Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette smoke-
induced pulmonary emphysema in mice and is upregulated in patients
K. C. Kent Lloyd
Harald von Melchner
- Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways responsible for maintaining lung integrity. Here we identify the antioxidant protein Sestrin 2 (Sesn2) as a repressor of PDGFRβ signalling and PDGFRβ signalling as an upstream regulator of alveolar maintenance programs. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke induced pulmonary emphysema by upregulating PDGFRβ expression via a selective accumulation of intracellular superoxide anions (O2-). We also show that SESN2 is overexpressed and PDGFRβ downregulated in the emphysematous lungs of patients with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2/PDGFRβ interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD.
Integer point sets minimizing average pairwise L1 distance: What is the optimal shape of a town?
Erik D. Demaine
Sándor P. Fekete
- An n-town, n[is an element of]N , is a group of n buildings, each occupying a distinct position on a 2-dimensional integer grid. If we measure the distance between two buildings along the axis-parallel street grid, then an n-town has optimal shape if the sum of all pairwise Manhattan distances is minimized. This problem has been studied for cities, i.e., the limiting case of very large n. For cities, it is known that the optimal shape can be described by a differential equation, for which no closed-form solution is known. We show that optimal n-towns can be computed in O(n[superscript 7.5]) time. This is also practically useful, as it allows us to compute optimal solutions up to n=80.
Analyst behaviour: the geography of social interaction
- An analyst who works in Germany is more likely to publish a high (low) price target regarding a DAX30 stock if other Germany based analysts are also optimistic (pessimistic) about the same stock. This finding is not biased by the fact that DAX30 companies are headquartered in Germany. In times of bull markets, price targets of analysts who regularly exchange their opinion are higher correlated compared to other analysts. This effect vanishes in a bearish market environment. This suggests that communication among analysts indeed plays an important role. However, analysts’ incentives induce them not to deviate too much from the overall average during an economic downturn.
Does social interaction destablise financial markets?
- With this paper, I propose a simple asset pricing model that accounts for the influence from social interaction. Investors are assumed to make up their mind about an asset’s price based on a forecasting strategy and its past profitability as well as on the contemporaneous expectations of other market participants. Empirically analysing stocks of the DAX30 index, I provide evidence that social interaction rather destabilises financial markets. Based on my results, I state that at least, it does not have a stabilising effect.
Fluctuations of social influence: evidence from the behaviour of mutual fund managers during the economic crisis 2008/09
- In this paper, I analyse the reciprocal social influence on investment decisions within an international group of roughly 2000 mutual fund managers that invested in companies of the DAX30. Using a robust estimation procedure, I provide empirical evidence that in the average a fund manager puts 0.69% more portfolio weight on a particular stock, if other fund managers increase the corresponding position by 1%. The dynamics of this influence on portfolio weights suggest that fund managers adjust their behaviour according to the prevailing market situation and are more strongly influenced by others in times of an economic downturn. Analysing the working locations of the fund managers, I conclude that more than 90% of the magnitude of influence is due to pure observation. While this form of influence varies much in time, the magnitude of influence resulting from the exchange of opinion is more or less constant.
Evidence regarding clinical use of microvolt T-wave alternans
Stefan H. Hohnloser
Richard J. Cohen
- Background: Microvolt T-wave alternans (MTWA) testing in many studies has proven to be a highly accurate predictor of ventricular tachyarrhythmic events (VTEs) in patients with risk factors for sudden cardiac death (SCD) but without a prior history of sustained VTEs (primary prevention patients). In some recent studies involving primary prevention patients with prophylactically implanted cardioverter-defibrillators (ICDs), MTWA has not performed as well. Objective: This study examined the hypothesis that MTWA is an accurate predictor of VTEs in primary prevention patients without implanted ICDs, but not of appropriate ICD therapy in such patients with implanted ICDs. Methods: This study identified prospective clinical trials evaluating MTWA measured using the spectral analytic method in primary prevention populations and analyzed studies in which: (1) few patients had implanted ICDs and as a result none or a small fraction (≤15%) of the reported end point VTEs were appropriate ICD therapies (low ICD group), or (2) many of the patients had implanted ICDs and the majority of the reported end point VTEs were appropriate ICD therapies (high ICD group). Results: In the low ICD group comprising 3,682 patients, the hazard ratio associated with a nonnegative versus negative MTWA test was 13.6 (95% confidence interval [CI] 8.5 to 30.4) and the annual event rate among the MTWA-negative patients was 0.3% (95% CI: 0.1% to 0.5%). In contrast, in the high ICD group comprising 2,234 patients, the hazard ratio was only 1.6 (95% CI: 1.2 to 2.1) and the annual event rate among the MTWA-negative patients was elevated to 5.4% (95% CI: 4.1% to 6.7%). In support of these findings, we analyzed published data from the Multicenter Automatic Defibrillator Trial II (MADIT II) and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trials and determined that in those trials only 32% of patients who received appropriate ICD therapy averted an SCD. Conclusion: This study found that MTWA testing using the spectral analytic method provides an accurate means of predicting VTEs in primary prevention patients without implanted ICDs; in particular, the event rate is very low among such patients with a negative MTWA test. In prospective trials of ICD therapy, the number of patients receiving appropriate ICD therapy greatly exceeds the number of patients who avert SCD as a result of ICD therapy. In trials involving patients with implanted ICDs, these excess appropriate ICD therapies seem to distribute randomly between MTWA-negative and MTWA-nonnegative patients, obscuring the predictive accuracy of MTWA for SCD. Appropriate ICD therapy is an unreliable surrogate end point for SCD. Key words: Arrhythmia; Sudden cardiac death; Cardiac arrest; ICD; T-wave alternans; Surrogate endpoint; Ventricular tachyarrhythmic event; Primary prevention
'Kiezdeutsch goes School' : a multiethnic variety of German from an educational perspective
- This article presents linguistic features of and educational approaches to a new variety of German that has emerged in multi-ethnic urban areas in Germany: Kiezdeutsch (‘Hood German’). From a linguistic point of view, Kiezdeutsch is very interesting, as it is a multi-ethnolect that combines features of a youth language with those of a contact language. We will present examples that illustrate the grammatical productivity and innovative potential of this variety. From an educational perspective, Kiezdeutsch has also a high potential in many respects: school projects can help enrich intercultural communication and weaken derogatory attitudes. In grammar lessons, Kiezdeutsch can be a means to enhance linguistic competence by having the adolescents analyse their own language. Keywords: German, Kiezdeutsch, multi-ethnolect, migrants’ language, language change, educational proposals
The performance of approximating ordinary differential equations by neural nets
Rüdiger W. Brause
- The dynamics of many systems are described by ordinary differential equations (ODE). Solving ODEs with standard methods (i.e. numerical integration) needs a high amount of computing time but only a small amount of storage memory. For some applications, e.g. short time weather forecast or real time robot control, long computation times are prohibitive. Is there a method which uses less computing time (but has drawbacks in other aspects, e.g. memory), so that the computation of ODEs gets faster? We will try to discuss this question for the assumption that the alternative computation method is a neural network which was trained on ODE dynamics and compare both methods using the same approximation error. This comparison is done with two different errors. First, we use the standard error that measures the difference between the approximation and the solution of the ODE which is hard to characterize. But in many cases, as for physics engines used in computer games, the shape of the approximation curve is important and not the exact values of the approximation. Therefore, we introduce a subjective error based on the Total Least Square Error (TLSE) which gives more consistent results. For the final performance comparison, we calculate the optimal resource usage for the neural network and evaluate it depending on the resolution of the interpolation points and the inter-point distance. Our conclusion gives a method to evaluate where neural nets are advantageous over numerical ODE integration and where this is not the case. Index Terms—ODE, neural nets, Euler method, approximation complexity, storage optimization.
Handwriting analysis for diagnosis and prognosis of Parkinson’s disease
Rüdiger W. Brause
- At present, there are no quantitative, objective methods for diagnosing the Parkinson disease. Existing methods of quantitative analysis by myograms suffer by inaccuracy and patient strain; electronic tablet analysis is limited to the visible drawing, not including the writing forces and hand movements. In our paper we show how handwriting analysis can be obtained by a new electronic pen and new features of the recorded signals. This gives good results for diagnostics. Keywords: Parkinson diagnosis, electronic pen, automatic handwriting analysis
On the scope of the referential hierarchy in the typology of grammatical relations
- In the late seventies, Bernard Comrie was one of the first linguists to explore the effects of the referential hierarchy (RH) on the distribution of grammatical relations (GRs). The referential hierarchy is also known in the literature as the animacy, empathy or indexibability hierarchy and ranks speech act participants (i.e. first and second person) above third persons, animates above inanimates, or more topical referents above less topical referents. Depending on the language, the hierarchy is sometimes extended by analogy to rankings of possessors above possessees, singulars above plurals, or other notions. In his 1981 textbook, Comrie analyzed RH effects as explaining (a) differential case (or adposition) marking of transitive subject ("A") noun phrases in low RH positions (e.g. inanimate or third person) and of object ("P") noun phrases in high RH positions (e.g. animate or first or second person), and (b) hierarchical verb agreement coupled with a direct vs. inverse distinction, as in Algonquian (Comrie 1981: Chapter 6).