E2F and p53 Induce Apoptosis Independently during Drosophila Development but Intersect in the Context of DNA Damage

In mammalian cells, RB/E2F and p53 are intimately connected, and crosstalk between these pathways is critical for the induction of cell cycle arrest or cell death in response to cellular stresses. Here we have investigated the genetic interactions between RBF/E2F and p53 pathways during Drosophila development. Unexpectedly, we find that the pro-apoptotic activities of E2F and p53 are independent of one another when examined in the context of Drosophila development: apoptosis induced by the deregulation of dE2F1, or by the overexpression of dE2F1, is unaffected by the elimination of dp53; conversely, dp53-induced phenotypes are unaffected by the elimination of dE2F activity. However, dE2F and dp53 converge in the context of a DNA damage response. Both dE2F1/dDP and dp53 are required for DNA damage-induced cell death, and the analysis of rbf1 mutant eye discs indicates that dE2F1/dDP and dp53 cooperatively promote cell death in irradiated discs. In this context, the further deregulation in the expression of pro-apoptotic genes generates an additional sensitivity to apoptosis that requires both dE2F/dDP and dp53 activity. This sensitivity differs from DNA damage-induced apoptosis in wild-type discs (and from dE2F/dDP-induced apoptosis in un-irradiated rbf1 mutant eye discs) by being dependent on both hid and reaper. These results show that pro-apoptotic activities of dE2F1 and dp53 are surprisingly separable: dp53 is required for dE2F-dependent apoptosis in the response to DNA damage, but it is not required for dE2F-dependent apoptosis caused simply by the inactivation of rbf1

Neurodevelopmental milestones and associated behaviours are similar among healthy children across diverse geographical locations.

It is unclear whether early child development is, like skeletal growth, similar across diverse regions with adequate health and nutrition. We prospectively assessed 1307 healthy, well-nourished 2-year-old children of educated mothers, enrolled in early pregnancy from urban areas without major socioeconomic or environmental constraints, in Brazil, India, Italy, Kenya and UK. We used a specially developed psychometric tool, WHO motor milestones and visual tests. Similarities across sites were measured using variance components analysis and standardised site differences (SSD). In 14 of the 16 domains, the percentage of total variance explained by between-site differences ranged from 1.3% (cognitive score) to 9.2% (behaviour score). Of the 80 SSD comparisons, only six were >±0.50 units of the pooled SD for the corresponding item. The sequence and timing of attainment of neurodevelopmental milestones and associated behaviours in early childhood are, therefore, likely innate and universal, as long as nutritional and health needs are met

An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus

DNA damage resulting from intrinsic or extrinsic sources activates DNA damage responses (DDRs) centered on protein kinase signaling cascades. The usual consequences of inducing DDRs include the activation of cell cycle checkpoints together with repair of the damaged DNA or induction of apoptosis. Many DNA viruses elicit host DDRs during infection and some viruses require the DDR for efficient replication. However, the mechanism by which DDRs are activated by viral infection is poorly understood. Human cytomegalovirus (HCMV) infection induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) protein kinase. Here we show that HCMV replication is compromised in cells with inactivated or depleted ATM and that ATM is essential for the host DDR early during infection. Likewise, a downstream target of ATM phosphorylation, H2AX, also contributes to viral replication. The ATM-dependent DDR is detected as discrete, nuclear γH2AX foci early in infection and can be activated by IE proteins. By 24 hpi, γH2AX is observed primarily in HCMV DNA replication compartments. We identified a role for the E2F1 transcription factor in mediating this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the accumulation of γH2AX during HCMV infection or IE protein expression. Moreover, E2F1 expression, but not the expression of E2F2 or E2F3, is required for efficient HCMV replication. These results reveal a novel role for E2F1 in mediating an ATM-dependent DDR that contributes to viral replication. Given that E2F activity is often deregulated by infection with DNA viruses, these observations raise the possibility that an E2F1-mediated mechanism of DDR activation may be conserved among DNA viruses

Context, cognition and communication in language

Questions pertaining to the unique structure and organisation of language have a long history in the field of linguistics. In recent years, researchers have explored cultural evolutionary explanations, showing how language structure emerges from weak biases amplified over repeated patterns of learning and use. One outstanding issue in these frameworks is accounting for the role of context. In particular, many linguistic phenomena are said to to be context-dependent; interpretation does not take place in a void, and requires enrichment from the current state of the conversation, the physical situation, and common knowledge about the world. Modelling the relationship between language structure and context is therefore crucial for developing a cultural evolutionary approach to language. One approach is to use statistical analyses to investigate large-scale, cross-cultural datasets. However, due to the inherent limitations of statistical analyses, especially with regards to the inadequacy of these methods to test hypotheses about causal relationships, I argue that experiments are better suited to address questions pertaining to language structure and context. From here, I present a series of artificial language experiments, with the central aim being to test how manipulations to context influence the structure and organisation of language. Experiment 1 builds upon previous work in iterated learning and communication games through demonstrating that the emergence of optimal communication systems is contingent on the contexts in which languages are learned and used. The results show that language systems gradually evolve to only encode information that is informative for conveying the intended meaning of the speaker - resulting in markedly different systems of communication. Whereas Experiment 1 focused on how context influences the emergence of structure, Experiments 2 and 3 investigate under what circumstances do manipulations to context result in the loss of structure. While the results are inconclusive across these two experiments, there is tentative evidence that manipulations to context can disrupt structure, but only when interacting with other factors. Lastly, Experiment 4 investigates whether the degree of signal autonomy (the capacity for a signal to be interpreted without recourse to contextual information) is shaped by manipulations to contextual predictability: the extent to which a speaker can estimate and exploit contextual information a hearer uses in interpreting an utterance. When the context is predictable, speakers organise languages to be less autonomous (more context-dependent) through combining linguistic signals with contextual information to reduce effort in production and minimise uncertainty in comprehension. By decreasing contextual predictability, speakers increasingly rely on strategies that promote more autonomous signals, as these signals depend less on contextual information to discriminate between possible meanings. Overall, these experiments provide proof-of-concept for investigating the relationship between language structure and context, showing that the organisational principles underpinning language are the result of competing pressures from context, cognition, and communication

Towards a geography of emotional analysis

This article is a forum response to a research article on self-reporting methodswhen studying discrete emotions in science education environments. Studying emotions in natural settings is a difficult task because of the complexity of deciphering verbal and non-verbal communication. In my response I present three main points that build on insights mainly from philosophy and anthropology. The three points are: first, the significance of connecting the visible and measurable with the invisible and intangible; second, what it means to think about the practices of knowing; and third, an argument to map out a geography of analysis that takes also into account who or what emotions are directed at