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Party unity is central to studying legislative politics and explaining the organization of legislative chambers, passage of policy, and even electoral outcomes. Its effect has been shown at the subnational, national, and international levels. While party unity has been used to explain many phenomena in legislative politics, there is much less known about the determinants of party unity, especially at the subnational level. We leverage a dataset of party unity in 95 U.S. state legislative chambers from 2002 to 2014, to test the impact of party structures, institutional rules, and contextual factors on the level of party unity. We find that majority status, party seat share, and the other party's unity impact party unity similarly for both parties, but the effect of inter‐party heterogeneity differs by party. These findings offer a new and unique insight to how partisan theories operate differently within state legislative versus Congressional parties. [ABSTRACT FROM AUTHOR]

Committee seats endow holders with both policy influence and labor obligation. These benefits and costs present the organizational majority with an interesting choice: how many seats should it allocate to the opposition? We present a theoretical framework for understanding the allocation of committee seats by the majority coalition that incorporates both procedural and electoral concerns in the decision calculus and predict that when the majority is strong, the minority will be overrepresented on committees, but when the majority is weak, the minority will be underrepresented. Mechanistic, institutional, and contextual moderators to this choice framework are also discussed. We test our predictions by examining original data on the composition of over 2,000 committees across 98 American state and federal legislative chambers. The analysis yields strong support for our central predictions while suggesting interesting and intuitive contextual constraints on the majority's tendency to exploit its position. [ABSTRACT FROM AUTHOR]

We present a parsimonious framework for understanding contextual variation in legislative nonresponse. We argue that legislators’ propensity to vote is a function of their willingness and ability to be physically present in the chamber and determine the best position to take on a given proposal. From this framework, we derive four hypotheses regarding the compensation legislators receive, their opportunity to pursue work outside of the chamber, and their informational resources. Analyzing data on over seven million voting opportunities across two sessions in ninety-nine chambers, we find robust evidence that longer legislative sessions decrease nonresponse and that informational resources increase nonresponse, but no evidence that compensation influences nonresponse. [ABSTRACT FROM AUTHOR]

The management of back-up strategies in drug discovery and development is usually done on an ad hoc basis depending upon a series of external factors including overall portfolio status and resource and/or budget availability. These are however an essential component of risk management and merit a more structured and systematic conduct throughout the lifetime of a project. An approach based upon a thorough alignment of decision points and data availability as well as a tailor-made progression of various types of back-up program as a function of project categorization is suggested. [ABSTRACT FROM AUTHOR]

The article focuses on the effectiveness of the diabetic retinopathy screening services which aim to reduce the risk of sight loss amongst patients with diabetes. It states that the diabetic retinopathy is prevalent in England with 2.4 million patients were recorded having diabetes and require timely screening to prevent sight loss. It examines the reports provided by the Gloucestershire Diabetic Retinopathy Screening Service that was initiated in 1998.

Abstract: SAR around alkyne–quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor. [Copyright &y& Elsevier]

Abstract: Introduction of 3-substituted azetidinyl substituents onto the 4,6-diaminopyrimidine scaffold allowed the improvement of PDE4 inhibiting activities. Preliminary in vivo activity in pulmonary inflammation models is reported. [Copyright &y& Elsevier]

On the sphere, global Fourier transforms are non Abelian and usually called Spherical Harmonic Transforms (SHTs). Discrete SHTs are defined for various grids of data but most applications have requirements in terms of preferred grids and polar considerations. Chebychev quadrature has proven most appropriate in discrete analysis and synthesis to very high degrees and orders. Multiresolution analysis and synthesis that involve convolutions, dilations and decimations are efficiently carried out using SHTs. The high-resolution global datasets becoming available from satellite systems require very high degree and order SHTs for proper representation of the fields. The implied computational efforts in terms of efficiency and reliability are very challenging. The efforts made to compute SHTs and their inverses to degrees and orders 3600 and higher are discussed with special emphasis on numerical stability and information preservation. Parallel and grid computations are imperative for a number of geodetic, geophysical and related applications where near kilometre resolution is required. Parallel computations have been investigated and preliminary results confirm the expectations in terms of efficiency. Further work is continuing on optimizing the computations. [ABSTRACT FROM AUTHOR]

Abstract: SAR around 4,6-diaminopyrimidine derivatives allowed the discovery of the first potent dual M3 antagonists and PDE4 inhibitors. Various chemical modulations around that scaffold led to the discovery of ucb-101333-3 which is characterized by the most interesting profile on both targets. [Copyright &y& Elsevier]

Abstract: P388D1 cells release free arachidonic acid (AA) and prostaglandin E2 (PGE2) upon stimulation with platelet-activating factor (PAF) and zymosan. The response to PAF is dependent on priming of the cells with bacterial lipopolysaccharide (LPS). In the LPS/PAF pathway, both AA and PGE2 release are dependent on transcription and translation, whereas in the zymosan pathway the release of these compounds appears to be largely independent of these processes. Using quantitative real-time PCR, we analyzed the expression of mRNAs that encode proteins potentially responsible for the dependency of the LPS/PAF pathway on gene expression. These include all the phospholipases A2 (PLA2) that we detected in P388D1 cells, cyclooxygenases (COX), COX-1 and COX-2, the membrane-associated prostaglandin E synthase-1 (mPGES-1), the lipocalin-type prostaglandin D2 synthase (PGDS), hematopoietic PGDS and the subunit Gαi2 of heterotrimeric G-proteins. None of the mRNAs encoding PLA2s, PGDSs, or Gαi2 are substantially altered during LPS priming. However, cyclooxygenase-2 is up-regulated during LPS priming and after stimulation of the cells with zymosan. A modest but significant increase of mPGES-1 mRNA was also detected upon stimulation with zymosan. Thus, the dependency of the LPS/PAF-induced PGE2 production on gene expression can be attributed to the production of cyclooxygenase-2. The dependency of AA release on gene expression is not due to altered expression of any of the PLA2s. We suggest that an accessory regulatory protein affecting the release of AA must be responsible. Using HPLC we separated lipids that are secreted upon stimulation with LPS/PAF and zymosan and found that in both pathways PGD2 is the dominant prostaglandin produced and also detected PGE2, PGF2α and AA besides several unidentified compounds. [Copyright &y& Elsevier]

Studies the genetic and environmental factors in the cerebral literalization in relation to handedness and speech. Discussion on the handedness and the effects of use or learning; Information on handedness and cerebral literalization; Revision of neural plasticity and speech.

Reviews the results of investigations on gaining control of limb movements and discussion on their contribution to understanding the development of manual asymmetries in relation to the discrimination and programming of appropriate neuromascular resources. Criteria for assessing differences in motor proficiency; Assessment of hand preferences; Conclusions.

The inhabitants of Tristan da Cunha are a socially and geographically isolated community, highly inter-related by blood or marriage with a large average family size. The handedness characteristics of a sample of 76 people out of the total Tristan population of 264 were assessed on eight criteria by personal interview. All subjects wrote with the right hand and only two could be classified as otherwise left-handed (i.e. 2.6%). Seven out of eight of those interviewed who claimed a left-handed parent were themselves right-handed and had only right-handed brothers or sisters. It is concluded that any genetic factor determining left-handedness must be very weak and a preferred explanation of the findings is offered in terms of social pressures such as (i) deference to authority and (ii) group conformity. [ABSTRACT FROM AUTHOR]

Objective: Various shirking behaviors in survey‐taking can inhibit researchers' ability to draw unbiased inferences from the resulting data. We define three types of shirking behavior, identify their demographic correlates among survey respondents, show how shirking may lead to biased or incorrect inferences, and offer suggestions for navigating these threats. Methods: We analyze responses from a large (N=3,256), representative survey of Americans, identify indicators of three types of shirking, and regress these indicators on survey firm administrative data on respondent characteristics to discover the respondent characteristics associated with different shirking types. Results: The data suggest women are more likely to break off during a survey, while men are more likely to shirk while completing the instrument. In addition, young, less educated respondents are more likely to use straight‐lining or other satisficing tactics. Conclusion: Systematic differences in shirking behaviors across these demographic groups make us likely to misunderstand the (reported) social behavior of women and men, young and old, or more and less educated, indifferent ways. This is particularly problematic for testing behavioral theories that generate gender, age, or education‐specific predictions, or, predictions regarding attitudes or behaviors that strongly correlated to these characteristics. [ABSTRACT FROM AUTHOR]

Introduction: Patients with burn injuries are at an increased risk of venous thromboembolism (VTE). This predisposition is secondary to the endothelial injury, hyper-coagulable state and stasis (Virchow's triad) associated with burn injury. Although the true incidence of VTE in burn patients has not been adequately quantified, symptomatic VTE occurs in 0.2-7% of this population. VTE prophylaxis has proven clinical effectiveness and affords a reduction in the morbidity associated with such events, but the benefits and risk of complications need to be balanced in order to provide the best quality of care. Owing to the lack of prospective data on VTE in burns, practice varies greatly, not only internationally, but also between local burns services. Our aim was to better understand current VTE practice within United Kingdom (UK) burn care services by performing a comprehensive survey.Methods: We contacted all the inpatient burn care services in the UK and collected data on current VTE practice via a standardised questionnaire. Services were given the choice to complete the survey by telephone or email and a follow-up plan was formulated.Results: Twenty-five burn care services were contacted and 23 agreed to participate (92% response rate). Responding services treated adults, children or both and lead burn nurses or senior medical staff familiar with current VTE practice were interviewed. Routine VTE prophylaxis was provided in 84% of burn services and the majority utilised a combination of chemoprophylaxis and thromboembolic deterrent stockings (TEDS). All used low molecular weight heparin (LMWH) as their choice of chemoprophylaxis. Of those treating adults, all used a VTE prophylaxis protocol, but none of these applied to children. Only 56% of services treating children had such a protocol. The majority discontinued prophylaxis once patients were mobile.Discussion and Conclusion: Although the true burden of VTE in burn patients is unknown, we recognise that they are a population at risk. In addition to changes in the inflammatory and clotting pathways associated with thermal injury, prolonged hospital stay, ventilatory support, multiple surgeries, numerous central venous cannulations and reduced mobility all multiply this risk. The risk associated with the administration of heparin (bleeding complications and heparin-induced thrombocytopaenia) is low and can be reduced even further to 0.1% by the use of LMWH. The risk of symptomatic VTE is far greater, therefore the benefits of VTE prophylaxis would seem to outweigh the risks of not undertaking prophylactic measures. A higher LMWH dose and routine monitoring of anti-factor Xa levels are useful for acute burn patients. Two previous surveys, performed in Canada and the United States of America (USA), found routine administration of VTE prophylaxis to be 50% and 76% respectively. Of the 71 centres in the USA participating in the survey, 30% used a combination of sequential compression devices (SCD) and heparin and 24% did not provide VTE prophylaxis at all. A lack of prospective data on VTE in burn patients appears to be associated with diverse practice, and consensus on this topic could ensure that the potential morbidity caused by VTE is reduced. A clinical tool for identifying patients at risk and guidelines for management will standardise practice, which in turn should allow us to improve and maintain high quality care for burn patients. [ABSTRACT FROM AUTHOR]

1(R)-trans-Chrysanthemic acid has been prepared in four steps from methyl 5-methyl-2,4-hexadienoate and isopropylidene diphenylsulfurane. [Copyright &y& Elsevier]

Although there have been many initiatives designed to regenerate relatively run-down and deprived parts of major urban areas, there have been surprisingly few attempts to value their benefits. This article presents the findings of research that has sought to value the benefits of urban regeneration policies. The focus has been on devising an approach that can build on the evidence provided from urban evaluations undertaken in many countries at the present time. It uses established techniques and statistical data sources that are fairly readily available. The evaluation of urban policy is subject to substantial conceptual and measurement problems and this should be recognised in interpreting valuation results and thus benefit–cost ratios. The article shows how the approach can be applied by drawing on recent UK evaluation evidence and data for England. It concludes by discussing where future research might be directed. [ABSTRACT FROM PUBLISHER]

Objective: The antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets: synaptic vesicle 2 proteins and γ‐aminobutyric acid type A receptors (GABAARs), respectively. Functional aspects of padsevonil at the postsynaptic target, GABAARs, were characterized in experiments reported here. Methods: The effect of padsevonil on GABA‐mediated Cl− currents was determined by patch clamp on recombinant human GABAARs (α1β2γ2) stably expressed in a CHO‐K1 cell line and on native GABAARs in cultured rat primary cortical neurons. Padsevonil selectivity for GABAAR subtypes was evaluated using a two‐electrode voltage clamp on recombinant human GABAARs (α1‐5/β2/γ2) in Xenopus oocytes. Results: In recombinant GABAARs, padsevonil did not evoke Cl− currents in the absence of the agonist GABA. However, when co‐administered with GABA at effective concentration (EC)20, padsevonil potentiated GABA responses by 167% (EC50 138 nmol/L) and demonstrated a relative efficacy of 41% compared with zolpidem, a reference benzodiazepine site agonist. Similarly, padsevonil demonstrated GABA‐potentiating activity at native GABAARs (EC50 208 nmol/L) in cultured rat cortical neurons. Padsevonil also potentiated GABA (EC20) responses in GABAARs expressed in oocytes, with higher potency at α1‐ and α5‐containing receptors (EC50 295 and 281 nmol/L) than at α2‐ and α3‐containing receptors (EC50 1737 and 2089 nmol/L). Compared with chlordiazepoxide—a nonselective, full GABAAR agonist—the relative efficacy of padsevonil was 60% for α1β2γ2, 26% for α2β2γ2, 56% for α3β2γ2, and 41% for α5β2γ2; no activity was observed at benzodiazepine‐insensitive α4β2γ2 receptors. Significance: Results of functional investigations on recombinant and native neuronal GABAARs show that padsevonil acts as a positive allosteric modulator of these receptors, with a partial agonist profile at the benzodiazepine site. These properties may confer better tolerability and lower potential for tolerance development compared with classic benzodiazepines currently used in the clinic. [ABSTRACT FROM AUTHOR]

Atmospheric nitrogen pollution has severe impacts on biodiversity, but approaches to value them are limited. This paper develops a spatially explicit methodology to value the benefits from improvements in biodiversity resulting from current policy initiatives to reduce nitrogen emissions. Using the UK as a case study, we quantify nitrogen impacts on plant diversity in four habitats: heathland, acid grassland, dunes and bogs, at fine spatial resolution. Focusing on non-use values for biodiversity we apply value-transfer based on household's willingness to pay to avoid changes in plant species richness, and calculate the benefit of projected emission declines of 37% for nitrogen dioxide (NO 2 ) and 6% for ammonia (NH 3 ) over the scenario period 2007–2020. The annualised benefit resulting from these pollutant declines is £32.7 m (£4.4 m to £109.7 m, 95% Confidence Interval), with the greatest benefit accruing from heathland and acid grassland due to their large area. We also calculate damage costs per unit of NO 2 and NH 3 emitted, to quantify some of the environmental impacts of air pollution for use alongside damage costs for human health in policy appraisal. The benefit is £103 (£33 to £237) per tonne of NO 2 saved, and £414 (£139 to £1022) per tonne of NH 3 saved. [ABSTRACT FROM AUTHOR]

Introduction Development of a selective and specific high affinity PET tracer, [ 11 C]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine V T . A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. Results 3–5 GBq of [ 11 C]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65 GBq/μmol. In vitro binding showed high selective binding towards SV2A. [ 11 C]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the V T could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [ 11 C]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. Conclusions We have developed the novel PET tracer, [ 11 C]UCB-A, that can be used to measure SV2A expression in vivo . The dosimetry allows up to 5 administrations of 400 MBq of [ 11 C]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline V T values. This will have to be further validated in human studies. [ABSTRACT FROM AUTHOR]

Abstract: A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model. [Copyright &y& Elsevier]

Abstract: N-Benzyl 2-acetamido-2-substituted acetamides, where the 2-substituent is a (hetero)aromatic moiety, are potent anticonvulsants. We report the synthesis and whole animal pharmacological evaluation of 16 analogues where the terminal 2-acetyl group was removed to give the corresponding primary amino acid derivatives (PAADs). Conversion to the PAAD structure led to a substantial drop in seizure protection in animal tests, demonstrating the importance of the N-acetyl moiety for anticonvulsant activity. However, several of the PAADs displayed notable pain-attenuating activities in a mouse model. [Copyright &y& Elsevier]

Abstract: The discovery and optimization of a novel class of selective submicromolar KCC2 blockers is described. Details of synthesis and SAR are given together with ADME properties of selected compounds. A methylsulfone residue on the R1 phenyl group improved the overall general profile of these prolinate derivatives. [Copyright &y& Elsevier]

Abstract: A new series of 2,6-quinolinyl derivatives was prepared leading to potent low nanomolar VLA-4/VCAM-1 antagonists. [Copyright &y& Elsevier]