Glioblastoma therapies have remained elusive due to limitations in understanding mechanisms of growth and survival of the tumorigenic population. Using CRISPR-Cas9 approaches in patient-derived GBM ...stem cells (GSCs) to interrogate function of the coding genome, we identify actionable pathways responsible for growth, which reveal the gene-essential circuitry of GBM stemness and proliferation. In particular, we characterize members of the SOX transcription factor family, SOCS3, USP8, and DOT1L, and protein ufmylation as important for GSC growth. Additionally, we reveal mechanisms of temozolomide resistance that could lead to combination strategies. By reaching beyond static genome analysis of bulk tumors, with a genome-wide functional approach, we reveal genetic dependencies within a broad range of biological processes to provide increased understanding of GBM growth and treatment resistance.
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•Genome-wide CRISPR-Cas9 screens in patient-derived glioblastoma stem cells•Identification of regulators of stemness governing glioblastoma stem cell growth•Multiple stress response pathways are genetic vulnerabilities in glioblastoma•Identification of modulators of sensitivity to standard of care chemotherapy
MacLeod et al. describe genome-wide CRISPR-Cas9 screens identifying genetic vulnerabilities across a panel of patient-derived glioblastoma stem cell cultures. Regulators of stemness (SOX2, SOX9, DOT1L, and SOCS3) and stress response (ufmylation and ERAD pathways) govern the growth of glioblastoma stem cells. Chemogenomic screens using temozolomide identify modulators of sensitivity to chemotherapy.
Existing anticoagulants effectively inhibit the activity of coagulation factors of the extrinsic and common pathway but have substantial limitations and can cause severe bleeding complications. Here ...we describe a novel therapeutic approach to thrombosis treatment. We have developed and characterized the efficacy and safety of selective second-generation antisense oligonucleotides (ASOs) targeting coagulation factor XI (FXI), a member of the intrinsic coagulation pathway. Systemic treatment of mice with FXI ASO led to a potent, specific, and dose-dependent reduction of FXI mRNA levels in the liver with corresponding reductions in plasma levels of FXI protein and activity. FXIASO treatment produced potent, dose-dependent antithrombotic activity in various venous and arterial thrombosis models, comparable with warfarin or enoxaparin. However, unlike warfarin or enoxaparin, FXI inhibition did not cause bleeding. Coadministration of FXI ASO with enoxaparin or the antiplatelet drug clopidogrel produced improved antithrombotic activity without increased bleeding. Finally, plasma-derived FXI concentrate was shown to effectively and rapidly reverse the anticoagulant effect of FXI antisense therapy. These results support the concept that inhibition of FXI through antisense therapy might serve as a new and effective strategy for the treatment and prevention of venous thromboembolism with improved specificity and safety.
A series of 4-hydroxy-1-3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl piperidines was investigated as potential selective h5-HT1D agonists for the treatment of migraine. The ...4-(N-benzyl-N-methyl)aminomethyl analog 12a was found to be a full agonist at the h5-HT1D receptor with good binding selectivity over the h5-HT1B receptor.
Inadequate Monitoring and Evaluation (M&E) is often thought to hinder adaptive management of socio-ecological systems. A key influence on environmental management practices are environmental ...policies: however, their consequences for M&E practices have not been well-examined.
We examine three policy areas - the Water Framework Directive, the Natura 2000 Directives, and the Agri-Environment Schemes of the Common Agricultural Policy - whose statutory requirements influence how the environment is managed and monitored across Europe. We use a comparative approach to examine what is monitored, how monitoring is carried out, and how results are used to update management, based on publicly available documentation across nine regional and national cases.
The requirements and guidelines of these policies have provided significant impetus for monitoring: however, we find this policy-driven M&E usually does not match the ideals of what is needed to inform adaptive management. There is a tendency to focus on understanding state and trends rather than tracking the effect of interventions; a focus on specific biotic and abiotic indicators at the expense of understanding system functions and processes, especially social components; and limited attention to how context affects systems, though this is sometimes considered via secondary data. The resulting data are sometimes publicly-accessible, but it is rarely clear if and how these influence decisions at any level, whether this be in the original policy itself or at the level of measures such as site management plans.
Adjustments to policy-driven M&E could better enable learning for adaptive management, by reconsidering what supports a balanced understanding of socio-ecological systems and decision-making. Useful strategies include making more use of secondary data, and more transparency in data-sharing and decision-making. Several countries and policy areas already offer useful examples. Such changes are essential given the influence of policy, and the urgency of enabling adaptive management to safeguard socio-ecological systems.
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•Policy strongly influences Monitoring & Evaluation (M&E) of socio-ecological systems.•We examine M&E of 3 major European policies in 9 regional and national cases.•Policy-driven M&E is imperfect versus ideals of M&E to support adaptive management.•Attention needed to systems, social issues, sharing data, and sharing intended uses.•Examples from across Europe and different policies offer ideas for improvement.
PURPOSEThe present study examines cross-sectional trends in performance on a quasi-universal non-word repetition (NWR) task. It also considers whether NWR performance is dependent on levels of ...exposure to a language and compares the performance of bilingual children across their two languages. METHODA cross-sectional design was employed. The English and French quasi-universal NWR tasks, featuring stimuli from two to five syllables in length, was administered to Canadian school-aged monolinguals and two groups of bilinguals: those who encountered their second language in early childhood and those who encountered their second language at school entry. RESULTWhen evaluated in English, the early-exposure bilinguals produced significantly fewer errors than the school-entry exposure bilinguals and the English monolingual groups. When evaluated in French, the early-exposure bilinguals and the French monolinguals produced significantly fewer errors than the school-entry exposure bilinguals. Compared across languages, the French monolinguals produced fewer errors on the French version of the NWR task than the English monolinguals did on the English version of the same task. In both languages and across all analyses, the youngest age group (7-8 years) produced more errors than the two older groups (9-10 years and 11-12 years). CONCLUSIONThe quasi-universal NWR task showed sensitivity to improvements from 7 to 11 years of age in English and up to 9 years of age in French. Better performance in French may be due to the relatively greater frequency of multisyllabic words in that language. The development and use of this particular NWR task with monolinguals and bilinguals-in both of their languages-contribute to a deeper understanding of quasi-universal NWR performance in typically developing children.
In 1980, George Mandler published an article in Psychological Review that has become very influential in the study of memory. As evidence, according to Google Scholar (as of August 17, 2020), this ...article has been cited 3,391 times. Writing about recognition memory, Mandler made a fundamental distinction between recognition involving familiarity and recognition involving recollection. Mandler introduced what has since become the label for his illustration, saying that "Specific identification of an event is not possible on the basis of its familiarity alone. The butcher-in-the-bus is one intuitive demonstration of such an assertion." The purpose of this note is, ironically, to provide context, in this case historical context. Twenty-seven years before Mandler's (1980) article, Charles Osgood (1953) provided a discussion of retention and interference theory in his book,
. Is it possible that Mandler inadvertently borrowed Osgood's illustration, a case of cryptomnesia? (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Many genome variants shaping mammalian phenotype are hypothesized to regulate gene transcription and/or to be under selection. However, most of the evidence to support this hypothesis comes from ...human studies. Systematic evidence for regulatory and evolutionary signals contributing to complex traits in a different mammalian model is needed. Sequence variants associated with gene expression (expression quantitative trait loci eQTLs) and concentration of metabolites (metabolic quantitative trait loci mQTLs) and under histone-modification marks in several tissues were discovered from multiomics data of over 400 cattle. Variants under selection and evolutionary constraint were identified using genome databases of multiple species. These analyses defined 30 sets of variants, and for each set, we estimated the genetic variance the set explained across 34 complex traits in 11,923 bulls and 32,347 cows with 17,669,372 imputed variants. The per-variant trait heritability of these sets across traits was highly consistent (r > 0.94) between bulls and cows. Based on the per-variant heritability, conserved sites across 100 vertebrate species and mQTLs ranked the highest, followed by eQTLs, young variants, those under histone-modification marks, and selection signatures. From these results,we defined a Functional-And-Evolutionary Trait Heritability (FAETH) score indicating the functionality and predicted heritability of each variant. In additional 7,551 cattle, the high FAETH-ranking variants had significantly increased genetic variances and genomic prediction accuracies in 3 production traits compared to the low FAETH-ranking variants. The FAETH framework combines the information of gene regulation, evolution, and trait heritability to rank variants, and the publicly available FAETH data provide a set of biological priors for cattle genomic selection worldwide.
Current accounts of the production effect suggest that production leads to the encoding of additional production-associated features and/or better feature encoding. Thus, if it is the act of ...production that leads to the storage and/or enhanced encoding of these features, then less of this act should reduce the resulting production effect. In two experiments, we provide a direct test of this idea by manipulating how much of a given item is produced within a single mode of production (typing). Results demonstrate that such partial production can yield a significant production effect that is smaller than the effect that emerges from producing the entire item. These results suggest that how much of an item is produced can moderate the size of the production effect and are considered in the context of recent modelling efforts.
Like all receptor tyrosine kinases (RTKs), ErbB4 signals through a canonical signaling involving phosphorylation cascades. However, ErbB4 can also signal through a non-canonical mechanism whereby the ...intracellular domain is released into the cytoplasm by regulated intramembrane proteolysis (RIP) and translocates to the nucleus where it regulates transcription. These different signaling mechanisms depend on the generation of alternative spliced isoforms, a RIP cleavable ErbB4-JMa and an uncleavable ErbB4-JMb. Non-canonical signaling by ErbB4-JMa has been implicated in the regulation of brain, heart, mammary gland, lung, and immune cell development. However, most studies on non-canonical ErbB4 signaling have been performed in vitro due to the lack of an adequate mouse model. We created an ErbB4-JMa specific knock out mouse and demonstrate that RIP-dependent, non-canonical signaling by ErbB4-JMa is required for the regulation of GFAP expression during cortical development. We also show that ErbB4-JMa signaling is not required for the development of the heart, mammary glands, sensory ganglia. Furthermore, we identify genes whose expression during cortical development is regulated by ErbB4, and show that the expression of three of them, CRYM and DBi, depend on ErbB4-JMa whereas WDFY1 relies on ErbB4-JMb. Thus, we provide the first animal model to directly study the roles of ErbB4-JMa and non-canonical ErbB4 signaling in vivo.
The enactment effect is the phenomenon that physically performing an action represented by a word or phrase (e.g., clap, clap your hands) results in better memory than does simply reading it. We ...examined data from three different methodological approaches to provide a comprehensive review of the enactment effect across 145 behavioral, 7 neuroimaging, and 31 neurological patient studies. Boosts in memory performance following execution of a physical action were compared to those produced by reading words or phrases, by watching an experimenter perform actions, or by engaging in self-generated imagery. Across the behavioral studies, we employed random-effects meta-regression with robust variance estimation (RVE) to reveal an average enactment effect size of g = 1.23. Further meta-analyses revealed that variations in study design and comparison task reliably influence the size of the enactment effect, whereas four other experiment factors-test format, learning instruction type, retention interval, and the presence of objects during encoding-likely do not influence the effect. Neuroimaging studies demonstrated enactment-related activation to be prevalent in the motor cortex and inferior parietal lobule. Patient studies indicated that, regardless of whether impairments of memory (e.g., Alzheimer's) or of motor capability (e.g., Parkinson's) were present, patients were able to benefit from enactment. The findings of this systematic review and meta-analysis highlight two components accounting for the memory benefit from enactment: a primary mental contribution relating to planning the action and a secondary physical contribution of the action itself.
Public Significance Statement
The enactment effect is the finding that physically performing an action represented by a word or phrase leads to enhanced memory for that information relative to simply reading it. This review integrates evidence from behavioral, neuroimaging, and patient studies to highlight the utility of encoding multiple facets of an item or an event to enhance its retention. Enactment was found to be a reliable and effective mnemonic tool for both neurotypical and patient populations.
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