Moralnost bez kategoričnosti

This paper argues that an agent’s moral obligations are necessarily connected to her desires. In doing so I will demonstrate that such a view is less revisionary—and more in line with our common-sense views on morality—than philosophers have previously taken it to be. You can hold a desire-based view of moral normativity, I argue, without being (e.g.) a moral relativist or error theorist about morality. I’ll make this argument by showing how two important features of an objective morality are compatible with such a desire-based account: 1) morality’s authoritative nature, 2) our ability to condemn immoral agents.U članku se tvrdi da su moralne obveze djelatnice nužno povezane s njezinim željama. Pri tome pokazujem da je takva perspektiva manje revizionistička – i više u skladu s našim zdravorazumskim stajalištima o moralu – nego što su ga filozofi prethodno smatrali. Tvrdim da možemo imati gledište na normativnost koje je utemeljeno na željama, a da nismo (na primjer) moralni relativisti ili teoretičari pogreške o moralu. Iznosim ovaj argument pokazujući kako su dvije važne značajke objektivnog morala kompatibilne s takvim gledištem temeljenim na želji: 1) autoritativna priroda morala, 2) naša sposobnost da osudimo nemoralne djelatnike

Attitudinal Theories of Pleasure and De Re Desires REPLY

AbstractThis article has two main aims. First, it will defend an ‘attitudinal’ account of pleasure, that is, an account of what it is that makes an experience pleasurable for a subject that explains it in terms of a certain kind of de re desire that the subject has towards that experience. Second, in doing so, the article aims to further our understanding of unconscious desires, and of what the subjects of such desires can be. The article begins by introducing two existing accounts of what makes an experience pleasurable. It then offers a diagnosis of a recent objection to attitudinal accounts from Bramble and existing responses from attitudinal theorists, arguing that the two positions are currently at a stalemate. After this, I argue for the possible existence of unknowable and unconscious de re desires, and show how such desires provide the best defence of such ‘attitudinal’ accounts.</jats:p

Epigenetic biomarker discovery in inflammatory bowel disease: unearthing clues for disease pathogenesis?

Epigenetic alterations including DNA methylation and microRNAs may provide important insights into gene-environment interaction in complex immune diseases such as inflammatory bowel disease (IBD). An integrative genome-wide approach was used to analyse whole blood genetic, DNA methylation and gene expression data in 240 newly diagnosed IBD patients and 190 controls. Using the Illumina 450k array, differences in whole blood DNA methylation were observed in IBD cases versus controls including 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs). The top DMP (RPS6KA2, discovery Holm adjusted p=1.22×10-16, replication p=1×10-9) and DMRs (VMP1, ITGB2, TXK) were replicated in an independent cohort using pyrosequencing. Paired genetic and epigenetic data allowed the identification of methylation quantitative trait loci (meQTL); two of the five DMRs (VMP1, ITGB2) demonstrated significant association with genetic polymorphisms. Methylation in the VMP1/microRNA-21 region was significantly associated with two single nucleotide polymorphisms (cg18942579 -rs10853015 [meQTL FDR adjusted p=9.4 × 10-5], cg16936953 - rs8078424 [meQTL FDR adjusted p=8.8 × 10-5]), both of which are in linkage disequilibrium with a known IBD susceptibility variant (rs1292053). Separated leukocyte methylation data highlight the cell type of origin of epigenetic signals seen in whole blood. IBD-associated hypermethylation within the TXK gene transcription start-site negatively correlated with gene expression in whole blood and CD8+ T-cells, but not other cell types, highlighting that cell-specificity and gene location-specificity of DNA methylation change is critical when associating methylation and gene expression. These data offer significant translational potential as diagnostic biomarkers. Least absolute shrinkage and selection operator (lasso) modelling identified 30 methylation probes can be used to accurately discriminate IBD cases from controls (Area under receiver operating characteristic curve = 0.898, sensitivity = 90.6%, specificity = 84.7%). MicroRNAs (miRNA) are small non-coding nucleic acids that have the capacity to modulate gene expression. MiRNAs have been increasingly implicated in many of the important IBD pathogenic pathways including autophagy, intestinal epithelial barrier integrity and the Th17 pathway. In common with all epigenetic mechanisms, miRNA expression is dynamic and cell-specific. Small RNA sequencing (RNA-seq) was performed on RNA extracted from CD14+, CD4+ and CD8+ cells isolated from 8 newly diagnosed cases of ileal or ileocolonic CD and 8 age and sex matched controls. There was a median of 2.4 million reads per sample (range 132,800-12.8 million reads per sample). One microRNA was differentially expressed in CD compared with controls (hsa-miR-503-5p log fold change = 0.7, FDR adjusted p = 9.1 × 10-5) in CD4+ lymphocytes, however this finding did not remain significant when alternative normalisation methods were used. The small number of cases used in microRNA analyses raises the possibility of both type I and II error, and limits the ability to draw firm conclusion from this series of experiments. Site-specific differences in DNA methylation in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression. This is the most detailed characterisation of the epigenome carried out in IBD to date. The findings strongly validate this approach in complex disease, are replicable, and provide clear translational opportunities

The evolution of British tactical and operational tank doctrine and training in the First World War

Thesis submitted for the award of the degree of Master of Philosophy by the University of WolverhamptonTanks were first used in action in September 1916. There had been no previous combat experience on which to base tactical and operational doctrine for the employment of this novel weapon of war. Training of crews and commanders was hampered by lack of vehicles and weapons. Time was short in which to train novice crews. Training facilities were limited. Despite mechanical limitations of the early machines and their vulnerability to adverse ground conditions, the tanks achieved moderate success in their initial actions. Advocates of the tanks, such as Fuller and Elles, worked hard to convince the sceptical of the value of the tank. Two years later, tanks had gained the support of most senior commanders. Doctrine, based on practical combat experience, had evolved both within the Tank Corps and at GHQ and higher command. Despite dramatic improvements in the design, functionality and reliability of the later marks of heavy and medium tanks, they still remained slow and vulnerable to ground conditions and enemy counter-measures. Competing demands for materiel meant there were never enough tanks to replace casualties and meet the demands of formation commanders. This thesis will argue that the somewhat patchy performance of the armoured vehicles in the final months of the war was less a product of poor doctrinal guidance and inadequate training than of an insufficiency of tanks and the difficulties of providing enough tanks in the right locations at the right time to meet the requirements of the manoeuvre battles of the ‘Hundred Days’

How to Apply for and Secure EU Funding for Collaborative IBD Research Projects.

peer reviewedThe European Union offers opportunities for high-level of funding of collaborative European research. Calls are regularly published: after the end of the FP7 funding programme the new round of Horizon 2020 calls started in 2015. Several topics are relevant to inflammatory bowel disease (IBD) challenges, including chronic disease management, biomarker discovery and new treatments developments. The aim of this Viewpoint article is to describe the new Horizon 2020 instrument and the project submission procedures, and to highlight these through the description of tips and tricks, taking advantage of four examples of successful projects in the field of IBD: the SADEL, IBD-BIOM, IBD Character and BIOCYCLE projects

Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC).

Background &amp; Aims: DNA methylation alterations may provide important insights into gene-environment interaction in cancer, aging, and complex diseases, such as inflammatory bowel disease (IBD). We aim first to determine whether the circulating DNA methylome in patients requiring surgery may predict Crohn's disease (CD) recurrence following intestinal resection; and second to compare the circulating methylome seen in patients with established CD with that we had reported in a series of inception cohorts. Methods: TOPPIC was a placebo-controlled, randomized controlled trial of 6-mercaptopurine at 29 UK centers in patients with CD undergoing ileocolic resection between 2008 and 2012. Genomic DNA was extracted from whole blood samples from 229 of the 240 patients taken before intestinal surgery and analyzed using 450KHumanMethylation and Infinium Omni Express Exome arrays (Illumina, San Diego, CA). Coprimary objectives were to determine whether methylation alterations may predict clinical disease recurrence; and to assess whether the epigenetic alterations previously reported in newly diagnosed IBD were present in the patients with CD recruited into the TOPPIC study. Differential methylation and variance analysis was performed comparing patients with and without clinical evidence of recurrence. Secondary analyses included investigation of methylation associations with smoking, genotype (MeQTLs), and chronologic age. Validation of our previously published case-control observation of the methylome was performed using historical control data (CD, n = 123; Control, n = 198). Results: CD recurrence in patients following surgery is associated with 5 differentially methylated positions (Holm P &lt;.05), including probes mapping to WHSC1 (P = 4.1 × 10 -9, Holm P =.002) and EFNA3 (P = 4.9 × 10 -8, Holm P =.02). Five differentially variable positions are demonstrated in the group of patients with evidence of disease recurrence including a probe mapping to MAD1L1 (P = 6.4 × 10 -5). DNA methylation clock analyses demonstrated significant age acceleration in CD compared with control subjects (GrimAge + 2 years; 95% confidence interval, 1.2–2.7 years), with some evidence for accelerated aging in patients with CD with disease recurrence following surgery (GrimAge +1.04 years; 95% confidence interval, -0.04 to 2.22). Significant methylation differences between CD cases and control subjects were seen by comparing this cohort in conjunction with previously published control data, including validation of our previously described differentially methylated positions (RPS6KA2 P = 1.2 × 10 -19, SBNO2 = 1.2 × 10 -11) and regions (TXK [false discovery rate, P = 3.6 × 10 -14], WRAP73 [false discovery rate, P = 1.9 × 10 -9], VMP1 [false discovery rate, P = 1.7 × 10 -7], and ITGB2 [false discovery rate, P = 1.4 × 10 -7]). Conclusions: We demonstrate differential methylation and differentially variable methylation in patients developing clinical recurrence within 3 years of surgery. Moreover, we report replication of the CD-associated methylome, previously characterized only in adult and pediatric inception cohorts, in patients with medically refractory disease needing surgery.</p