KENT (Reino Unido) (Inglaterra) (Condado). Mapas generales (1779). 1:31680

Dedicatoria : "To His Most Sacred Majesty George the Third and the Nobility and Gentry who have been pleased to Encourage this Undertaking ; this Actual Survey of Gratitude for their Generous Assistance, by their most Dutiful and Devoted Servants"Escala tambien dada en forma gráfica en 6 millas inglesas de 69 1/² al grado, y 1600 perticas. Coordenadas referidas al meridiano de Londres (E 0°02'00''--E 1°28'30''/N 51°31'00''--N 50°51'40''). Orientado con lis en rosa de treinta y dos vientosOrografía por trazos. Sondas batimétricas y bancosDestaca mediante colores, la división administrativa en hundreds del condadoRelación por orden alfabético de los lugares de Gloucester y CumberlandHojas numeradasAdornado con el dibujo de varios navíosCartela barroca, conteniendo dedicatoria y relación, decorada con motivos vegetales, fauna, animales mitológicos, motivos bélicos y coronado con el escudo del condadoInserta : "A Plan of the Town of Sandwich". Escala [ca. 1:1600], 48 pérticas [= 7'4 cm

The sweet spot in sustainability: a framework for corporate assessment in sugar manufacturing

The assessment of corporate sustainability has become an increasingly important topic, both within academia and in industry. For manufacturing companies to conform to their commitments to sustainable development, a standard and reliable measurement framework is required. There is, however, a lack of sector-specific and empirical research in many areas, including the sugar industry. This paper presents an empirically developed framework for the assessment of corporate sustainability within the Thai sugar industry. Multiple case studies were conducted, and a survey using questionnaires was also employed to enhance the power of generalisation. The developed framework is an accurate and reliable measurement instrument of corporate sustainability, and guidelines to assess qualitative criteria are put forward. The proposed framework can be used for a company’s self-assessment and for guiding practitioners in performance improvement and policy decision-maki

Decadal changes in fire frequencies shift tree communities and functional traits

Global change has resulted in chronic shifts in fire regimes. Variability in the sensitivity of tree communities to multi-decadal changes in fire regimes is critical to anticipating shifts in ecosystem structure and function, yet remains poorly understood. Here, we address the overall effects of fire on tree communities and the factors controlling their sensitivity in 29 sites that experienced multi-decadal alterations in fire frequencies in savanna and forest ecosystems across tropical and temperate regions. Fire had a strong overall effect on tree communities, with an average fire frequency (one fire every three years) reducing stem density by 48% and basal area by 53% after 50 years, relative to unburned plots. The largest changes occurred in savanna ecosystems and in sites with strong wet seasons or strong dry seasons, pointing to fire characteristics and species composition as important. Analyses of functional traits highlighted the impact of fire-driven changes in soil nutrients because frequent burning favoured trees with low biomass nitrogen and phosphorus content, and with more efficient nitrogen acquisition through ectomycorrhizal symbioses. Taken together, the response of trees to altered fire frequencies depends both on climatic and vegetation determinants of fire behaviour and tree growth, and the coupling between fire-driven nutrient losses and plant traits

Critical international relations and the impact agenda

How should critical International Relations (IR) scholars approach the ‘impact agenda’? While most have been quite resistant to it, I argue in this essay that critical IR should instead embrace the challenge of impact – and that both IR as a field and the impact agenda more broadly would gain greatly from it doing so. I make this case through three steps. I show, firstly, that critical IR has till now been very much at the impact agenda’s margins, and that this situation contrasts strikingly with its well-established importance within IR teaching and research. I argue, secondly, that critical IR scholars both could and should do more impact work – that the current political conjuncture demands it, that many of the standard objections to doing so are misplaced, and indeed that ‘critical’ modes of research are in some regards better suited than ‘problem-solving’ ones to generating meaningful change – and offer a series of recommended principles for undertaking critically-oriented impact and engagement work. But I also argue, thirdly, that critical social science holds important lessons for the impact agenda, and that future impact assessments need to take these lessons on board – especially if critical IR scholarship is to embrace impact more fully. Critical IR, I submit, should embrace impact; but at the same time, research councils and assessments could do with modifying their approach to it, including by embracing a more critical and political understanding of what impact is and how it is achieved

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist