In praise of folly: flexible goals and human cognition.

Humans often pursue idiosyncratic goals that appear remote from functional ends, including information gain. We suggest that this is valuable because goals (even prima facie foolish or unachievable ones) contain structured information that scaffolds thinking and planning. By evaluating hypotheses and plans with respect to their goals, humans can discover new ideas that go beyond prior knowledge and observable evidence. These hypotheses and plans can be transmitted independently of their original motivations, adapted across generations, and serve as an engine of cultural evolution. Here, we review recent empirical and computational research underlying goal generation and planning and discuss the ways that the flexibility of our motivational system supports cognitive gains for both individuals and societies.

iCatcher+: Robust and Automated Annotation of Infants' and Young Children's Gaze Behavior From Videos Collected in Laboratory, Field, and Online Studies.

Technological advances in psychological research have enabled large-scale studies of human behavior and streamlined pipelines for automatic processing of data. However, studies of infants and children have not fully reaped these benefits because the behaviors of interest, such as gaze duration and direction, still have to be extracted from video through a laborious process of manual annotation, even when these data are collected online. Recent advances in computer vision raise the possibility of automated annotation of these video data. In this article, we built on a system for automatic gaze annotation in young children, iCatcher, by engineering improvements and then training and testing the system (referred to hereafter as iCatcher+) on three data sets with substantial video and participant variability (214 videos collected in U.S. lab and field sites, 143 videos collected in Senegal field sites, and 265 videos collected via webcams in homes; participant age range = 4 months-3.5 years). When trained on each of these data sets, iCatcher+ performed with near human-level accuracy on held-out videos on distinguishing "LEFT" versus "RIGHT" and "ON" versus "OFF" looking behavior across all data sets. This high performance was achieved at the level of individual frames, experimental trials, and study videos; held across participant demographics (e.g., age, race/ethnicity), participant behavior (e.g., movement, head position), and video characteristics (e.g., luminance); and generalized to a fourth, entirely held-out online data set. We close by discussing next steps required to fully automate the life cycle of online infant and child behavioral studies, representing a key step toward enabling robust and high-throughput developmental research.

Not Playing by the Rules: Exploratory Play, Rational Action, and Efficient Search.

Recent studies suggest children's exploratory play is consistent with formal accounts of rational learning. Here we focus on the tension between this view and a nearly ubiquitous feature of human play: In play, people subvert normal utility functions, incurring seemingly unnecessary costs to achieve arbitrary rewards. We show that four-and-five-year-old children not only infer playful behavior from observed violations of rational action (Experiment 1), but themselves take on unnecessary costs during both retrieval (Experiment 2) and search (Experiments 3A-B) tasks, despite acting efficiently in non-playful, instrumental contexts. We discuss the value of such apparently utility-violating behavior and why it might serve learning in the long run.

Children selectively endorse speculative conjectures.

Young children are epistemically vigilant, attending to the reliability, expertise, and confidence of their informants and the prior probability and verifiability of their claims. But the pre-eminent requirement of any hypothesis is that it provides a potential solution to the question at hand. Given questions with no known answer, the ability to selectively adopt new, unverified, speculative proposals may be critical to learning. This study explores when people might reasonably reject known facts in favor of unverified conjectures. Across four experiments, when conjectures answer questions that available facts do not, both adults (n = 48) and children (4.0-7.9 years, n = 241, of diverse race and ethnicity) prefer the conjectures, even when the conjectures are preceded by uncertainty markers or explicitly violate prior expectations.

Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is one of the main causes of death in chronic liver disease. Oxidative stress and pyroptosis are important factors leading to ALD. Bromodomain-containing protein 4 (BRD4) is a factor that we have confirmed to regulate ALD. As a phenolic acid compound, sinapic acid (SA) has significant effects in antioxidant, anti-inflammatory and liver protection. In this study, we explored whether SA regulates oxidative stress and pyroptosis through BRD4 to play a protective effect in ALD. Male C57BL/6 mice and AML-12 cells were used for experiments. We found that SA treatment largely abolished the up-regulation of BRD4 and key proteins of the canonical pyroptosis signalling in the liver of mice fed with alcohol, while conversely enhanced the antioxidant response. Consistantly, both SA pretreatment and BRD4 knockdown inhibited oxidative stress, pyroptosis, and liver cell damage in vitro. More importantly, the expression levels of BRD4 and pyroptosis indicators increased significantly in ALD patients. Molecule docking analysis revealed a potent binding of SA with BRD4. In conclusion, this study demonstrates that SA reduces ALD through BRD4, which is a valuable lead compound that prevents the ALD process.

Ubiquitin-specific protease 22 ameliorates chronic alcohol-associated liver disease by regulating BRD4.

Alcohol-associated liver disease (ALD) is a liver system disease caused by alcohol abuse, and it involves complex processes ranging from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma. Steatosis and inflammation are the main phenomena involved in ALD. Ubiquitin-specific protease 22 (USP22) plays an important role in liver steatosis; however, its functional contribution to ALD remains unclear. USP22-silenced mice were fed a Lieber-DeCarli liquid diet. AML-12 and HEK293T cells were used to detect the interaction between USP22 and BRD4. Here, we report that hepatic USP22 expression was dramatically upregulated in mice with ALD. Inflammation and steatosis were significantly ameliorated following USP22 silencing in vivo, as indicated by decreased IL-6 and IL-1ß levels. We further showed that the overexpression of USP22 increased inflammation, while knocking down BRD4 suppressed the inflammatory response in AML-12 cells. Notably, USP22 functioned as a BRD4 deubiquitinase to facilitate BRD4 inflammatory functions. More importantly, the expression levels of USP22 and BRD4 in patients with ALD were significantly increased. In conclusion, USP22 acts a key pathogenic factor in ALD by deubiquitinating BRD4, which facilitates the inflammatory response and aggravates ALD.

More rapid dechlorination of 2,4-dichlorophenol using acclimated bacteria.

The key step for anaerobic biodegradation of 2,4-dichlorophenol (2,4-DCP) is an initial dechlorination reaction, but Cl in the para-position is more difficult to remove than Cl in the ortho-position using normal 2,4-DCP-acclimated bacteria. In this work, a bacterial community previously acclimated to biodegrading 2,4-DCP slowly dechlorinated 4-chlorophenol (4-CP Cl only in the para-position), which limited mineralization. That community was exposed to the selective pressure of having 4-CP as its only organic substrate in order to generate a 4-CP-dechlorinating community. When the 4-CP-dechlorinating community was challenged with 2,4-DCP, 4-CP hardly accumulated, although the kinetics for 2,4-DCP biodegradation were slower. When the community acclimated to 4-CP was mixed with the community acclimated to 2,4-DCP, the 2,4-DCP removal rate remained high, and 4-CP was more rapidly biodegraded. The genera Treponema, Blvii28, Dechloromonas, Nitrospira, and Thauera were significantly more abundant in the 4-CP-dechlorinating biomass and may have played roles in 2,4-DCP dechlorination and mineralization.

Counting to Infinity: Does Learning the Syntax of the Count List Predict Knowledge That Numbers Are Infinite?

By around the age of 5½, many children in the United States judge that numbers never end, and that it is always possible to add 1 to a set. These same children also generally perform well when asked to label the quantity of a set after one object is added (e.g., judging that a set labeled "five" should now be "six"). These findings suggest that children have implicit knowledge of the "successor function": Every natural number, n, has a successor, n + 1. Here, we explored how children discover this recursive function, and whether it might be related to discovering productive morphological rules that govern language-specific counting routines (e.g., the rules in English that represent base-10 structure). We tested 4- and 5-year-old children's knowledge of counting with three tasks, which we then related to (a) children's belief that 1 can always be added to any number (the successor function) and (b) their belief that numbers never end (infinity). Children who exhibited knowledge of a productive counting rule were significantly more likely to believe that numbers are infinite (i.e., there is no largest number), though such counting knowledge was not directly linked to knowledge of the successor function, per se. Also, our findings suggest that children as young as 4 years of age are able to implement rules defined over their verbal count list to generate number words beyond their spontaneous counting range, an insight which may support reasoning over their acquired verbal count sequence to infer that numbers never end.

Salvianic acid A alleviates chronic alcoholic liver disease by inhibiting HMGB1 translocation via down-regulating BRD4.

Alcoholic liver disease (ALD) is the major cause of chronic liver disease and a global health concern. ALD pathogenesis is initiated with liver steatosis, and ALD can progress to steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Salvianic acid A (SAA) is a phenolic acid component of Danshen, a Chinese herbal medicine with possible hepatoprotective properties. The purpose of this study was to investigate the effect of SAA on chronic alcoholic liver injury and its molecular mechanism. We found that SAA significantly inhibited alcohol-induced liver injury and ameliorated ethanol-induced hepatic inflammation. These protective effects of SAA were likely carried out through its suppression of the BRD4/HMGB1 signalling pathway, because SAA treatment largely diminished alcohol-induced BRD4 expression and HMGB1 nuclear translocation and release. Importantly, BRD4 knockdown prevented ethanol-induced HMGB1 release and inflammatory cytokine production in AML-12 cells. Similarly, alcohol-induced pro-inflammatory cytokines were blocked by HMGB1 siRNA. Collectively, our results reveal that activation of the BRD4/HMGB1 pathway is involved in ALD pathogenesis. Therefore, manipulation of the BRD4/HMGB1 pathway through strategies such as SAA treatment holds great therapeutic potential for chronic alcoholic liver disease therapy.

Do children's number words begin noisy?

How do children acquire exact meanings for number words like three or forty-seven? In recent years, a lively debate has probed the cognitive systems that support learning, with some arguing that an evolutionarily ancient "approximate number system" drives early number word meanings, and others arguing that learning is supported chiefly by representations of small sets of discrete individuals. This debate has centered around the findings generated by Wynn's (, ) Give-a-Number task, which she used to categorize children into discrete "knower level" stages. Early reports confirmed Wynn's analysis, and took these stages to support the "small sets" hypothesis. However, more recent studies have disputed this analysis, and have argued that Give-a-Number data reveal a strong role for approximate number representations. In the present study, we use previously collected Give-a-Number data to replicate the analyses of these past studies, and to show that differences between past studies are due to assumptions made in analyses, rather than to differences in data themselves. We also show how Give-a-Number data violate the assumptions of parametric tests used in past studies. Based on simple non-parametric tests and model simulations, we conclude that (a) before children learn exact meanings for words like one, two, three, and four, they first acquire noisy preliminary meanings for these words, (b) there is no reliable evidence of preliminary meanings for larger meanings, and (c) Give-a-Number cannot be used to readily identify signatures of the approximate number system.

Prognostic efficacy of circulating asymmetric dimethylarginine in patients with peripheral arterial disease: A meta-analysis of prospective cohort studies.

Background Asymmetric dimethylarginine is suggested to be a marker of poor prognosis in patients with atherosclerosis. However, the predictive role of circulating asymmetric dimethylarginine for clinical outcome in patients with peripheral arterial disease has not been determined. Aims To quantitatively assess the predictive value of circulating asymmetric dimethylarginine for clinical outcome in patients with peripheral arterial disease in a meta-analysis of prospective cohort studies. Methods Relevant studies were identified by systematically searching of PubMed and Embase databases. A random-effect model was used to synthesize the results. Sensitivity analyses by omitting one study at a time were performed to evaluate the robustness of the results. Results Six studies with 2535 peripheral arterial disease patients were included. Patients with higher circulating asymmetric dimethylarginine at baseline were associated with higher risk of all-cause mortality (adjusted hazard ratio: 1.63, 95% confidence interval: 1.28-2.06, I2 = 16%), and major adverse cardiovascular events (adjusted hazard ratio: 2.01, 95% confidence interval: 1.08-3.73, I2 = 78%) as compared with those with lower circulating asymmetric dimethylarginine at baseline. Specifically, every increment of 0.1 µmol/l of asymmetric dimethylarginine was associated with 18% (adjusted hazard ratio: 1.18, 95% confidence interval: 1.06-1.31) increased risk for all-cause mortality and 14% (adjusted hazard ratio: 1.14, 95% confidence interval: 1.04-1.25) increased risk for major adverse cardiovascular disease. Sensitivity analyses by omitting one study at a time did not significantly change the results. Conclusion Higher circulating asymmetric dimethylarginine at baseline may be associated with higher incidence of cardiovascular events and mortality in patients with peripheral arterial disease.

Diagrams benefit symbolic problem-solving.

BACKGROUND: The format of a mathematics problem often influences students' problem-solving performance. For example, providing diagrams in conjunction with story problems can benefit students' understanding, choice of strategy, and accuracy on story problems. However, it remains unclear whether providing diagrams in conjunction with symbolic equations can benefit problem-solving performance as well. AIMS: We tested the impact of diagram presence on students' performance on algebra equation problems to determine whether diagrams increase problem-solving success. We also examined the influence of item- and student-level factors to test the robustness of the diagram effect. SAMPLE: We worked with 61 seventh-grade students who had received 2 months of pre-algebra instruction. METHOD: Students participated in an experimenter-led classroom session. Using a within-subjects design, students solved algebra problems in two matched formats (equation and equation-with-diagram). RESULTS: The presence of diagrams increased equation-solving accuracy and the use of informal strategies. This diagram benefit was independent of student ability and item complexity. CONCLUSIONS: The benefits of diagrams found previously for story problems generalized to symbolic problems. The findings are consistent with cognitive models of problem-solving and suggest that diagrams may be a useful additional representation of symbolic problems.