively influence memory for contextual details. Oscillations in the alpha (8-12 Hz) and beta (13-30 Hz) frequency bands are crucial for various cognitive functions (e.g., attention control and episodic memory) and may help to explain the relationship between trait rumination and memory for contextual details. Our study uses EEG recorded during a source memory task to assess how alpha and beta oscillations during memory for contextual details may change as a function of trait rumination, anxiety, and depression level (n = 43). The source memory task instructs participants to remember objects and their associated contextual details. Memory for contextual details is lessened for participants higher in trait rumination paired with higher trait anxiety. Oscillations were analyzed in posterior parietal/occipital regions. During encoding, an interaction of nonclinical depression level and rumination predicts higher alpha power for items that were later not successfully remembered. During test, depression and rumination interact and predict higher alpha power for both successful and unsuccessful memory. These results suggest that trait anxiety, depression, and rumination impact accuracy and alpha oscillatory dynamics during contextual memory via changes in attention control.

Development of CDK2 and CDK5 Dual Degrader TMX-2172.

Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of cancer. Development of CDK2 inhibitors has been extremely challenging as its ATP-binding site shares high similarity with CDK1, a related kinase whose inhibition causes toxic effects. Here, we report the development of TMX-2172, a heterobifunctional CDK2 degrader with degradation selectivity for CDK2 and CDK5 over not only CDK1, but transcriptional CDKs (CDK7 and CDK9) and cell cycle CDKs (CDK4 and CDK6) as well. In addition, we demonstrate that antiproliferative activity in ovarian cancer cells (OVCAR8) depends on CDK2 degradation and correlates with high expression of cyclin E1 (CCNE1), which functions as a regulatory subunit of CDK2. Collectively, our work provides evidence that TMX-2172 represents a lead for further development and that CDK2 degradation is a potentially valuable therapeutic strategy in ovarian and other cancers that overexpress CCNE1.