Party mandates and the politics of attention:Party platforms, public priorities and the policy agenda in Britain

This paper develops an attention-based model of party mandates and policy agendas, where parties and governments are faced with an abundance of issues, and must divide their scarce attention across them. In government, parties must balance their desire to deliver on their electoral mandate (i.e. the “promissory agenda”) with a need to continuously adapt their policy priorities in response to changes in public concerns and to deal with unexpected events and the emergence of new problems (i.e. the “anticipatory agenda”). Parties elected to office also have incentives to respond to issues prioritized by the platforms of their rivals. To test this theory, time series cross-sectional models are used to investigate how the policy content of the legislative program of British government responds to governing and opposition party platforms, the executive agenda, issue priorities of the public and mass medi

A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis

We report the formicapyridines which are structurally and biosynthetically related to the pentacyclic fasamycin and formicamycin aromatic polyketides but comprise a rare pyridine moiety. These new compounds are trace level metabolites formed by derailment of the major biosynthetic pathway. Inspired by evolutionary logic we show that rational mutation of a single gene in the biosynthetic gene cluster leads to a significant increase both in total formicapyridine production and their enrichment relative to the fasamycins/formicamycins. Our observations broaden the polyketide biosynthetic landscape and identify a non-catalytic role for ABM superfamily proteins in type II polyketide synthase assemblages for maintaining biosynthetic pathway fidelity

Dicer Is Required for Maintaining Adult Pancreas

Dicer1, an essential component of RNA interference and the microRNA pathway, has many important roles in the morphogenesis of developing tissues. Dicer1 null mice have been reported to die at E7.5; therefore it is impossible to study its function in adult tissues. We previously reported that Dicer1-hypomorphic mice, whose Dicer1 expression was reduced to 20% in all tissues, were unexpectedly viable. Here we analyzed these mice to ascertain whether the down-regulation of Dicer1 expression has any influence on adult tissues. Interestingly, all tissues of adult (8–10 week old) Dicer1-hypomorphic mice were histologically normal except for the pancreas, whose development was normal at the fetal and neonatal stages; however, morphologic abnormalities in Dicer1-hypomorphic mice were detected after 4 weeks of age. This suggested that Dicer1 is important for maintaining the adult pancreas

Dicer Is Required for Maintaining Adult Pancreas

Dicer1, an essential component of RNA interference and the microRNA pathway, has many important roles in the morphogenesis of developing tissues. Dicer1 null mice have been reported to die at E7.5; therefore it is impossible to study its function in adult tissues. We previously reported that Dicer1-hypomorphic mice, whose Dicer1 expression was reduced to 20% in all tissues, were unexpectedly viable. Here we analyzed these mice to ascertain whether the down-regulation of Dicer1 expression has any influence on adult tissues. Interestingly, all tissues of adult (8–10 week old) Dicer1-hypomorphic mice were histologically normal except for the pancreas, whose development was normal at the fetal and neonatal stages; however, morphologic abnormalities in Dicer1-hypomorphic mice were detected after 4 weeks of age. This suggested that Dicer1 is important for maintaining the adult pancreas

A westward extension of the warm pool leads to a westward extension of the Walker circulation, drying eastern Africa

Observations and simulations link anthropogenic greenhouse and aerosol emissions with rapidly increasing Indian Ocean sea surface temperatures (SSTs). Over the past 60 years, the Indian Ocean warmed two to three times faster than the central tropical Pacific, extending the tropical warm pool to the west by ~40° longitude (><4,000 km). This propensity toward rapid warming in the Indian Ocean has been the dominant mode of interannual variability among SSTs throughout the tropical Indian and Pacific Oceans (55°E–140°W) since at least 1948, explaining more variance than anomalies associated with the El Niño-Southern Oscillation (ENSO). In the atmosphere, the primary mode of variability has been a corresponding trend toward greatly increased convection and precipitation over the tropical Indian Ocean. The temperature and rainfall increases in this region have produced a westward extension of the western, ascending branch of the atmospheric Walker circulation. Diabatic heating due to increased mid-tropospheric water vapor condensation elicits a westward atmospheric response that sends an easterly flow of dry air aloft toward eastern Africa. In recent decades (1980–2009), this response has suppressed convection over tropical eastern Africa, decreasing precipitation during the ‘long-rains’ season of March–June. This trend toward drought contrasts with projections of increased rainfall in eastern Africa and more ‘El Niño-like’ conditions globally by the Intergovernmental Panel on Climate Change. Increased Indian Ocean SSTs appear likely to continue to strongly modulate the Warm Pool circulation, reducing precipitation in eastern Africa, regardless of whether the projected trend in ENSO is realized. These results have important food security implications, informing agricultural development, environmental conservation, and water resource planning

Translational Systems Biology of Inflammation

Inflammation is a complex, multi-scale biologic response to stress that is also required for repair and regeneration after injury. Despite the repository of detailed data about the cellular and molecular processes involved in inflammation, including some understanding of its pathophysiology, little progress has been made in treating the severe inflammatory syndrome of sepsis. To address the gap between basic science knowledge and therapy for sepsis, a community of biologists and physicians is using systems biology approaches in hopes of yielding basic insights into the biology of inflammation. “Systems biology” is a discipline that combines experimental discovery with mathematical modeling to aid in the understanding of the dynamic global organization and function of a biologic system (cell to organ to organism). We propose the term translational systems biology for the application of similar tools and engineering principles to biologic systems with the primary goal of optimizing clinical practice. We describe the efforts to use translational systems biology to develop an integrated framework to gain insight into the problem of acute inflammation. Progress in understanding inflammation using translational systems biology tools highlights the promise of this multidisciplinary field. Future advances in understanding complex medical problems are highly dependent on methodological advances and integration of the computational systems biology community with biologists and clinicians

Understanding the (non-)Use of Societal Wellbeing Indicators in National Policy Development : What Can We Learn from Civil Servants? A UK Case Study

Gross Domestic Product is often used as a proxy for societal well-being in the context of policy development. Its shortcomings in this context are, however, well documented, and numerous alternative indicator sets have been developed. Despite this, there is limited evidence of widespread use of these alternative indicator sets by people working in policy areas relevant to societal wellbeing. Civil servants are an important group of indicator end-users. Better understanding their views concerning measuring societal wellbeing can support wider discussions about what factors determine indicator use and influence in policy decision-making. Taking the UK as a case study, we ask what views exist among civil servants in the UK about measuring societal well-being? To answer this question, we used a bootstrapped Q methodology, interviewing 20 civil servants to elicit their views about measuring societal well-being. Three distinct discourses emerged from our analysis: one that was concerned about the consequences of ignoring natural, social and human capital in decision making; one that emphasised opportunity and autonomy as key determinants of well-being; and one that focused on the technical aspects of measuring societal well-being. Each of these discourses has direct implications for the way that we integrate societal wellbeing into policy making and highlights the potential benefits of including end-users in indicator development and strategy

Targeted Deficiency of the Transcriptional Activator Hnf1α Alters Subnuclear Positioning of Its Genomic Targets

DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary β-cells and hepatocytes freshly isolated from mice lacking Hnf1α, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3). We show that in Hnf1a−/− cells inactive endogenous Hnf1α-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1α-targets in Hnf1a−/− cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease

Female sexual preferences toward conspecific and hybrid male mating calls in two species of polygynous deer, Cervus elaphus and C. nippon

The behavioral processes at the basis of hybridization and introgression are understudied in terrestrial mammals. We use a unique model to test the role of sexual signals as a reproductive barrier to introgression by investigating behavioral responses to male sexual calls in estrous females of two naturally allopatric but reproductively compatible deer species, red deer and sika deer. Previous studies demonstrated asymmetries in acoustic species discrimination between these species: most but not all female red deer prefer conspecific over sika deer male calls while female sika deer exhibit no preference differences. Here, we extend this examination of acoustic species discrimination to the role of male sexual calls in introgression between parent species and hybrids. Using two-speaker playback experiments, we compared the preference responses of estrous female red and sika deer to male sexual calls from conspecifics versus red × sika hybrids. These playbacks simulate early secondary contact between previously allopatric species after hybridization has occurred. Based on previous conspecific versus heterospecific playbacks, we predicted that most female red deer would prefer conspecific calls while female sika deer would show no difference in their preference behaviors toward conspecific and hybrid calls. However, results show that previous asymmetries did not persist as neither species exhibited more preferences for conspecific over hybrid calls. Thus, vocal behavior is not likely to deter introgression between these species during the early stages of sympatry. On a wider scale, weak discrimination against hybrid sexual signals could substantially contribute to this important evolutionary process in mammals and other taxa

Selective Cholinergic Depletion in Medial Septum Leads to Impaired Long Term Potentiation and Glutamatergic Synaptic Currents in the Hippocampus

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning