RAS-extracellular signal regulated kinase (ERK) signaling governs multiple aspects of cell fate specification, cellular transitions, and growth by regulating downstream substrates through phosphorylation. Understanding how perturbations to the ERK signaling pathway lead to developmental disorders and cancer hinges critically on identification of the substrates. Yet, only a limited number of substrates have been identified that function in vivo to execute ERK-regulated processes. The Caenorhabditis elegans germ line utilizes the well-conserved RAS-ERK signaling pathway in multiple different contexts. Here, we present an integrated functional genomic approach that identified 30 ERK substrates, each of which functions to regulate one or more of seven distinct biological processes during C. elegans germ-line development. Our results provide evidence for three themes that underlie the robustness and specificity of biological outcomes controlled by ERK signaling in C. elegans that are likely relevant to ERK signaling in other organisms: (i) multiple diverse ERK substrates function to control each individual biological process; (ii) different combinations of substrates function to control distinct biological processes; and (iii) regulatory feedback loops between ERK and its substrates help reinforce or attenuate ERK activation. Substrates identified here have conserved orthologs in humans, suggesting that insights from these studies will contribute to our understanding of human diseases involving deregulated ERK activity.functional genomics ͉ signaling ͉ MPK-1 ͉ RNAi screen T he RTK-RAS-ERK pathway relays extracellular signals via a conserved kinase cascade that results in phosphorylation and activation of ERK, the terminal member of this pathway (1, 2). Active ERK in turn phosphorylates substrates to execute many cellular and developmental processes (2) (Fig. 1A). Comprehensive insight into mechanisms underlying ERK-dependent control of biological processes depends on identification of ERK substrates. Although bona fide ERK substrates have been identified in cultured cells (3-5) and potential substrates documented from proteomic studies (6, 7), the function of most of these substrates in vivo has not been defined. Additionally, currently identified substrates do not account for most ERK-dependent events in mammals, making it likely that more substrates remain to be identified. Forward genetic studies in Caenorhabditis elegans and Drosophila have identified a few ERK substrates that act in defined biological contexts (8-10); however, the mutant phenotypes of these genes account for some but not all ERK-regulated processes. To obtain molecular insight into how ERK signaling controls multiple biological processes in vivo through substrates, we devised an integrated bioinformatic, genetic, and biochemical approach by using C. elegans germ-line development as the model system.In C. elegans RAS and ERK are encoded by let-60 and mpk-1, respectively, and loss-of-function or null mutations in these core components abrogate pat...

Although audio archives are available for a number of political institutions, the data they provide receive scant attention from researchers. Yet, audio data offer important insights, including information about speakers’ emotional states. Using one of the largest collections of natural audio ever compiled—74,158 Congressional floor speeches—we introduce a novel measure of legislators’ emotional intensity: small changes in vocal pitch that are difficult for speakers to control. Applying our measure to MCs’ floor speeches about women, we show that female MCs speak with greater emotional intensity when talking about women as compared with both their male colleagues and their speech on other topics. Our two supplementary analyses suggest that increased vocal pitch is consistent with legislators’ broader issue commitments, and that emotionally intense speech may affect other lawmakers’ behavior. More generally, by demonstrating the utility of audio-as-data approaches, our work highlights a new way of studying political speech.

Moral Foundations Theory (MFT) explains liberal-conservative differences as arising from different moral intuitions, with liberals endorsing "individualizing" foundations (Harm and Fairness) and conservatives also endorsing "binding" foundations (Authority, Respect, and Purity). We argue these labels misconstrue ideological differences and propose Evolutionary-Coalitional Theory (ECT) as an alternative, explaining how competitive dynamics in the ancestral social environment could produce the observed ideological differences. We test ECT against MFT across three studies. Study 1 shows the so-called "binding" orientation entails the threat-sensitivity and outgroup antagonism predicted by ECT; that is, an authoritarian motive. Similarly, Study 2 shows the so-called "individualizing" orientation is better described as a universalizing motive, one reflecting a broader set of moral commitments (e.g., to nature) and a broader sociality than the egocentrism implied by MFT. Study 3 provides a factor analysis reducing "binding" to authoritarianism and "individualizing" to universalism, with the latter loading against social dominance orientation (SDO). A hierarchical regression then provides additional evidence for ECT, showing this dominating motive (SDO) accounts for variance in conservatism that MFT leaves unexplained. Collectively, these three studies suggest that ECT offers a more accurate and precise explanation of the key psychological differences between liberals and conservatives.

Ensuring that reasonable adjustments are made in the general hospital setting promotes person-centred care and equal health outcomes for people with a learning disability. This view accords with 'Getting it right' charter produced by the UK Charity Mencap which argues that healthcare professionals need support, encouragement and guidance to make reasonable adjustments for this group. LDLNs have an important and increasing role to play in advising on and establishing adjustments that are both reasonable and achievable.

The LDLN Services were valued by stakeholders by achieving person-centred outcomes. With their expert knowledge and skills, the liaison nurses had an important role in developing effective systems and processes within general hospital settings. The outcomes highlight the importance of supporting and promoting LDLN Services and the challenges in delivering the multifaceted elements of the role. There is a need to take account of the complex and multidimensional nature of the LDLN role and the possible tensions between achieving clinical outcomes, education and practice developments and organisational strategic initiatives.