The absence of angiopoietin-2 leads to abnormal vascular maturation and persistent proliferative retinopathy

Angiopoietin-2 (Ang-2) antagonises the maturing effect of angiopoietin-1 (Ang-1) on blood vessels, and cooperates with VEGF to induce neovascularisation. In knockout mice, Ang-2 displayed a specific role in postnatal angiogenic remodelling. Here, we demonstrate that mice deficient in Ang-2 fail to form a proper spatial retinal vascular network. The retinal vasculature was characterised by reduced large vessel numbers and defects forming the superficial periphery mostly on the arteriolar site, and the secondary and tertiary deep capillary network. Hypoxia in the retinal periphery induced a four-fold VEGF upregulation and active endothelial proliferation for up to 60 days. Concomitantly, retinal digest preparations showed increased arteriolar (+33%) and capillary diameters (+90%), and fluorescein angiograms revealed leakiness of neovascular front. At one year of age, persistent preretinal vessels were non-leaky in accordance with a relative increase in the ratio of Ang-1 to VEGF. Taken together, the data suggest that Ang-2 has an important function in the spatial configuration of the three-dimensional retinal vasculature. Secondarily, prolonged VEGF activity results in a model of persistent proliferative retinopathy.

Mesenchymal stromal cells improve survival during sepsis in the absence of heme oxygenase-1: the importance of neutrophils

The use of mesenchymal stromal cells (MSCs) for treatment of bacterial infections, including systemic processes like sepsis, is an evolving field of investigation. This study was designed to investigate the potential use of MSCs, harvested from compact bone, and their interactions with the innate immune system, during polymicrobial sepsis induced by cecal ligation and puncture (CLP). We also wanted to elucidate the role of endogenous heme oxygenase (HO)-1 in MSCs during a systemic bacterial infection. MSCs harvested from the bones of HO-1 deficient (-/-) and wild-type (+/+) mice improved the survival of HO-1(-/-) and HO-1(+/+) recipient mice when administered after the onset of polymicrobial sepsis induced by CLP, compared with the administration of fibroblast control cells. The MSCs, originating from compact bone in mice, enhanced the ability of neutrophils to phagocytize bacteria in vitro and in vivo and to promote bacterial clearance in the peritoneum and blood after CLP. Moreover, after depleting neutrophils in recipient mice, the beneficial effects of MSCs were entirely lost, demonstrating the importance of neutrophils for this MSC response. MSCs also decreased multiple organ injury in susceptible HO-1(-/-) mice, when administered after the onset of sepsis. Taken together, these data demonstrate that the beneficial effects of treatment with MSCs after the onset of polymicrobial sepsis is not dependent on endogenous HO-1 expression, and that neutrophils are crucial for this therapeutic response.

Precise Orbit Determination of Low Earth Satellites at AIUB using GPS and SLR data

An ever increasing number of low Earth orbiting (LEO) satellites is, or will be, equipped with retro-reflectors for Satellite Laser Ranging (SLR) and on-board receivers to collect observations from Global Navigation Satellite Systems (GNSS) such as the Global Positioning Sys- tem (GPS) and the Russian GLONASS and the European Galileo systems in the future. At the Astronomical Insti- tute of the University of Bern (AIUB) LEO precise or- bit determination (POD) using either GPS or SLR data is performed for a wide range of applications for satellites at different altitudes. For this purpose the classical numeri- cal integration techniques, as also used for dynamic orbit determination of satellites at high altitudes, are extended by pseudo-stochastic orbit modeling techniques to effi- ciently cope with potential force model deficiencies for satellites at low altitudes. Accuracies of better than 2 cm may be achieved by pseudo-stochastic orbit modeling for satellites at very low altitudes such as for the GPS-based POD of the Gravity field and steady-state Ocean Circula- tion Explorer (GOCE).

Matrix models for quantifying competitive intransitivity from species abundance data

In a network of competing species, a competitive intransitivity occurs when the ranking of competitive abilities does not follow a linear hierarchy (A > B > C but C > A). A variety of mathematical models suggests that intransitive networks can prevent or slow down competitive exclusion and maintain biodiversity by enhancing species coexistence. However, it has been difficult to assess empirically the relative importance of intransitive competition because a large number of pairwise species competition experiments are needed to construct a competition matrix that is used to parameterize existing models. Here we introduce a statistical framework for evaluating the contribution of intransitivity to community structure using species abundance matrices that are commonly generated from replicated sampling of species assemblages. We provide metrics and analytical methods for using abundance matrices to estimate species competition and patch transition matrices by using reverse-engineering and a colonization-competition model. These matrices provide complementary metrics to estimate the degree of intransitivity in the competition network of the sampled communities. Benchmark tests reveal that the proposed methods could successfully detect intransitive competition networks, even in the absence of direct measures of pairwise competitive strength. To illustrate the approach, we analyzed patterns of abundance and biomass of five species of necrophagous Diptera and eight species of their hymenopteran parasitoids that co-occur in beech forests in Germany. We found evidence for a strong competitive hierarchy within communities of flies and parasitoids. However, for parasitoids, there was a tendency towards increasing intransitivity in higher weight classes, which represented larger resource patches. These tests provide novel methods for empirically estimating the degree of intransitivity in competitive networks from observational datasets. They can be applied to experimental measures of pairwise species interactions, as well as to spatio-temporal samples of assemblages in homogenous environments or environmental gradients.

Towards a data-driven analysis of hadronic light-by-light scattering

The hadronic light-by-light contribution to the anomalous magnetic moment of the muon was recently analyzed in the framework of dispersion theory, providing a systematic formalism where all input quantities are expressed in terms of on-shell form factors and scattering amplitudes that are in principle accessible in experiment. We briefly review the main ideas behind this framework and discuss the various experimental ingredients needed for the evaluation of one- and two-pion intermediate states. In particular, we identify processes that in the absence of data for doubly-virtual pion–photon interactions can help constrain parameters in the dispersive reconstruction of the relevant input quantities, the pion transition form factor and the helicity partial waves for γ⁎γ⁎→ππ.

Untangling a Holocene pollen record with forest model simulations and independent climate data

Adaptation potential of forests to rapid climatic changes can be assessed from vegetation dynamics during past climatic changes as preserved in fossil pollen data. However, pollen data reflect the integrated effects of climate and biotic processes, such as establishment, survival, competition, and migration. To disentangle these processes, we compared an annually laminated late Würm and Holocene pollen record from the Central Swiss Plateau with simulations of a dynamic forest patch model. All input data used in the simulations were largely independent from pollen data; i.e. the presented analysis is non-circular. Temperature and precipitation scenarios were based on reconstructions from pollen-independent sources. The earliest arrival times of the species at the study site after the last glacial were inferred from pollen maps. We ran a series of simulations under different combinations of climate and immigration scenarios. In addition, the sensitivity of the simulated presence/absence of four major species to changes in the climate scenario was examined. The pattern of the pollen record could partly be explained by the used climate scenario, mostly by temperature. However, some features, in particular the absence of most species during the late Würm could only be simulated if the winter temperature anomalies of the used scenario were decreased considerably. Consequently, we had to assume in the simulations, that most species immigrated during or after the Younger Dryas (12 000 years BP), Abies and Fagus even later. Given the timing of tree species immigration, the vegetation was in equilibrium with climate during long periods, but responded with lags at the time-scale of centuries to millennia caused by a secondary succession after rapid climatic changes such as at the end of Younger Dryas, or immigration of dominant taxa. Climate influenced the tree taxa both directly and indirectly by changing inter-specific competition. We concluded, that also during the present fast climatic change, species migration might be an important process, particularly if geographic barriers, such as the Alps are in the migrational path.

A Bootstrap-Regression Procedure to Capture Unit Specific Effects in Data Envelopment Analysis

The Data Envelopment Analysis (DEA) efficiency score obtained for an individual firm is a point estimate without any confidence interval around it. In recent years, researchers have resorted to bootstrapping in order to generate empirical distributions of efficiency scores. This procedure assumes that all firms have the same probability of getting an efficiency score from any specified interval within the [0,1] range. We propose a bootstrap procedure that empirically generates the conditional distribution of efficiency for each individual firm given systematic factors that influence its efficiency. Instead of resampling directly from the pooled DEA scores, we first regress these scores on a set of explanatory variables not included at the DEA stage and bootstrap the residuals from this regression. These pseudo-efficiency scores incorporate the systematic effects of unit-specific factors along with the contribution of the randomly drawn residual. Data from the U.S. airline industry are utilized in an empirical application.

The burden of parainfluenza virus infection in patients with hematological malignancy and hematopoietic stem cell transplant (HSCT) recipients in the absence of active immunization and approved therapy: The role of infection control

Background. Community respiratory viruses, mainly RSV and influenza, are significant causes of morbidity and mortality in patients with leukemia and HSCT recipients. The data on impact of PIV infections in these patients is lacking. Methods. We reviewed the records of patients with leukemia and HSCT recipients who developed PIV infection from Oct'02–Nov'07 to determine the outcome of such infections. Results. We identified 200 patients with PIV infections including 80(40%) patients with leukemia and 120 (60%) recipients of HSCT. Median age was 55 y (17-84 y). As compared to HSCT recipients, patients with leukemia had higher APACHE II score (14 vs. 10, p<0.0001); were more likely to have ANC<500 (48% vs. 10%, p<0.0001) and ALC<200 (45% vs. 23.5%, p=0.02). PIV type III was the commonest isolate (172/200, 86%). Most patients 141/200 (70%) had upper respiratory infection (URI), and 59/200 (30%) had pneumonia at presentation. Patients in leukemia group were more likely to require hospitalization due to PIV infection (77% vs. 36% p=0.0001) and were more likely to progress to pneumonia (61% vs. 39%, p=0.002). Fifty five patients received aerosolized ribavirin and/or IVIG. There were no significant differences in the duration of symptoms, length of hospitalization, progression to pneumonia or mortality between the treated verses untreated group. The clinical outcome was unknown in 13 (6%) patients. Complete resolution of symptoms was noted in 91% (171/187) patients and 9% (16/187) patients died. Mortality rate was 17% (16/95) among patients who had PIV pneumonia, with no significant difference between leukemia and HSCT group (16% vs. 17%). The cause of death was acute respiratory failure and/or multi-organ failure in (13, 81%) patients. Conclusions. Patients with leukemia and HSCT could be at high risk for serious PIV infections including PIV pneumonia. Treatment with aerosolized ribavirin and/or IVIG may not have significant effect on the outcome of PIV infection.^

Functional activation of p53 induces apoptosis in the absence of MDM2

The p53 tumor suppressor gene product is negatively regulated by the product of its downstream target, mdm2. The mdm2 oncogene abrogates p53 transactivation function. Amplification of mdm2 occurs in 36% of human sarcomas, which often retain p53 in wild type form, suggesting that overexpression of mdm2 in tumors results in p53 inactivation. Thus, the relationship of p53 to mdm2 is important in tumorigenesis. The deletion of mdm2 in the mouse results in embryonic lethality by 5.5 days post coitum. Embryonic lethality of the mdm2 null embryos was overcome by simultaneous loss of the p53 tumor suppressor, which substantiates the importance of the negative regulatory function of MDM2 on p53 function in vivo. These data suggest that the loss of MDM2 function allowed the constitutively active p53 protein to induce either a complete G1 arrest or the p53-dependent apoptotic pathway, resulting in the death of the mdm2−/− embryos.^ The present study examines the hypothesis that the absence of mdm2 induces apoptosis due to p53 activation. Viability of the p53−/−mdm2−/− mice has allowed establishment of mouse embryo fibroblasts (MEFs) and a detailed examination of the properties of these cells. To introduce p53 into this system, and essentially recreate a mdm2 null cell, a temperature sensitive p53 (tsp53) point mutant (A135V) was used, which exhibits a nonfunctional, mutant conformation at 39°C and wild type, functional conformation at 32°C. Infected pools of p53−/− and p53−/−mdm2−/− MEFs with the tsp53 gene were established and single-cell clonal populations expressing tsp53 were selected. Shifting the cells from 39°C to 32°C caused p53−/−mdm2 −/− lines expressing tsp53 to undergo up to 80% apoptosis, which did not occur in the p53−/− lines expressing tsp53 nor the parental lines lacking p53 expression. Furthermore, the amount of p53 present in the clonal population determined the extent of apoptosis. Tsp53 is transcriptionally active in this system, however, it discriminates among different target promoters and does not induce the apoptosis effector targets bax or Fas/Apo1. ^ In summary, this study indicates that the presence or absence of mdm2 is the determining factor for the ability of p53 to trigger apoptosis in this system. The loss of mdm2 promotes p53-dependent apoptosis in MEFs in a cell cycle and dose-dependent manner. p53 is differentially phosphorylated in the presence and absence of mdm2, but does not induce the apoptosis effectors, bax or Fas/ Apo1. ^

Mineralogical and geochemical data from five lake sediment cores of Lake Donggi Cona

Sediments of Lake Donggi Cona on the northeastern Tibetan Plateau were studied to infer changes in the lacustrine depositional environment, related to climatic and non-climatic changes during the last 19 kyr. The lake today fills a 30 X 8 km big and 95 m deep tectonic basin, associated with the Kunlun Fault. The study was conducted on a sediment-core transect through the lake basin, in order to gain a complete picture of spatiotemporal environmental change. The recovered sediments are partly finely laminated and are composed of calcareous muds with variable amounts of carbonate micrite, organic matter, detrital silt and clay. On the basis of sedimentological, geochemical, and mineralogical data up to five lithological units (LU) can be distinguished that document distinct stages in the development of the lake system. The onset of the lowermost LU with lacustrine muds above basal sands indicates that lake level was at least 39 m below the present level and started to rise after 19 ka, possibly in response to regional deglaciation. At this time, the lacustrine environment was characterized by detrital sediment influx and the deposition of siliciclastic sediment. In two sediment cores, upward grain-size coarsening documents a lake-level fall after 13 cal ka BP, possibly associated with the late-glacial Younger Dryas stadial. From 11.5 to 4.3 cal ka BP, grainsize fining in sediment cores from the profundal coring sites and the onset of lacustrine deposition at a litoral core site (2m water depth) in a recent marginal bay of Donggi Cona document lake-level rise during the early tomid-Holocene to at least modern level. In addition, high biological productivity and pronounced precipitation of carbonate micrites are consistent with warm and moist climate conditions related to an enhanced influence of summer monsoon. At 4.3 cal ka BP the lake system shifted from an aragonite- to a calcite-dominated system, indicating a change towards a fully open hydrological lake system. The younger clay-rich sediments are moreover non-laminated and lack any diagenetic sulphides, pointing to fully ventilated conditions, and the prevailing absence of lake stratification. This turning point in lake history could imply either a threshold response to insolation-forced climate cooling or a response to a non-climatic trigger, such as an erosional event or a tectonic pulse that induced a strong earthquake, which is difficult to decide from our data base.

(Table 2) Actual and synthetic mass accumulation rate data and their absolute differences for ODP Site 115-707

Synthetic mass accumulation rates have been calculated for ODP Site 707 using depth-density and depth-porosity functions to estimate values for these parameters with increasing sediment thickness, at 1 Ma time intervals determined on the basis of published microfossil datums. These datums were the basis of the age model used by Peterson and Backman (1990, doi:10.2973/odp.proc.sr.115.163.1990) to calculate actual mass accumulation rate data using density and porosity measurements. A comparison is made between the synthetic and actual mass accumulation rate values for the time interval 37 Ma to the Recent for 1 Myr time intervals. There is a correlation coefficient of 0.993 between the two data sets, with an absolute difference generally less than 0.1 g/cm**2/kyr. We have used the method to extend the mass accumulation rate analysis back to the Late Paleocene (60 Ma) for Site 707. Providing age datums (e.g. fossil or magnetic anomaly data) are available the generation of synthetic mass accumulation rates can be calculated for any sediment sequence.