Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.

Power allocation strategies for distributed space-time codes in two-way relay networks

We study a two-way relay network (TWRN), where distributed space-time codes are constructed across multiple relay terminals in an amplify-and-forward mode. Each relay transmits a scaled linear combination of its received symbols and their conjugates,with the scaling factor chosen based on automatic gain control. We consider equal power allocation (EPA) across the relays, as well as the optimal power allocation (OPA) strategy given access to instantaneous channel state information (CSI). For EPA, we derive an upper bound on the pairwise-error-probability (PEP), from which we prove that full diversity is achieved in TWRNs. This result is in contrast to one-way relay networks, in which case a maximum diversity order of only unity can be obtained. When instantaneous CSI is available at the relays, we show that the OPA which minimizes the conditional PEP of the worse link can be cast as a generalized linear fractional program, which can be solved efficiently using the Dinkelback-type procedure.We also prove that, if the sum-power of the relay terminals is constrained, then the OPA will activate at most two relays.

Solvability and spectral properties of integral equations on the real line: I. Weighted spaces of continuous functions

We consider in this paper the solvability of linear integral equations on the real line, in operator form (λ−K)φ=ψ, where and K is an integral operator. We impose conditions on the kernel, k, of K which ensure that K is bounded as an operator on . Let Xa denote the weighted space as |s|→∞}. Our first result is that if, additionally, |k(s,t)|⩽κ(s−t), with and κ(s)=O(|s|−b) as |s|→∞, for some b>1, then the spectrum of K is the same on Xa as on X, for 01. As an example where kernels of this latter form occur we discuss a boundary integral equation formulation of an impedance boundary value problem for the Helmholtz equation in a half-plane.

Regional changes in wind energy potential over Europe using regional climate model ensemble projections

The impact of climate change on wind power generation potentials over Europe is investigated by considering ensemble projections from two regional climate models (RCMs) driven by a global climate model (GCM). Wind energy density and its interannual variability are estimated based on hourly near-surface wind speeds. Additionally, the possible impact of climatic changes on the energy output of a sample 2.5-MW turbine is discussed. GCM-driven RCM simulations capture the behavior and variability of current wind energy indices, even though some differences exist when compared with reanalysis-driven RCM simulations. Toward the end of the twenty-first century, projections show significant changes of energy density on annual average across Europe that are substantially stronger in seasonal terms. The emergence time of these changes varies from region to region and season to season, but some long-term trends are already statistically significant in the middle of the twenty-first century. Over northern and central Europe, the wind energy potential is projected to increase, particularly in winter and autumn. In contrast, energy potential over southern Europe may experience a decrease in all seasons except for the Aegean Sea. Changes for wind energy output follow the same patterns but are of smaller magnitude. The GCM/RCM model chains project a significant intensification of both interannual and intra-annual variability of energy density over parts of western and central Europe, thus imposing new challenges to a reliable pan-European energy supply in future decades.

Loss potentials associated with European windstorms under future climate conditions

Possible changes in the frequency and intensity of windstorms under future climate conditions during the 21st century are investigated based on an ECHAM5 GCM multi-scenario ensemble. The intensity of a storm is quantified by the associated estimated loss derived with using an empirical model. The geographical focus is ‘Core Europe’, which comprises countries of Western Europe. Possible changes of losses are analysed by comparing ECHAM5 GCM data for recent (20C, 1960 to 2000) and future climate conditions (B1, A1B, A2; 2060 to 2100), each with 3 ensemble members. Changes are quantified using both rank statistics and return periods (RP) estimated by fitting an extreme value distribution using the peak over threshold method to potential storm losses. The estimated losses for ECHAM5 20C and reanalysis events show similar statistical features in terms of return periods. Under future climate conditions, all climate scenarios show an increase in both frequency and magnitude of potential losses caused by windstorms for Core Europe. Future losses that are double the highest ECHAM5 20C loss are identified for some countries. While positive changes of ranking are significant for many countries and multiple scenarios, significantly shorter RPs are mostly found under the A2 scenario for return levels correspondent to 20 yr losses or less. The emergence time of the statistically significant changes in loss varies from 2027 to 2100. These results imply an increased risk of occurrence of windstorm-associated losses, which can be largely attributed to changes in the meteorological severity of the events. Additionally, factors such as changes in the cyclone paths and in the location of the wind signatures relative to highly populated areas are also important to explain the changes in estimated losses.

Wind gust estimation for Mid-European winter storms: towards a probabilistic view

Three wind gust estimation (WGE) methods implemented in the numerical weather prediction (NWP) model COSMO-CLM are evaluated with respect to their forecast quality using skill scores. Two methods estimate gusts locally from mean wind speed and the turbulence state of the atmosphere, while the third one considers the mixing-down of high momentum within the planetary boundary layer (WGE Brasseur). One hundred and fifty-eight windstorms from the last four decades are simulated and results are compared with gust observations at 37 stations in Germany. Skill scores reveal that the local WGE methods show an overall better behaviour, whilst WGE Brasseur performs less well except for mountain regions. The here introduced WGE turbulent kinetic energy (TKE) permits a probabilistic interpretation using statistical characteristics of gusts at observational sites for an assessment of uncertainty. The WGE TKE formulation has the advantage of a ‘native’ interpretation of wind gusts as result of local appearance of TKE. The inclusion of a probabilistic WGE TKE approach in NWP models has, thus, several advantages over other methods, as it has the potential for an estimation of uncertainties of gusts at observational sites.

Projections of global warming-induced impacts on winter storm losses in the German private household sector

We present projections of winter storm-induced insured losses in the German residential building sector for the 21st century. With this aim, two structurally most independent downscaling methods and one hybrid downscaling method are applied to a 3-member ensemble of ECHAM5/MPI-OM1 A1B scenario simulations. One method uses dynamical downscaling of intense winter storm events in the global model, and a transfer function to relate regional wind speeds to losses. The second method is based on a reshuffling of present day weather situations and sequences taking into account the change of their frequencies according to the linear temperature trends of the global runs. The third method uses statistical-dynamical downscaling, considering frequency changes of the occurrence of storm-prone weather patterns, and translation into loss by using empirical statistical distributions. The A1B scenario ensemble was downscaled by all three methods until 2070, and by the (statistical-) dynamical methods until 2100. Furthermore, all methods assume a constant statistical relationship between meteorology and insured losses and no developments other than climate change, such as in constructions or claims management. The study utilizes data provided by the German Insurance Association encompassing 24 years and with district-scale resolution. Compared to 1971–2000, the downscaling methods indicate an increase of 10-year return values (i.e. loss ratios per return period) of 6–35 % for 2011–2040, of 20–30 % for 2041–2070, and of 40–55 % for 2071–2100, respectively. Convolving various sources of uncertainty in one confidence statement (data-, loss model-, storm realization-, and Pareto fit-uncertainty), the return-level confidence interval for a return period of 15 years expands by more than a factor of two. Finally, we suggest how practitioners can deal with alternative scenarios or possible natural excursions of observed losses.

A simple syllogism-solving test: empirical findings and implications for g research

It has been reported that the ability to solve syllogisms is highly g-loaded. In the present study, using a self-administered shortened version of a syllogism-solving test, the BAROCO Short, we examined whether robust findings generated by previous research regarding IQ scores were also applicable to BAROCO Short scores. Five syllogism-solving problems were included in a questionnaire as part of a postal survey conducted by the Keio Twin Research Center. Data were collected from 487 pairs of twins (1021 individuals) who were Japanese junior high or high school students (ages 13–18) and from 536 mothers and 431 fathers. Four findings related to IQ were replicated: 1) The mean level increased gradually during adolescence, stayed unchanged from the 30s to the early 50s, and subsequently declined after the late 50s. 2) The scores for both children and parents were predicted by the socioeconomic status of the family. 3) The genetic effect increased, although the shared environmental effect decreased during progression from adolescence to adulthood. 4) Children's scores were genetically correlated with school achievement. These findings further substantiate the close association between syllogistic reasoning ability and g.

A review of the performance of different ventilation and airflow distribution systems in buildings

The objective of this article is to review the scientific literature on airflow distribution systems and ventilation effectiveness to identify and assess the most suitable room air distribution methods for various spaces. In this study, different ventilation systems are classified according to specific requirements and assessment procedures. This study shows that eight ventilation methods have been employed in the built environment for different purposes and tasks. The investigation shows that numerous studies have been carried out on ventilation effectiveness but few studies have been done regarding other aspects of air distribution. Amongst existing types of ventilation systems, the performance of each ventilation methods varies from one case to another due to different usages of the ventilation system in a room and the different assessment indices used. This review shows that the assessment of ventilation effectiveness or efficiency should be determined according to each task of the ventilation system, such as removal of heat, removal of pollutant, supply fresh air to the breathing zone or protecting the occupant from cross infection. The analysis results form a basic framework regarding the application of airflow distribution for the benefit of designers, architects, engineers, installers and building owners.

Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study

BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.

Whatever works: proportionality as a constitutional doctrine

In The Global Model of Constitutional Rights Kai Möller claims that the proportionality test is underlain by an expansive moral right to autonomy. This putative right protects everything that advances one’s self-conception. It may of course be limited when balanced against other considerations such as the rights of others. But it always creates a duty on the state to justify the limitation. Möller further contends that the practice of proportionality can best be understood as protecting the right to autonomy. This review article summarizes the main tenets of Möller’s theory and criticizes them on two counts. First, it disputes the existence of a general right to autonomy; such a right places an unacceptably heavy burden on others. Second, it argues that we do not need to invoke a right to autonomy to explain and justify the main features of the practice of proportionality. Like other constitutional doctrines, proportionality is defensible, if it is grounded in pragmatic –mainly epistemic and institutional- considerations about how to increase overall rights compliance. These considerations are independent of any substantive theory of rights.

Can dynamically downscaled windstorm footprints be improved by observations through a probabilistic approach?

Windstorms are a main feature of the European climate and exert strong socioeconomic impacts. Large effort has been made in developing and enhancing models to simulate the intensification of windstorms, resulting footprints, and associated impacts. Simulated wind or gust speeds usually differ from observations, as regional climate models have biases and cannot capture all local effects. An approach to adjust regional climate model (RCM) simulations of wind and wind gust toward observations is introduced. For this purpose, 100 windstorms are selected and observations of 173 (111) test sites of the German Weather Service are considered for wind (gust) speed. Theoretical Weibull distributions are fitted to observed and simulated wind and gust speeds, and the distribution parameters of the observations are interpolated onto the RCM computational grid. A probability mapping approach is applied to relate the distributions and to correct the modeled footprints. The results are not only achieved for single test sites but for an area-wide regular grid. The approach is validated using root-mean-square errors on event and site basis, documenting that the method is generally able to adjust the RCM output toward observations. For gust speeds, an improvement on 88 of 100 events and at about 64% of the test sites is reached. For wind, 99 of 100 improved events and ~84% improved sites can be obtained. This gives confidence on the potential of the introduced approach for many applications, in particular those considering wind data.