From successful measurement to the birth of a law: Disentangling coordination in Ohm's scientific practice

In this paper, I argue for a distinction between two scales of coordination in scientific inquiry, through which I reassess Georg Simon Ohm's work on conductivity and resistance. Firstly, I propose to distinguish between measurement coordination, which refers to the specific problem of how to justify the attribution of values to a quantity by using a certain measurement procedure, and general coordination, which refers to the broader issue of justifying the representation of an empirical regularity by means of abstract mathematical tools. Secondly, I argue that the development of Ohm's measurement practice between the first and the second experimental phase of his work involved the change of the measurement coordination on which he relied to express his empirical results. By showing how Ohm relied on different calibration assumptions and practices across the two phases, I demonstrate that the concurrent change of both Ohm's experimental apparatus and the variable that Ohm measured should be viewed based on the different form of measurement coordination. Finally, I argue that Ohm's assumption that tension is equally distributed in the circuit is best understood as part of the general coordination between Ohm's law and the empirical regularity that it expresses, rather than measurement coordination.     

Forecasting interest rates through Vasicek and CIR models: A partitioning approach

The aim of this paper is to propose a new methodology that allows forecasting, through Vasicek and CIR models, of future expected interest rates based on rolling windows from observed financial market data. The novelty, apart from the use of those models not for pricing but for forecasting the expected rates at a given maturity, consists in an appropriate partitioning of the data sample. This allows capturing all the statistically significant time changes in volatility of interest rates, thus giving an account of jumps in market dynamics. The new approach is applied to different term structures and is tested for both models. It is shown how the proposed methodology overcomes both the usual challenges (e.g., simulating regime switching, volatility clustering, skewed tails) as well as the new ones added by the current market environment characterized by low to negative interest rates.     

Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase

Skp2 and its cofactor Cks1 are the substrate-targeting subunits of the SCF(Skp2-Cks1) (Skp1/Cul1/F-box protein) ubiquitin ligase complex that regulates entry into S phase by inducing the degradation of the cyclin-dependent kinase inhibitors p21 and p27 (ref. 1). Skp2 is an oncoprotein that often shows increased expression in human cancers; however, the mechanism that regulates its cellular abundance is not well understood. Here we show that both Skp2 and Cks1 proteins are unstable in G1 and that their degradation is mediated by the ubiquitin ligase APC/C(Cdh1) (anaphase-promoting complex/cyclosome and its activator Cdh1). Silencing of Cdh1 by RNA interference in G1 cells stabilizes Skp2 and Cks1, with a consequent increase in p21 and p27 proteolysis. Depletion of Cdh1 also increases the percentage of cells in S phase, whereas concomitant downregulation of Skp2 reverses this effect, showing that Skp2 is an essential target of APC/C(Cdh1). Expression of a stable Skp2 mutant that cannot bind APC/C(Cdh1) induces premature entry into S phase. Thus, the induction of Skp2 and Cks1 degradation in G1 represents a principal mechanism by which APC/C(Cdh1) prevents the unscheduled degradation of SCF(Skp2-Cks1) substrates and maintains the G1 state.     

Dystrophic heart failure blocked by membrane sealant poloxamer

Dystrophin deficiency causes Duchenne muscular dystrophy (DMD) in humans, an inherited and progressive disease of striated muscle deterioration that frequently involves pronounced cardiomyopathy. Heart failure is the second leading cause of fatalities in DMD. Progress towards defining the molecular basis of disease in DMD has mostly come from studies on skeletal muscle, with comparatively little attention directed to cardiac muscle. The pathophysiological mechanisms involved in cardiac myocytes may differ significantly from skeletal myofibres; this is underscored by the presence of significant cardiac disease in patients with truncated or reduced levels of dystrophin but without skeletal muscle disease. Here we show that intact, isolated dystrophin-deficient cardiac myocytes have reduced compliance and increased susceptibility to stretch-mediated calcium overload, leading to cell contracture and death, and that application of the membrane sealant poloxamer 188 corrects these defects in vitro. In vivo administration of poloxamer 188 to dystrophic mice instantly improved ventricular geometry and blocked the development of acute cardiac failure during a dobutamine-mediated stress protocol. Once issues relating to optimal dosing and long-term effects of poloxamer 188 in humans have been resolved, chemical-based membrane sealants could represent a new therapeutic approach for preventing or reversing the progression of cardiomyopathy and heart failure in muscular dystrophy.