The foundations of influencing policy and practice: How risk science discourse shaped government action during COVID-19.

COVID-19 demonstrated the complex manner in which discourses from risk science are manipulated to legitimize government action. We use Foucault's theory of Governmentality to explore how a risk science discourse shaped national and local government action during COVID-19. We theorize how national government policymakers and local government risk managers were objectified by (and subjectified themselves to) risk science models, results, and discourses. From this theoretical position we analyze a dataset, including observations of risk science discourse and 22 qualitative interviews, to understand the challenges that national government policymakers, risk scientists, and local government risk managers faced during COVID-19. Findings from our Foucauldian discourse analysis show how, through power and knowledge, competing discourses emerge in a situation that was disturbed by uncertainty-which created disturbed senders (policymakers and risk scientists) and disturbed receivers (risk managers) of risk science. First, we explore the interaction between risk science and policymakers, including how the disturbed context enabled policymakers to select discourse from risk science to justify their policies. This showed government's sociopolitical leveraging of scientific power and knowledge by positioning itself as being submissive to "follow the science." Second, we discuss how risk managers (1) were objectified by the discourse from policymakers that required them to be obedient to risk science, and paradoxically (2) used the disturbed context to justify resisting government objectification through their human agency to subjectify themselves and take action. Using these concepts, we explore the foundation of risk science influence in COVID-19.

People in a pandemic: Rethinking the role of 'Community' in community resilience practices.

How has the idea of community featured in attempts to build resilience to emergencies? The paper explores this question by presenting evidence from interviews with emergency responders across the world in the midst of the early and uncertain phases of the Covid-19 pandemic. Although reflecting different contexts, we discern two ways in which the notion of community featured in authorities' narrations of their efforts to respond to the pandemic. Firstly, we demonstrate how community was deployed as a discursive mechanism that offered a particular framing of the vulnerabilities the pandemic instigated. Departing from accounts that reduce people's identities to demographic categories, the deployment of community stressed that the pandemic's effects should be understood by the different, yet coexistent, vulnerabilities it brought to the surface for people. Such renditions of vulnerability paved the way for styles of governance that prioritised adapting to the pandemic's uncertain and indeterminate unfolding in the absence of prepared plans. Secondly, addressing a register of collective social life between individuals and the state, an emphasis on community engendered the decentralised arrangement of emergency governance with which resilience has become synonymous. Here, community proved pivotal in temporarily expanding resources to deal with an emergency whose effects threatened to exceed governments' pre-existing capabilities. We substantiate this claim through examining how allusions to community worked to enrol non-state based efforts at response into a broader public security apparatus. Enveloped within the broader politics of emergency resilience, community shaped how the pandemic's effects were understood whilst also ensuring adequate provisions for its governance.

Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension.

A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.

Aerosol technology to mimic dry powder inhalation in vitro using pulmonary cell models.

Inhaled therapy confers key advantages for the treatment of topical pulmonary diseases and offers potential for systemic delivery of medicines. Dry powder inhalers (DPIs) are generally the preferred devices for pulmonary delivery due to improved stability and satisfactory patient compliance. However, the mechanisms governing drug powder dissolution and availability in the lung and poorly understood. Here, we report a new in vitro system to study epithelial absorption of inhaled dry powders in lung barrier models of the upper and lower airway. The system is based on a CULTEX® RFS (Radial Flow System) cell exposure module joined to a Vilnius aerosol generator and allows the coupling of drug dissolution and permeability assessments. The cellular models recapitulate the barrier morphology and function of healthy and diseased pulmonary epithelium and incorporate the mucosal barrier to enable the investigation of drug powder dissolution in biorelevant conditions. With this system, we found differences in permeability across the airway tree and pinpointed the impact of diseased barriers in paracellular drug transport. Furthermore, we identified a different rank order of permeability for compounds tested in solution or powder form. These results highlight the value of this in vitro drug aerosolization setup for use in research and development of inhaled medicines.

Design and Synthesis of Inhibitors of the E3 Ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 as a Treatment for Lung Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating rare disease, which despite currently available treatments, still represents a high unmet medical need. Specific E3 ubiquitin protein ligase 1 (SMURF1) is a HECT E3 ligase that ubiquitinates key signaling molecules from the TGFß/BMP pathways, which are of great relevance in the pathophysiology of PAH. Herein, the design and synthesis of novel potent small-molecule SMURF1 ligase inhibitors are described. Lead molecule 38 has demonstrated good oral pharmacokinetics in rats and significant efficacy in a rodent model of pulmonary hypertension.

CMIP and ATP2C2 modulate phonological short-term memory in language impairment.

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.

The TGM2 gene is associated with schizophrenia in a British population.

Several lines of evidence have suggested an interesting link between gluten ingestion and schizophrenia. Increased levels of gliadin antibodies have been observed in patients with schizophrenia. Tissue transglutaminase (transglutaminase 2, TGM2) is involved in the production of gliadin antibodies. To investigate genetic association of the TGM2 gene with schizophrenia, we detected eight single nucleotide polymorphisms (SNPs) present in the gene among 131 family trios composed of fathers, mothers and affected offspring with schizophrenia. Data analysis with the UNPHASED program showed allelic association for rs2076380 (chi(2) = 5.51, P = 0.019), rs7270785 (chi(2) = 8.13, P = 0.004), rs4811528 (chi(2) = 6.13, P = 0.013) and rs6023526 (chi(2) = 6.13, P = 0.013). The global P-value was 0.029 for 10,000 permutations with the TDT analysis. The strongest association was observed for the rs7270785-rs4811528 haplotypes (chi(2) = 16.18, df = 3, P = 0.001), and the global P-value was 0.008 for 10,000 permutations with the 2-SNP haplotype analysis. The 8-SNP haplotype analysis also revealed a strong haplotypic association (chi(2) = 44.82, df = 18, P = 0.0004) and the 1-df test showed that the A-T-A-A-T-G-A-G haplotype was excessively transmitted (chi(2) = 16.98, corrected P = 0.0007). The present results suggest that the TGM2 gene may be involved in the development of schizophrenia.

Molecular phylogenetic analysis of Candida tropicalis isolates by multi-locus sequence typing.

Multi-locus sequencing data for 242 different isolates of Candida tropicalis generated a dendrogram showing 235 strains assigned to a single large recently evolved group which contained several small clonal clusters. Haplotype analysis of a representative strain subset revealed a high level of recombination events in an otherwise clonal population. Pairs of isolates from single sources showed non-identity attributable to loss of heterozygosity in some genes in a manner similar to that established for C. albicans.

Comparison of Candida albicans strain types among isolates from three countries.

Multi-locus sequence typing data for 217 Candida albicans isolates cultured since 1990 from blood and vaginal samples in Japan, England/Wales and the USA were analysed for geographically related variations. While no significant differences were found between distributions of diploid sequence types (DSTs) in blood vs. vaginal isolates, there were highly significant differences in the clade distributions of isolates from the three geographical sources. Clade 2 strains were predominantly isolates from England/Wales, while clade 3 strains came mainly from the USA. The isolates from Japan were highly prevalent among strains in clades 5-17, and provided the first example seen so far in C. albicans of an amino acid encoded by three separate codons. Within clade 1, the most commonly encountered clade for isolates from all three regions, 15 Japanese isolates and 1 English isolate formed a separate clonal cluster in eBURST analysis. A similarly well demarcated clonal cluster rich in isolates from Japan was also found among the clade 4 strains. The data suggest C. albicans undergoes localized evolution, but human movements and person-to-person spread considerably blur the boundaries of such evolution.

Variation in WNT7A is unlikely to be a cause of familial congenital talipes equinovarus.

BACKGROUND: Genetic factors make an important contribution to the aetiology of congenital talipes equinovarus (CTEV), the most common developmental disorder of the lower limb. WNT7A was suggested as a candidate gene for CTEV on the basis of a genome-wide scan for linkage in a large multi-case family. WNT7A is a plausible candidate gene for CTEV as it provides a signal for pattern formation during limb development, and mutation in WNT7A has been reported in a number of limb malformation syndromes. METHODS: We investigated the role of WNT7A using a family-based linkage approach in our large series of European multi-case CTEV families. Three microsatellite markers were used, of which one (D3S2385) is intragenic, and the other two (D3S2403, D3S1252) are 700 kb 5' to the start and 20 kb from the 3' end of the gene, respectively. Ninety-one CTEV families, comprising 476 individuals of whom 211 were affected, were genotyped. LOD scores using recessive and incomplete-dominant inheritance models, and non-parametric linkage scores, excluded linkage. RESULTS: No significant evidence for linkage was observed using either parametric or non-parametric models. LOD scores for the parametric models remained strongly negative in the regions between the markers, and in the 0.5 cM intervals outside the marker map. No significant lod scores were obtained when the data were analysed allowing for heterogeneity. CONCLUSION: Our evidence suggests that the WNT7A gene is unlikely to be a major contributor to the aetiology of familial CTEV.

Interactions between ß2-Adrenoceptor Ligands and Membrane: Atomic-Level Insights from Magic-Angle Spinning NMR.

To understand the relationship between structural properties of the ß2-adrenoceptor ligands and their interactions with membranes, we have investigated the location and distribution of five ß2 agonists with distinct clinical durations and onsets of action (indacaterol, two indacaterol analogues, salmeterol and formoterol) in monounsaturated model membranes using magic angle spinning NMR to measure these interactions through both 1H nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) techniques. The hydrophilic aromatic groups of all five ß2 agonists show maximum distribution in the lipid/water interface, but distinct location and dynamic behavior were observed for the lipophilic aromatic rings. Our study elucidates at atomic level that the hydrophobicity and substitution geometry of lipophilic groups play important roles in compound-lipid interactions.

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma.

Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

Correction to "Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma".

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].

Uncoupling the Structure-Activity Relationships of ß2 Adrenergic Receptor Ligands from Membrane Binding.

Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein-ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the ß2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure-activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure-activity relationships of ß2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions.

Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension.

A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.

Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells.

Several lines of evidence suggest that a calcitonin-gene related peptide (CGRP) receptor antagonist may serve as a novel abortive migraine treatment. Here we present data on a human cell line and isolated human vessels for such an antagonist, BIBN4096BS. On SK-N-MC membranes, radiolabelled CGRP was displaced by both CGRP-(8-37) and BIBN4096BS, yielding pK(i) values of 8.5 and 11.4, respectively. Functional studies with SK-N-MC cells demonstrated that CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and BIBN4096BS with pA(2) values of 7.8 and 11.2, respectively. Isolated human cerebral, coronary, and omental arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation that was antagonized by both CGRP-(8-37) and BIBN4096BS in a competitive manner. CGRP was a weaker agonist on coronary arteries as compared to intracranial arteries; however, BIBN4096BS was an equally effective antagonist. In human omental arteries, CGRP did not induce relaxation. BIBN4096 had a pA(2) value of 10.1 in cerebral and 10.4 in coronary arteries. The results of clinical trials with BIBN4096BS for acute migraine attacks are awaited with great interest.

Emergency planning and management in health care: priority research topics.

Many major incidents have significant impacts on people's health, placing additional demands on health-care organisations. The main aim of this paper is to suggest a prioritised agenda for organisational and management research on emergency planning and management relevant to U.K. health care, based on a scoping study. A secondary aim is to enhance knowledge and understanding of health-care emergency planning among the wider research community, by highlighting key issues and perspectives on the subject and presenting a conceptual model. The study findings have much in common with those of previous U.S.-focused scoping reviews, and with a recent U.K.-based review, confirming the relative paucity of U.K.-based research. No individual research topic scored highly on all of the key measures identified, with communities and organisations appearing to differ about which topics are the most important. Four broad research priorities are suggested: the affected public; inter- and intra-organisational collaboration; preparing responders and their organisations; and prioritisation and decision making.

Genetic association of the AKT1 gene with schizophrenia in a British population.

OBJECTIVES: A number of studies have reported a genetic association of the AKT1 gene with schizophrenia, although some have failed to replicate the AKT1 association. This study was undertaken to further explore the AKT1 association with more single nucleotide polymorphisms in a British sample. METHODS: A total of 221 families, consisting of 148 fathers, 204 mothers and 222 offspring affected with schizophrenia, were recruited for genetic analysis. Analysis for allelic and haplotypic associations was performed with the UNPHASED program, using likelihood-based association analysis for nuclear families with missing parental genotype data. RESULTS: Allelic association was detected at rs1130214 (chi(2)=6.28, P=0.012) and at rs11847866 (chi(2)=4.64, P=0.031), although the remaining single nucleotide polymorphisms did not show allelic association with schizophrenia. The global P value of overall associations was 0.059 after 10000 permutations. Assessment using the Haploview program revealed rs1130214, rs2494746 and rs11847866 in the same linkage disequilibrium block and haplotype analysis showed disease association for the rs1130214-rs2494746-rs11847866 haplotypes (chi(2)=10.18, d.f.=4, P=0.037), of which the T-G-A haplotype was excessively transmitted (chi(2)=6.93, uncorrected P=0.008) and this haplotypic association survived Bonferroni correction (P=0.04). CONCLUSION: The present results provide further evidence to support the AKT1 association with schizophrenia.

No association between the PPARG gene and schizophrenia in a British population.

It has consistently been reported that patients with schizophrenia have an increased risk of type-2 diabetes. To investigate a genetic link between these two diseases, the combined effects of the PLA2G4A, PTGS2 and PPARG genes were tested among 221 British nuclear families consisting of fathers, mothers and affected offspring with schizophrenia. A total of 10 single nucleotide polymorphisms (SNPs) were tested and the likelihood-based association analysis for nuclear families was used to analyse the genotyping data. Eight SNPs detected across the PPARG gene did not show allelic association with schizophrenia; a weak association was detected at rs2745557 in the PTGS2 locus (chi2=4.19, p=0.041) and rs10798059 in the PLA2G4A locus (chi2=4.28, p=0.039) but these associations did not survive after 10,000 permutations to correct the p-value (global p=0.246). The gene-gene interaction test did not show any evidence of either cis-phase interactions for the PLA2G4A and PTGS2 combinations or a trans-phase interaction for the PLA2G4A and PPARG combinations. The PPARG gene has been reported to be strongly associated with type-2 diabetes, but the present study did not support the hypothesis that the PPARG gene may also play an important role in the development of schizophrenia.

Mitochondrial haplotypes and recombination in Candida albicans.

Candida albicans is a common commensal and opportunistic pathogenic fungus. Although it normally reproduces clonally, several lines of evidence exist for genetic recombination and some form of sexual reproduction. We have sequenced seven regions of its mitochondrial genome in 36 strains and constructed haplotypes for the 66 polymorphic sites, which include single-nucleotide polymorphisms and insertion/deletions. Nineteen different haplotypes were observed. Strains with the same mitochondrial haplotype were found in different clades defined by nuclear multilocus sequence typing (MLST) and the UPGMA dendrograms constructed using either set of data were different in topology. There was no apparent correlation between mitochondrial haplotype and the source of the strain (geographical or anatomical). Examination of the mitochondrial haplotypes revealed substantial evidence for recombination between polymorphic sites. This suggests that the use of mitochondrial haplotypes in phylogenetic studies should be approached with caution. These results provide further evidence for recombination and genetic exchange in the biology of C. albicans.