Building a sustainable national Indigenous representative body - issues for consideration

Issues of Indigenous disadvantage and dysfunction are before our eyes more frequently and more prominently than ever before. Barely a day goes by without another chilling and heartbreaking story of abuse, violence or neglect; or of demonstrations of the impact of entrenched poverty and despair among our communities. Without proper engagement with Aboriginal and Torres Strait Islander peoples, (Indigenous peoples) governments will struggle in their efforts to make lasting progress in improving the conditions of Indigenous people and in our communities. A National Indigenous Representative Body is a fundamental component of any future action if we are to achieve positive change. At present, there is not a transparent, rigorous process for engaging with Indigenous peoples in determining the policy settings and to hold governments accountable for their performance

From data to decisions: empowering brownfield redevelopment with a novel decision support system

This research evaluates a novel decision support system (DSS) for planning brownfield redevelopment. The DSS is implemented within a web-based geographical information system that contains the spatial data informing three modules comprising land use suitability, economic viability, and ground risk. Using multi-criteria decision analysis, an evaluation was conducted on 31,942 ha of post-industrial land and around Liverpool, UK. The representativeness and credibility of the DSS outputs were evaluated through user trials with fifteen land-use planning and development stakeholders from the Liverpool City Region Combined Authority. The DSS was used to explore land use planning scenarios and it could be used to support decision making. Our research reveals that the DSS has the potential to positively inform the identification of brownfield redevelopment opportunities by offering a reliable, carefully curated, and user-driven digital evidence base. This expedites the traditionally manual process of conducting assessments of land suitability and viability. This research has important implications for assessing the impact of current and future planning policy and the potential for the use of digital tools for land use planning and sustainability in the UK and globally.Natural Environment Research Council (NERC): NE/S007350/1 WSP UK Ltd and Groundsure Lt

The development of a novel decision support system for regional land use planning for brownfield land

Digital tools, particularly specialised decision support systems (DSSs), can be utilized to assist in the complex process of brownfield redevelopment. Existing brownfield DSSs typically focus on site-specific, late-stage applications, and socioeconomic factors are often overlooked. In this paper, we present a novel DSS aimed at providing support for early-stage, city region-scale brownfield land use planning and redevelopment. The proposed DSS is a prototype WebGIS application that enables land use planners and other brownfield regeneration professionals to examine a region and a set of sites during the initial planning phase for brownfield redevelopment. The DSS includes three bespoke modules comprising: (1) Land Use Potential (residential, commercial, and public open space), (2) risks posed by contamination and geotechnical hazards, (3) data pertinent to brownfield economic viability assessments. We outline a use case for this DSS, developed through comprehensive user-requirements gathering, and subsequently describe the techniques employed to construct the DSS modules and user interface. Finally, we present the results of user testing, wherein case-study stakeholders assessed the DSS. The feedback obtained during user testing aided in the identification of areas for improvement with regard to the functionality, usability, and effectiveness of the DSS in supporting decision-makers. The feedback was utilized to implement iterative improvements to the DSS and to plan future developments for the prototype DSS.Natural Environment Research Council (NERC): NE/S007350/1. WSP UK Ltd; Groundsure Lt

De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology

Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

The impact of language and citizenship policies on integration: contrasting case studies of ‘new’ migration in Spain and the UK

This chapter investigates linguistic diversity in Europe by focusing on the interacting and overlapping issues of language policy, migration and citizenship (Castles & Davidson 2000, Hampshire 2005). We frame these concepts within the context of the increasing labour mobility of EU citizens in recent years, and the migratory flows which have been witnessed within and beyond these enlarged EU borders. We argue that such substantial transnational movements of people have repercussions for notions of language and policy, particularly in receiving countries as they seek to deal with issues of ‘integration’ and ‘cohesion’.In particular, we examine two case studies in detail which explore the notion that national and regional language policies can exist in a spectrum from ‘no policy’ to ‘explicit policy’ . We show how evidence from the case studies – Barcelona and Castelló in Spain, and Southampton in the UK— locates countries at different points of this spectrum, tracking the emergence of the distinct policies (or lack of), as well as critically analysing the public debates around cultural integration, translation services and language learning for migrants. We explore how far national language policies—and their local implementations—affect migrant populations and their aspirations to become citizens of host countries.Of particular interest to us are the responses of migrants that arise from the debates and policies in each of these differing locations and circumstances. We present qualitative data in order to examine reactions towards the acquisition of the host-country’s language(s) by migrants, and the role of language learning in citizenship. We also examine changing views about the acquisition of language(s) in transnational settings in both host and migrant communities. We ask whether the existence of a language policy (e.g. in Spain) influences the way migrants do (or do not) acquire the ‘host’ country’s language, and specifically in multilingual settings. Furthermore we consider whether aspirations amongst migrants differ in contexts such as the UK where there is little or no explicit policy. We ask if migrants perceive the language policy—or where this is lacking, a policy on citizenship—as designed to ‘naturalise’ them into ‘being British/Spanish/Catalan/etc’. Finally, we question how these differences might relate to ‘Europe’ and European aims to converge policies on language and citizenship in order to appear as a cohesive unit

Assemblies of the gyr falcon

Chromosome level genome assembly and comparative genomics between three falcon species reveals a pattern of genome organization not typical for birdsWhole genome assemblies are crucial for understanding a wide range of aspects of falcon biology including morphology, ecology and physiology and thus essential for their care and conservation. A key aspect of the genome of any species is its karyotype, the arrangement of its chromosomes, which can then be linked to the whole genome sequence to generate a so-called chromosome level assembly. Chromosome level assemblies are essential for marker assisted selection and genotype-phenotype correlations in breeding regimes as well as determining patterns of gross genomic evolution. To date only two falcon species have been sequenced and neither initially to chromosome level. Falcons have atypical avian karyotypes with fewer chromosomes than other birds, presumably brought about by wholesale fusion. To date however published chromosome preparations are of poor quality, few chromosomes have been distinguished and standard ideograms have not been made. The purpose of this study was to generate analyzable karyotypes and ideograms of peregrine, saker and gyr falcons, report on our recent generation of chromosome level sequence assemblies of peregrine and saker falcons, and for the first time sequence the gyr falcon genome. Finally, we aimed to generate comparative genomic data between all three species and the reference chicken genome. Results revealed a diploid number of 2n=50 for peregrine falcon and 2n=52 for saker and gyr through high quality banded chromosomes. Standard ideograms generated here helped to map predicted chromosomal fragments (PCFs) from the genome sequences directly to chromosomes and thus generate chromosome level sequence assemblies for peregrine and saker falcons. Whole genome sequencing was successful in gyr falcon but read depth and coverage was not sufficient to generate a chromosome level assembly. Nonetheless comparative genomics revealed no differences in genome organization between gyr and saker falcons. When compared to peregrine falcon, saker/gyr differed by 1 interchromosomal and 7 intrachromosomal rearrangements (a fusion plus 7 inversions) whereas peregrine and saker/gyr differ from the reference chicken genomes by 14/13 fusions (11 microchromosomal) and 6 fissions. The chromosomal differences between the species could possibly provide the basis of a screening test for hybrid animals. We have preserved these partial assemblies here for future use. The final assemblies for this genome will be submitted to the nucleotide archives GenBank/ENA.Griffin, Darren; Watson, Mick. (2018). Assemblies of the gyr falcon, [dataset]. University of Edinburgh. University of Kent. http://dx.doi.org/10.7488/ds/2379