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SUMMARY Complex ethological behaviors could be constructed from finite modules that are reproducible functional units of behavior. Here, we test this idea for foraging and develop methods to dissect rich behavior patterns in mice. We uncover discrete modules of foraging behavior reproducible across different strains and ages, as well as nonmodular behavioral sequences. Modules differ in terms of form, expression frequency, and expression timing and are expressed in a probabilistically determined order. Modules shape economic patterns of feeding, exposure, activity, and perseveration responses. The modular architecture of foraging changes developmentally, and different developmental, genetic, and parental effects are found to shape the expression of specific modules. Dissecting modules from complex patterns is powerful for phenotype analysis. We discover that both parental alleles of the imprinted Prader-Willi syndrome gene Magel2 are functional in mice but regulate different modules. Our study found that complex economic patterns are built from finite, genetically controlled modules., Graphical Abstract, In Brief The principles and mechanisms involved in constructing complex behavior patterns are not well defined. Stacher Hörndli et al. find that complex foraging patterns in mice are constructed from finite modules, defined as significantly reproducible behavioral sequences. Modules are expressed in a probabilistically defined order to construct complex patterns and controlled by genetic mechanisms.

AIMS To determine the fetal and maternal outcomes in pregnant women with Glucokinase-Maturity onset diabetes of the young (GCK-MODY). METHODS We studied the obstetric and perinatal outcomes in 99 pregnancies of 34 women with GCK-MODY. The mutation status of the offspring was known in 29 and presumed in 33. Clinical outcomes were determined and compared between affected (n = 39) and unaffected (n = 23) offspring. RESULTS 59% of pregnancies were treated with diet alone and 41% received insulin. Birthweight, percentage of large for gestational age (LGA) and caesarean section (CS) in GCK-unaffected offspring was significantly higher than in GCK-affected offspring (4.0 ± 0.7 vs. 3.4 ± 0.4 kg, p = 0.001), 15 (65%) vs. 5(13%) (p = 0.00006) and 17 (74%) vs. 11 (28%) (p = 0.001), respectively. We observed an earlier gestational age at delivery on insulin in unaffected offspring (38.3 ± 1.0 vs. 39.5 ± 1.5 weeks, p = 0.03) with no significant change in LGA (9 (82%) vs. 6 (50%); p = 0.12), and a higher rate of CS (8 [73%] vs. 3 [11%]; p

Background Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO). To test this hypothesis, we evaluated a DNMT inhibitor in PO in rats and analysed DNA methylation in cardiomyocytes. Methods and results Young male Wistar rats were subjected to PO by transverse aortic constriction (TAC) or to sham surgery. Rats from both groups received solvent or 12.5 mg/kg body weight of the non-nucleosidic DNMT inhibitor RG108, initiated on the day of the intervention. After 4 weeks, we analysed cardiac function by MRI, fibrosis with Sirius Red staining, gene expression by RNA sequencing and qPCR, and DNA methylation by reduced representation bisulphite sequencing (RRBS). RG108 attenuated the ~70% increase in heart weight/body weight ratio of TAC over sham to 47% over sham, partially rescued reduced contractility, diminished the fibrotic response and the downregulation of a set of genes including Atp2a2 (SERCA2a) and Adrb1 (beta1-adrenoceptor). RG108 was associated with significantly lower global DNA methylation in cardiomyocytes by ~2%. The differentially methylated pathways were “cardiac hypertrophy”, “cell death” and “xenobiotic metabolism signalling”. Among these, “cardiac hypertrophy” was associated with significant methylation differences in the group comparison sham vs. TAC, but not significant between sham+RG108 and TAC+RG108 treatment, suggesting that RG108 partially prevented differential methylation. However, when comparing TAC and TAC+RG108, the pathway cardiac hypertrophy was not significantly differentially methylated. Conclusions DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification.

Our study explored evaluative beliefs of failure to see whether positive and negative beliefs of failure are bivariate in nature within three domains of an adolescent's life (academic, social, and athletic) and how such beliefs are differentially linked to the importance of a domain, the frequency of failure in a domain, and the extremity of negative emotions experienced when encountering failure in a domain. A total of 163 Chinese Singaporean students in Secondary 3 and 4 (Grades 9 and 10) from two Singapore schools participated in the study by completing a questionnaire. Results from various analyses converged to demonstrate that evaluative beliefs could be distinguished by both valence (positive and negative) and domain (academic, social, and athletic). The six evaluative beliefs were also distinguished from failure attributions. While there was consensus in what constituted negative beliefs of failure across domains, positive beliefs of failure showed some domain specificity, with unique aspects in particular domains (e.g., the inevitability of failure only in the academic domain). Positive and negative beliefs in the different domains were correlated among themselves, but positive and negative beliefs were uncorrelated within (except for academic) and across domains. Positive and negative beliefs were also differentially linked to domain importance, failure frequency, and extremity of negative emotion. Unexpectedly, domain importance was not linked to negative beliefs but was linked to positive beliefs, while positive and negative beliefs showed domain-specific links with failure frequency. As expected, however, negative beliefs were (positively) linked to extremity of negative emotions while positive beliefs were not linked to such extremity. The conceptual, substantive, and practical implications of these results are discussed.

SummaryTranscription factors (TFs) and their specific interactions with targets are crucial for specifying gene-expression programs. To gain insights into the transcriptional regulatory networks in embryonic stem (ES) cells, we use chromatin immunoprecipitation coupled with ultra-high-throughput DNA sequencing (ChIP-seq) to map the locations of 13 sequence-specific TFs (Nanog, Oct4, STAT3, Smad1, Sox2, Zfx, c-Myc, n-Myc, Klf4, Esrrb, Tcfcp2l1, E2f1, and CTCF) and 2 transcription regulators (p300 and Suz12). These factors are known to play different roles in ES-cell biology as components of the LIF and BMP signaling pathways, self-renewal regulators, and key reprogramming factors. Our study provides insights into the integration of the signaling pathways into the ES-cell-specific transcription circuitries. Intriguingly, we find specific genomic regions extensively targeted by different TFs. Collectively, the comprehensive mapping of TF-binding sites identifies important features of the transcriptional regulatory networks that define ES-cell identity.