First Results of the PixelGEM Central Tracking System for COMPASS

For its physics program with a high-intensity hadron beam of up to 2e7 particles/s, the COMPASS experiment at CERN requires tracking of charged particles scattered by very small angles with respect to the incident beam direction. While good resolution in time and space is mandatory, the challenge is imposed by the high beam intensity, requiring radiation-hard detectors which add very little material to the beam path in order to minimize secondary interactions. To this end, a set of triple-GEM detectors with a hybrid readout structure consisting of pixels in the beam region and 2-D strips in the periphery was designed and built. Successful prototype tests proved the performance of this new detector type, showing both extraordinary high rate capability and detection efficiency. The amplitude information allowed to achieve spatial resolutions about a factor of 10 smaller than the pitch and a time resolution close to the theoretical limit imposed by the layout. The PixelGEM central tracking system consisting of five detectors, slightly improved with respect to the prototype, was completely installed in the COMPASS spectrometer in spring 2008

The impact of superficial femoral artery (SFA) occlusion on the outcome of proximal sartorius muscle transposition flaps in vascular surgery patients

ObjectivesTo demonstrate the feasibility and safety of proximal sartorius muscle rotational flaps in patients with peripheral occlusive artery disease.MethodsRetrospective analysis of 53 patients with 56 proximal sartorius muscle flaps. Indication for a flap procedure was postoperative calcitrant lymphorrhea in nine, graft at risk in 13, and graft infection in 34 procedures. Pre- and postoperative patencies of the superficial femoral artery (SFA) and profundal femoral artery (PFA) were documented. Flap viability, wound healing, and limb salvage were examined at follow-up.ResultsIn 59% of the procedures in this series, the SFA was occluded. The PFA was patent in all patients. Flap viability (100% vs 94%), rate of new (4% vs 6%), and recurrent infections (9% vs 6%), loss of vascular reconstruction rate (9% vs 9%), and limb salvage rate (100% vs 88%) did not differ significantly between the SFA patent and the SFA occluded group. There were four new infections (7%) and three recurrent infections (5.5%) during follow-up, five of which led to a loss of reconstruction. In four of those five patients, the sartorius flap was viable. Two patients died during the immediate postoperative period from septic multi-organ failure (3%). At a median follow-up of 6.4 months, 54 flaps were viable and wound closure was achieved in all surviving 51 patients. Limb salvage rate was 93%.ConclusionsBiologic protection procedures as local muscle flaps are vital adjuncts to vascular surgery techniques in the treatment of complicated wounds in the groin. Occlusion of the SFA in the presence of a patent PFA is not associated with an increased risk of flap loss in proximal sartorius muscle rotational flaps

DPX-Q9H36 und DPX-QKS91 – Neue Komplettlösungen gegen Ungräser und Unkräuter im Mais

DPX-Q9H36 (120 g/kg Nicosulfuron, 30 g/kg Rimsulfuron, 360 g/kg Mesotrione) stellt mit einer Aufwandmenge von 330 g/ha + 0,1 % (v/v) DuPont™ Trend® eine neue Komplettlösung im Mais gegen Ungräser und breitblättrige Unkräuter dar. Dabei zeichnet sich DPX-Q9H36 durch eine sehr gute Wirksamkeit, ein breites Wirkungsspektrum, ein breites Anwendungsfenster (Mais BBCH 10 – 18) eine geringe Aufwandmenge und eine hohe Kulturverträglichkeit aus. DPX-Q9H36 ist ein homogener Blend aus wasserdispergierbaren Granulaten. Mehrjährige Versuche belegen die Wirksamkeit von DPX-Q9H36 vor allem gegen schwer bekämpfbare Unkräuter wie z.B. Schwarzer Nachtschatten (Solanum nigrum), aber auch gegen mehrjährige Ungräser wie Gemeine Quecke (Agropyron repens) und verschiedene Hirse-Arten wie Hühner- (Echinochloa crus-galli) und Borstenhirse (Setaria viridis). DPX-QKS91 (92 g/kg Nicosulfuron, 23 g/kg Rimsulfuron, 550 g/kg Dicamba), formuliert als homogener Blend aus wasserdispergierbaren Granulaten bekämpft sowohl ein breites Spektrum einjähriger Unkrautarten als auch mehrjährige Unkräuter und Ungräser. Die Anwendung erfolgt im Nachauflauf des Mais (BBCH 12 – 16) mit einer Aufwandmenge von 440 g/ha + 0,1 % (v/v) DuPontTM Trend®. Mehrjährige Versuche belegen die Wirksamkeit von DPX-QKS91 u. a. gegen den Weißen Gänsefuss (Chenopodium album) und Knöterich-Arten (Polygonum spp.), aber auch gegen Ungräser wie Gemeine Quecke (Agropyron repens), Einjährige Rispe (Poa annua) und verschiedene Hirse-Arten. Stichwörter: Agropyron repens, Chenopodium album, Dicamba, Hirse-Arten, Mesotrione, Nicosulfuron, Rimsulfuron, Solanum nigrumDPX-Q9H36 and DPX-QKS91 – New complete solutions against grass weeds and broad leaf weeds in cornDPX-Q9H36 (12 % nicosulfuron, 3 % rimsulfuron, 36 % mesotrione) with an application rate of 330 g/ha + 0.1 % (v/v) DuPont™ Trend® represents a new complete solution in corn against grass weeds and broadleaf weeds. DPX-Q9H36 is characterized by a very good efficacy, a wide spectrum of efficacy, a user-friendly application in a single treatment (corn BBCH 10 - 18) with low-input and high plant tolerance. DPX-Q9H36 as a homogeneous blend of water-dispersible granules. Several years of trials demonstrating the efficacy of DPX-Q9H36 especially against difficult to control weeds such as black nightshade (Solanum nigrum), but also against perennial weeds like quackgrass (Agropyron repens) and several millet species such as barnyard grass (Echinochloa crus-galli) and green foxtail (Setaria viridis).DPX-QKS91 (9.2 % nicosulfuron, 2.3 % rimsulfuron, 55 % dicamba), formulated as a homogeneous blend of water-dispersible granules, controls perennial weeds and grasses as well as annual species. The application is in the post-emergence corn (BBCH 12 - 16) with an application rate of 440 g/ha + 0.1 % (v/v) DuPont™ Trend®. Several years of trials demonstrating the efficacy of DPX-QKS91 i.e. against field bindweed (Convolvulus arvensis), spotted ladysthumb (Polygonum persicae) and back bindweed (Polygonum convolvulus), but also against grass weeds such as quackgrass (Agropyron repens), annual bluegrass (Poa annua) and several species of millet. Keywords: Agropyron repens, annual millet species, Chenopodium album, dicamba, mesotrione, nicosulfuron, rimsulfuron, Solanum nigru

Single Bead Labeling Method for Combining Confocal Fluorescence On-Bead Screening and Solution Validation of Tagged One-Bead One-Compound Libraries

SummaryScreening of one-bead one-compound libraries by incubating beads with fluorescently labeled target protein requires isolation and structure elucidation of a large number of primary hit beads. However, the potency of the identified ligands is only revealed after time consuming and expensive larger scale resynthesis and testing in solution. Often, many of the resynthesized compounds turn out to be weak target binders in solution due to large differences between surface and solution binding affinities. For an industry style high-throughput screening (HTS) process a high false positive rate is detrimental. We have therefore combined single bead and single molecule/single cell techniques into an integrated HTS process in which the picomole amount of substance contained on one isolated hit bead is sufficient for quality control, structure determination, and precise affinity determination to the target protein in solution

Urokinase-Type Plasminogen Activator Promotes Paracellular Transmigration of Neutrophils Via Mac-1, But Independently of Urokinase-Type Plasminogen Activator Receptor

Background: Urokinase-type plasminogen activator (uPA) has recently been implicated in the pathogenesis of ischemia-reperfusion (I/R) injury. The underlying mechanisms remain largely unclear. Methods and Results: Using in vivo microscopy on the mouse cremaster muscle, I/R-elicited firm adherence and transmigration of neutrophils were found to be significantly diminished in uPA-deficient mice and in mice treated with the uPA inhibitor WX-340, but not in uPA receptor (uPAR)–deficient mice. Interestingly, postischemic leukocyte responses were significantly reduced on blockade of the integrin CD11b/Mac-1, which also serves as uPAR receptor. Using a cell transfer technique, postischemic adherence and transmigration of wild-type leukocytes were significantly decreased in uPA-deficient animals, whereas uPA-deficient leukocytes exhibited a selectively reduced transmigration in wild-type animals. On I/R or stimulation with recombinant uPA, >90% of firmly adherent leukocytes colocalized with CD31-immunoreactive endothelial junctions as detected by in vivo fluorescence microscopy. In a model of hepatic I/R, treatment with WX-340 significantly attenuated postischemic neutrophil infiltration and tissue injury. Conclusions: Our data suggest that endothelial uPA promotes intravascular adherence, whereas leukocyte uPA facilitates the subsequent paracellular transmigration of neutrophils during I/R. This process is regulated via CD11b/Mac-1, and does not require uPAR. Pharmacological blockade of uPA interferes with these events and effectively attenuates postischemic tissue injury

Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90

Radiotherapy is an essential part of multi-modal cancer therapy. Nevertheless, for certain cancer entities such as colorectal cancer (CRC) the indications of radiotherapy are limited due to anatomical peculiarities and high radiosensitivity of the surrounding normal tissue. The development of molecularly targeted, combined modality approaches may help to overcome these limitations. Preferably, such strategies should not only enhance radiation-induced tumor cell killing and the abrogation of tumor cell clonogenicity, but should also support the stimulation of anti-tumor immune mechanisms – a phenomenon which moved into the center of interest of preclinical and clinical research in radiation oncology within the last decade. The present study focuses on inhibition of heat shock protein 90 (HSP90) whose combination with radiotherapy has previously been reported to exhibit convincing therapeutic synergism in different preclinical cancer models. By employing in vitro and in vivo analyses, we examined if this therapeutic synergism also applies to the priming of anti-tumor immune mechanisms in model systems of CRC. Our results indicate that the combination of HSP90 inhibitor treatment and ionizing irradiation induced apoptosis in colorectal cancer cells with accelerated transit into secondary necrosis in a hyperactive Kras-dependent manner. During secondary necrosis, dying cancer cells released different classes of damage-associated molecular patterns (DAMPs) that stimulated migration and recruitment of monocytic cells in vitro and in vivo. Additionally, these dying cancer cell-derived DAMPs enforced the differentiation of a monocyte-derived antigen presenting cell (APC) phenotype which potently triggered the priming of allogeneic T cell responses in vitro. In summary, HSP90 inhibition – apart from its radiosensitizing potential – obviously enables and supports the initial steps of anti-tumor immune priming upon radiotherapy and thus represents a promising partner for combined modality approaches. The therapeutic performance of such strategies requires further in-depth analyses, especially for but not only limited to CRC

Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo

Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-alpha secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-alpha. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate beta 2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies

RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-kappa B pathway

The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNF alpha mRNA decay via a 3'UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify similar to 3, 800 mRNA targets with 416, 000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-kappa B pathway regulators such as I kappa B alpha and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 30UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with I kappa B kinase and NF-kappa B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-kappa B pathway

Sectoral policies as drivers of forest management and ecosystems services: A case study in Bavaria, Germany

European countries have national sectoral polices to regulate and promote the provision of a wide range of forest ecosystems services (FES). However, potential incoherencies among these policies can negatively affect the efficient provision of FES. In this work, we evaluated the coherence among three national policies from Germany and their ability to effectively provide FES in the future: the Forest Strategy 2020 (FS), the National Strategy on Biological Diversity (BDS), and the German National Policy Strategy on Bioeconomy (BES). Using forest inventory data from the Federal State of Bavaria, we simulated a range of forest management options under three climate trajectories for 100 years into the future (2012–2112). Then, with multi-objective optimization, we translated each policy into a specific scenario and identified the best combination of management regimes that maximizes the targets defined in each policy scenario. The three policies were vague in the definition of FES. The FS was the most comprehensive policy aiming for a higher degree of multifunctionality, whereas the BES and BDS focused on less FES. The FS and the BDS showed the highest coherence, while the BES showed a stronger focus on timber production. As a result, the optimal management programs of FS and BDS showed high integration, with a dominance of Continuous Cover Forestry (CCF), and certain shares of set asides. Climate change led to an increase of set aside areas due to increased productivity. In the BES, the share of land among management regimes was strongly segregated between CCF and rotation forestry. Our policy coherence analysis showed that achieving a multifunctional provision of FES requires policy coherence, fostering a diverse management of the landscape that mainly takes advantage of integrative management, like CCF, but also segregates important parts of the landscape for intensive use and set asides. Nevertheless, the current high standing volumes in Bavaria will pose an additional risk to implement such management.peerReviewe