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microRNAs (miRNAs) regulate gene expression through translational repression and/or messenger RNA (mRNA) deadenylation and decay. Because translation, deadenylation, and decay are closely linked processes, it is important to establish their ordering and thus to define the molecular mechanism of silencing. We have investigated the kinetics of these events in miRNA-mediated gene silencing by using a Drosophila S2 cell-based controllable expression system and show that mRNAs with both natural and engineered 3' untranslated regions with miRNA target sites are first subject to translational inhibition, followed by effects on deadenylation and decay. We next used a natural translational elongation stall to show that miRNA-mediated silencing inhibits translation at an early step, potentially translation initiation.

The cognitive model (Hirsch & Mathews, 2012) and attentional control theory (Eysenck & Derakshan, 2011) postulate that compromised executive function (EF) and other cognitive constructs are negatively linked to increased excessive and uncontrollable worry, the core symptom of generalized anxiety disorder (GAD). However, the prospective link between neuropsychological constructs and GAD are not well understood. A nationally representative sample of 2605 community-dwelling adults whose average age was 55.20 (s.d. = 11.41, range 33-84; 56.31% females) participated at baseline and 9-year follow-up. Baseline neuropsychological function and symptoms were measured using the Brief Test of Adult Cognition by Telephone and Composite International Diagnostic Interview - Short Form. Multivariate Poisson and negative binomial regression analyses were conducted with 11 baseline covariates entered simultaneously: age, gender, years of formal education, perceived control, hypertension/diabetes, body mass index, exercise status, as well as GAD severity, panic disorder severity, and depression severity. Those with baseline GAD were also removed. Lower Time 1 composite global cognition z-score independently predicted higher Time 2 GAD severity and diagnosis [odds ratio (OR) 0.60, 95% confidence interval (CI) 0.40-0.89, p = 0.01]. Poor inhibition, set-shifting, working memory (WM) updating, inductive reasoning, and global cognition sequentially forecasted heightened GAD. However, processing speed, verbal WM, verbal fluency, and episodic memory did not predict future GAD. Global cognition, inductive reasoning, inhibition, set-shifting, and WM updating EF impairments may be distal risk factors for elevated GAD nearly a decade later.

Previous research has implicated demographic, psychological, behavioral, and cognitive variables in the onset and maintenance of pediatric overweight/obesity. No adequately-powered study has simultaneously modeled these variables to assess their relative associations with body mass index (BMI; kg/m2) in a nationally representative sample of youth. Multiple machine learning regression approaches were employed to estimate the relative importance of 43 demographic, psychological, behavioral, and cognitive variables previously associated with BMI in youth to elucidate the associations of both fixed (e.g. demographics) and potentially modifiable (e.g. psychological/behavioral) variables with BMI in a diverse representative sample of youth. The primary analyses consisted of 9-10 year olds divided into a training (n = 2724) and test (n = 1123) sets. Secondary analyses were conducted by sex, ethnicity, and race. The full sample model captured 12% of the variance in both the training and test sets, suggesting good generalizability. Stimulant medications and demographic factors were most strongly associated with BMI. Lower attention problems and matrix reasoning (i.e. nonverbal abstract problem solving and inductive reasoning) and higher social problems and screen time were robust positive correlates in the primary analyses and in analyses separated by sex. Beyond demographics and stimulant use, this study highlights abstract reasoning as an important cognitive variable and reaffirms social problems and screen time as significant correlates of BMI and as modifiable therapeutic targets. Prospective data are needed to understand the predictive power of these variables for BMI gain.

Noise in gene expression can lead to reversible phenotypic switching. Several experimental studies have shown that the abundance distributions of proteins in a population of isogenic cells may display multiple distinct maxima. Each of these maxima may be associated with a subpopulation of a particular phenotype, the quantification of which is important for understanding cellular decision-making. Here, we devise a methodology which allows us to quantify multimodal gene expression distributions and single-cell power spectra in gene regulatory networks. Extending the commonly used linear noise approximation, we rigorously show that, in the limit of slow promoter dynamics, these distributions can be systematically approximated as a mixture of Gaussian components in a wide class of networks. The resulting closed-form approximation provides a practical tool for studying complex nonlinear gene regulatory networks that have thus far been amenable only to stochastic simulation. We demonstrate the applicability of our approach in a number of genetic networks, uncovering previously unidentified dynamical characteristics associated with phenotypic switching. Specifically, we elucidate how the interplay of transcriptional and translational regulation can be exploited to control the multimodality of gene expression distributions in two-promoter networks. We demonstrate how phenotypic switching leads to birhythmical expression in a genetic oscillator, and to hysteresis in phenotypic induction, thus highlighting the ability of regulatory networks to retain memory.

The concept of Higher-Order Thinking Skills (HOTS) is one of the highlighted aspects in producing human capital of high quality. However, the level of HOTS among students in Malaysia is still at a lower stage. Among the causes of this problem is the learning strategy used in classroom, which is less effective in creating and enhancing HOTS optimally. Therefore, the main focus in this study was to investigate the potential role of an inductive reasoning strategy using Geogebra in increasing the students’ level of HOTS. Besides, it also aimed to identify the relationship between HOTS and students’ inductive reasoning for the topic of Graphs of Functions II. The design of study was quasi-experimental which involved 94 form-four students from a secondary school in Johor. The sample of this study was divided into three groups: (1) Treatment Group 1 (inductive reasoning strategy using Geogebra); Treatment Group 2 (inductive reasoning strategy); and (3) a control group (conventional). The instrument of the study comprised a set of HOTS questions and a worksheet based on an inductive reasoning strategy using Geogebra. Using the Multivariate Analysis of Variance (MANOVA), it was found that the overall HOTS level of the students, which included applying, analysing, evaluating and creating skills, could be enhanced through this strategy. The findings also show that there was a positive relationship between HOTS and inductive reasoning. In conclusion, an inductive reasoning strategy can provide positive impacts on students’ HOTS in the topic of Graphs of Functions II

The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward.

Key Points For well over a century, hypnotic suggestion has been used to successfully treat a wide range of clinical conditions, including chronic and acute pain, irritable bowel syndrome, post-traumatic stress disorder, phobias and eating disorders. Hypnosis uses the powerful effects of attention and suggestion to produce, modify and enhance a broad range of subjectively compelling experiences and behaviours. Participants typically describe these perceptual and behavioural changes as 'real', not imaginary and beyond voluntary control. Hypnotic suggestibility is normally distributed in human populations and remains a stable individual trait. None of the major personality variables, however, correlate with hypnotic suggestibility. Many of the striking effects produced by targeted suggestions in hypnosis can be generated without prior hypnotic induction in a substantial number of people. The availability of functional imaging techniques and growing acceptance of the 'cognitive unconscious' in shaping experience and behaviour has provided opportunities for cognitive neuroscientists to explore the neurocognitive correlates of hypnosis and suggestion. Improvements in experimental design have made it possible to make inroads into the functional anatomy of hypnosis itself (intrinsic research). The induction of hypnosis is associated with reduced brain activity in anterior parts of the default-mode system and increased activity in prefrontal attentional systems. Several recent studies using hypnotic suggestion have modified established examples of 'automaticity' in cognitive processing (such as the Flanker, Stroop and McGurk effects), demonstrating the potential that hypnotic suggestion has for probing theories of cognitive functioning in the laboratory. Recent studies using hypnotic suggestion as an experimental tool for neuroscience research (instrumental research) show how manipulating subjective awareness in the laboratory can provide theoretical insights into normal brain mechanisms involved in attention, motor control, pain perception, beliefs and volition. This instrumental approach allows researchers to uncover the putative cognitive origins of clinical symptoms, such as medically unexplained paralysis seen in conversion disorder (hysteria), hallucinations, delusions and alterations in control over thought and action seen in schizophrenia. Hypnosis is used in treatment contexts and, recently, also as an investigative tool in cognitive neuroscience. Oakley and Halligan review the potential for hypnosis to provide insights into brain mechanisms involved in attention, motor control, pain perception, beliefs and volition and also to produce informative analogues of clinical conditions. Hypnosis uses the powerful effects of attention and suggestion to produce, modify and enhance a broad range of subjectively compelling experiences and behaviours. For more than a century, hypnotic suggestion has been used successfully as an adjunctive procedure to treat a wide range of clinical conditions. More recently, hypnosis has attracted a growing interest from a cognitive neuroscience perspective. Recent studies using hypnotic suggestion show how manipulating subjective awareness in the laboratory can provide insights into brain mechanisms involved in attention, motor control, pain perception, beliefs and volition. Moreover, they indicate that hypnotic suggestion can create informative analogues of clinical conditions that may be useful for understanding these conditions and their treatments.

Inductive learning--that is, learning a new concept or category by observing exemplars--happens constantly, for example, when a baby learns a new word or a doctor classifies x-rays. What influence does the spacing of exemplars have on induction? Compared with massing, spacing enhances long-term recall, but we expected spacing to hamper induction by making the commonalities that define a concept or category less apparent. We asked participants to study multiple paintings by different artists, with a given artiste's paintings presented consecutively (massed) or interleaved with other artists' paintings (spaced). We then tested induction by asking participants to indicate which studied artist (Experiments 1a and 1b) or whether any studied artist (Experiment 2) painted each of a series of new paintings. Surprisingly, induction profited from spacing, even though massing apparently created a sense of fluent learning: Participants rated massing as more effective than spacing, even after their own test performance had demonstrated the opposite.

In metazoans, cells depend on extracellular growth factors for energy homeostasis. We found that glycogen synthase kinase-3 (GSK3), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60-Ser⁸⁶, which directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60 S86A that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in ULK1 -/- mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. These findings uncover an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.