A Domino Theory of Disease

This paper advances a theory of disease as domino dysfunction. It is often argued that diseases are biological dysfunctions. However, a theory of disease as biological dysfunction is complicated by some plausible cases of dysfunction, which seem clearly non-pathological. I argue that pathological conditions are not just dysfunctions but domino dysfunctions, and that domino dysfunctions can be distinguished on principled biological grounds from non-pathological dysfunctions. I then show how this theory can make sense of the problem cases; they are not diseases because they are not domino dysfunctions

Proper Functions are Proximal Functions

This paper argues that proper functions are proximal functions. In other words, it rejects the notion that there are distal biological functions – strictly speaking, distal functions are not functions at all, but simply beneficial effects normally associated with a trait performing its function. Once we rule out distal functions, two further positions become available: dysfunctions are simply failures of proper function, and pathological conditions are dysfunctions. Although elegant and seemingly intuitive, this simple view has had surprisingly little uptake in the literature. Indeed, our position departs from that of almost every theorist who has engaged with the issue at any depth. We start by presenting three arguments for the position that proper functions are proximal: one from the specificity of functions, one from their relation to intervention, and one from their relation to pathology. We then consider two case studies evidencing the trouble that accepting distal functions causes for philosophical reflection on the nature of pathological conditions. Finally, we anticipate and respond to three objections: that there can be failure of function without dysfunction; that our account is unacceptably revisionary in respect of normal function-talk; and that our thesis over-generalises from a narrow set of cases

Faecal calprotectin in suspected paediatric inflammatory bowel disease.

Objectives: The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data. Methods: MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator. Results: According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92–0.99) and a specificity of 0.70 (0.59–0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 mg/g there would be 17% (95% CI 15–20) false-positive and 2% (1–3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89–0.94). Conclusions: In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients’ risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation

Government institutions and the dynamics of urban growth in China

Economic growth in China in recent decades has largely rested on the dynamism of its cities. High economic growth has coincided with measures aimed at improving the efficiency of local governments and with a mounting political drive to curb corruption. Yet the connection between government institutions and urban growth in China remains poorly understood. This paper is the first to look into the link between government efficiency and corruption, on the one hand, and urban growth in China, on the other hand and to assess what is the role of institutions relative to more traditional factors for economic growth in Chinese cities. Using panel data for 283 cities over the period between 2003 and 2014, the results show that the urban growth in China is a consequence of a combination of favorable human capital, innovation, density, local conditions, foreign direct investment, and city-level government institutions. Both government quality—especially for those cities with the best governments—and the fight against corruption at the city level have a direct effect on urban growth. Measures to tackle corruption at the provincial level matter in a more indirect way, by raising or lowering the returns of other growth-inducing factors

Motivations for innovation in the built environment: new directions for research

Innovation in the built environment involves multiple actors with diverse motivations. Policy-makers find it difficult to promote changes that require cooperation from these numerous and dispersed actors and to align their sometimes divergent interests. Established research traditions on the economics and management of innovation pay only limited attention to stakeholder choices, engagement and motivation. This paper reviews the insights that emerge as research in these traditions comes into contact with work on innovation from sociological and political perspectives. It contributes by highlighting growing areas of research on user involvement in complex innovation, collective action, distributed innovation and transition management. To differing extents, these provide approaches to incorporate the motivations of different actors into theoretical understanding. These indicate new directions for research that promise to enrich understanding of innovation

Architecture of Pol II(G) and molecular mechanism of transcription regulation by Gdown1.

Tight binding of Gdown1 represses RNA polymerase II (Pol II) function in a manner that is reversed by Mediator, but the structural basis of these processes is unclear. Although Gdown1 is intrinsically disordered, its Pol II interacting domains were localized and shown to occlude transcription factor IIF (TFIIF) and transcription factor IIB (TFIIB) binding by perfect positioning on their Pol II interaction sites. Robust binding of Gdown1 to Pol II is established by cooperative interactions of a strong Pol II binding region and two weaker binding modulatory regions, thus providing a mechanism both for tight Pol II binding and transcription inhibition and for its reversal. In support of a physiological function for Gdown1 in transcription repression, Gdown1 co-localizes with Pol II in transcriptionally silent nuclei of early Drosophila embryos but re-localizes to the cytoplasm during zygotic genome activation. Our study reveals a self-inactivation through Gdown1 binding as a unique mode of repression in Pol II function

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure