The congruency sequence effect (CSE) is one of the most investigated effects in the cognitive control literature. The conflict monitoring theory suggests that the CSE is the result of adjustments in ...cognitive control based on perceived conflict. A recent paper by Zhang and colleagues, has investigated whether the manipulation of conflict level by changing distractor incompatibility in a flanker task affects the amount of adjustments in cognitive control. Their study produced mixed findings, somewhat supporting the original conflict monitoring theory, but also suggesting other explanations, such as the repetition expectancy account. We replicated the experimental design in a multisite online study (N = 347), with Hungarian, Italian, and Singaporean participants. Our results supported the prediction that changes in the level of conflict trigger conflict adaptation, revealing that increasing conflict levels induced stronger adaptive control. Bayesian hypothesis testing indicated a monotonic reduction in congruency effects as a function of previous conflict strength. This finding is in line with the extension of the traditional conflict monitoring theory, as well as other theories like affective signaling and expected value of control, implying that the relationship between conflict and interference effects is gradual, rather than a binary function.
Exploring the mechanisms of cognitive control is central to understanding how we control our behaviour. These mechanisms can be studied in conflict paradigms, which require the inhibition of ...irrelevant responses to perform the task. It has been suggested that in these tasks, the detection of conflict enhances cognitive control resulting in improved conflict resolution of subsequent trials. If this is the case, then this so-called congruency sequence effect can be expected to occur in cross-domain tasks. Previous research on the domain-generality of the effect presented inconsistent results. In this study, we provide a multi-site replication of three previous experiments of Kan
. (Kan IP, Teubner-Rhodes S, Drummey AB, Nutile L, Krupa L, Novick JM 2013
, 637-651) which test congruency sequence effect between very different domains: from a syntactic to a non-syntactic domain (Experiment 1), and from a perceptual to a verbal domain (Experiments 2 and 3). Despite all our efforts, we found only partial support for the claims of the original study. With a single exception, we could not replicate the original findings; the data remained inconclusive or went against the theoretical hypothesis. We discuss the compatibility of the results with alternative theoretical frameworks.
Cognitive control is a set of mechanisms that help us process conflicting stimuli and maintain goal-relevant behaviour. According to the Affective Signalling Hypothesis, conflicting stimuli are ...aversive and thus elicit (negative) affect, moreover - to avoid aversive signals - affective and cognitive systems work together by increasing control and thus, drive conflict adaptation. Several studies have found that affective stimuli can indeed modulate conflict adaptation, however, there is currently no evidence that phasic affective states not triggered by conflict also trigger improved cognitive control. To investigate this possibility, we intermixed trials of a conflict task and trials involving the passive viewing of emotional words. We tested whether affective states induced by affective words in a given trial trigger improved cognitive control in a subsequent conflict trial. Applying Bayesian analysis, the results of four experiments supported the lack of adaptation to aversive signals, both in terms of valence and arousal. These results suggest that phasic affective states by themselves are not sufficient to elicit an increase in control.
Many people have flipped coins but few have stopped to ponder the statistical and physical intricacies of the process. In a preregistered study we collected \(350{,}757\) coin flips to test the ...counterintuitive prediction from a physics model of human coin tossing developed by Diaconis, Holmes, and Montgomery (DHM; 2007). The model asserts that when people flip an ordinary coin, it tends to land on the same side it started -- DHM estimated the probability of a same-side outcome to be about 51%. Our data lend strong support to this precise prediction: the coins landed on the same side more often than not, \(\text{Pr}(\text{same side}) = 0.508\), 95% credible interval (CI) \(0.506\), \(0.509\), \(\text{BF}_{\text{same-side bias}} = 2359\). Furthermore, the data revealed considerable between-people variation in the degree of this same-side bias. Our data also confirmed the generic prediction that when people flip an ordinary coin -- with the initial side-up randomly determined -- it is equally likely to land heads or tails: \(\text{Pr}(\text{heads}) = 0.500\), 95% CI \(0.498\), \(0.502\), \(\text{BF}_{\text{heads-tails bias}} = 0.182\). Furthermore, this lack of heads-tails bias does not appear to vary across coins. Additional exploratory analyses revealed that the within-people same-side bias decreased as more coins were flipped, an effect that is consistent with the possibility that practice makes people flip coins in a less wobbly fashion. Our data therefore provide strong evidence that when some (but not all) people flip a fair coin, it tends to land on the same side it started. Our data provide compelling statistical support for the DHM physics model of coin tossing.
Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive ...mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30 % of HGGs). To identify additional driver mutations in ...HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in
SETD2
, a H3K36 trimethyltransferase, in 15 % of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most
SETD2
alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed
SETD2
mutations to be specific to high-grade tumors affecting 15 % of pediatric HGGs (11/73) and 8 % of adult HGGs (5/65) while no
SETD2
mutations were identified in low-grade diffuse gliomas (0/45). Furthermore,
SETD2
mutations were mutually exclusive with
H3F3A
mutations in HGGs (
P
= 0.0492) while they partly overlapped with
IDH1
mutations (4/14), and
SETD2
-mutant tumors were found exclusively in the cerebral hemispheres (
P
= 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and
SETD2
-mutant tumors showed a substantial decrease in H3K36me3 levels (
P
< 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.
Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids ...(K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.
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► We identified six distinct GBM subgroups based on global DNA methylation patterns ► Three epigenetic GBM subgroups correlate strictly with mutations in H3F3A and IDH1 ► H3F3A K27- and G34 mutant GBMs clearly arise in different anatomic compartments ► One GBM subgroup (G34) lacks important markers of neural lineage commitment
Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities ...affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA.
We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes.
Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic β-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7 was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation.
OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.
Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To ...explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
The
MYC
oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and ...comprehensive investigations of
MYCC
,
MYCN
and
MYCL
in an extensive medulloblastoma cohort (
n
= 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy.
MYCC
and
MYCN
expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall
MYC
copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material.
MYCC
and
MYCN
amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0–16.0 years), but
MYCC
conferred a greater hazard to survival than
MYCN
when considered across this treatment group.
MYCN
’s weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups;
MYCN
predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or
MYCC
/
MYCN
amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported
MYC
amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.
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