Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) have been identified as ligands with different effector functions of the vascular assembly and maturation-mediating receptor tyrosine kinase Tie-2. To understand the molecular interactions of the angiopoietins with their receptor, we have studied the binding of Ang-1 and Ang-2 to the Tie-2 receptor. Enzyme-linked immunosorbent assay-based competition assays and co-immunoprecipitation experiments analyzing the binding of Ang-1 and Ang-2 to truncation mutants of the extracellular domain of Tie-2 showed that the first Ig-like loop of Tie-2 in combination with the epidermal growth factor (EGF)-like repeats (amino acids 1-360) is required for angiopoietin binding. The first Ig-like domain or the EGF-like repeats alone are not capable of binding Ang-1 and Ang-2. Concomitantly, we made the surprising finding that Tie-2 exon-2 knockout mice do express a mutated Tie-2 protein that lacks 104 amino acids of the first Ig-like domain. This mutant Tie-2 receptor is functionally inactive as shown by the lack of ligand binding and receptor phosphorylation. Collectively, the data show that the first 104 amino acids of the Tie-2 receptor are essential but not sufficient for angiopoietin binding. Conversely, the first 360 amino acids (Ig-like domain plus EGF-like repeats) of the Tie-2 receptor are necessary and sufficient to bind both Ang-1 and Ang-2, which suggests that differential receptor binding is not likely to be responsible for the different functions of Ang-1 and Ang-2.

Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2

During development of the vertebrate vascular system essential signals are transduced via protein-tyrosine phosphorylation. Null-mutations of receptor-tyrosine kinase (RTK) genes expressed in endothelial cells (ECs) display early lethal vascular phenotypes. We aimed to identify endothelial protein-tyrosine phosphatases (PTPs), which should have similar importance in EC-biology. A murine receptor-type PTP was identified by a degenerated PCR cloning approach from endothelial cells (VE-PTP). By in situ hybridization this phosphatase was found to be specifically expressed in vascular ECs throughout mouse development. In experiments using GST-fusion proteins, as well as in transient transfections, trapping mutants of VE-PTP co-precipitated with the Angiopoietin receptor Tie-2, but not with the Vascular Endothelial Growth Factor receptor 2 (VEGFR-2/Flk-1). In addition, VE-PTP dephosphorylates Tie-2 but not VEGFR-2. We conclude that VE-PTP is a Tie-2 specific phosphatase expressed in ECs, and VE-PTP phosphatase activity serves to specifically modulate Angiopoietin/Tie-2 function. Based on its potential role as a regulator of blood vessel morphogenesis and maintainance, VE-PTP is a candidate gene for inherited vascular malformations similar to the Tie-2 gene.

Capacity optimization of a prestressed concrete railroad tie

Today the use of concrete ties is on the rise in North America as they become an economically competitive alternative to the historical industry standard wood ties, while providing performance which exceeds its competition in terms of durability and capacity. Similarly, in response to rising energy costs, there is increased demand for efficient and sustainable transportation of people and goods. One source of such transportation is the railroad. To accommodate the increased demand, railroads are constructing new track and upgrading existing track. This update to the track system will increase its capacity while making it a more reliable means of transportation compared to other alternatives. In addition to increasing the track system capacity, railroads are considering an increase in the size of the typical freight rail car to allow larger tonnage. An increase in rail car loads will in turn affect the performance requirements of the track. Due to the increased loads heavy haul railroads are considering applying to their tracks, current designs of prestressed concrete railroad ties for heavy haul applications may be undersized. In an effort to maximize tie capacity while maintaining tie geometry, fastening systems and installation equipment, a parametric study to optimize the existing designs was completed. The optimization focused on maximizing the capacity of an existing tie design through an investigation of prestressing quantity, configuration, stress levels and other material properties. The results of the parametric optimization indicate that the capacity of an existing tie can be increased most efficiently by increasing the diameter of the prestressing and concrete strength. However, researchers also found that current design specifications and procedures do not include consideration of tie behavior beyond the current tie capacity limit of cracking to the first layer of prestressing. In addition to limiting analysis to the cracking limit, failure mechanisms such as shear in deep beams at the rail seat or pullout failure of the prestressing due to lack of development length were absent from specified design procedures, but discussed in this project.

VE-PTP controls blood vessel development by balancing Tie-2 activity

Vascular endothelial protein tyrosine phosphatase (VE-PTP) is an endothelial-specific receptor-type tyrosine phosphatase that associates with Tie-2 and VE-cadherin. VE-PTP gene disruption leads to embryonic lethality, vascular remodeling defects, and enlargement of vascular structures in extraembryonic tissues. We show here that antibodies against the extracellular part of VE-PTP mimic the effects of VE-PTP gene disruption exemplified by vessel enlargement in allantois explants. These effects require the presence of the angiopoietin receptor Tie-2. Analyzing the mechanism we found that anti-VE-PTP antibodies trigger endocytosis and selectively affect Tie-2-associated, but not VE-cadherin-associated VE-PTP. Dissociation of VE-PTP triggers the activation of Tie-2, leading to enhanced endothelial cell proliferation and enlargement of vascular structures through activation of Erk1/2. Importantly, the antibody effect on vessel enlargement is also observed in newborn mice. We conclude that VE-PTP is required to balance Tie-2 activity and endothelial cell proliferation, thereby controlling blood vessel development and vessel size.

Questionnaire-based study to assess the association between management practices and mastitis within tie-stall and free-stall dairy housing systems in Switzerland.

BACKGROUND Prophylactic measures are key components of dairy herd mastitis control programs, but some are only relevant in specific housing systems. To assess the association between management practices and mastitis incidence, data collected in 2011 by a survey among 979 randomly selected Swiss dairy farms, and information from the regular test day recordings from 680 of these farms was analyzed. RESULTS The median incidence of farmer-reported clinical mastitis (ICM) was 11.6 (mean 14.7) cases per 100 cows per year. The median annual proportion of milk samples with a composite somatic cell count (PSCC) above 200,000 cells/ml was 16.1 (mean 17.3) %. A multivariable negative binomial regression model was fitted for each of the mastitis indicators for farms with tie-stall and free-stall housing systems separately to study the effect of other (than housing system) management practices on the ICM and PSCC events (above 200,000 cells/ml). The results differed substantially by housing system and outcome. In tie-stall systems, clinical mastitis incidence was mainly affected by region (mountainous production zone; incidence rate ratio (IRR) = 0.73), the dairy herd replacement system (1.27) and farmers age (0.81). The proportion of high SCC was mainly associated with dry cow udder controls (IRR = 0.67), clean bedding material at calving (IRR = 1.72), using total merit values to select bulls (IRR = 1.57) and body condition scoring (IRR = 0.74). In free-stall systems, the IRR for clinical mastitis was mainly associated with stall climate/temperature (IRR = 1.65), comfort mats as resting surface (IRR = 0.75) and when no feed analysis was carried out (IRR = 1.18). The proportion of high SSC was only associated with hand and arm cleaning after calving (IRR = 0.81) and beef producing value to select bulls (IRR = 0.66). CONCLUSIONS There were substantial differences in identified risk factors in the four models. Some of the factors were in agreement with the reported literature while others were not. This highlights the multifactorial nature of the disease and the differences in the risks for both mastitis manifestations. Attempting to understand these multifactorial associations for mastitis within larger management groups continues to play an important role in mastitis control programs.

Ausst. 201 - Speculu[m] patie[n]tie cum theologycis consolationibus fratris Ioannis de Tambaco

Vorbesitzer: Heinrich Anton Cornill-d'Orville (Exlibris im Vorderdeckel);

Revised depth scale, splice tie points and chron boundaries of ODP Hole 151-907A and Site 162-907

The magnetic polarity stratigraphy at Site 907 obtained from the shipboard pass-through magnetometer and from discrete samples is readily interpretable back to the onset of the Gilbert Chron (5.89 Ma). From this level to the base of the section at ~14 Ma, the interpretation is corroborated by silicoflagellate datums with predictable correlation to polarity chrons. The resulting magnetostratigraphic interpretation differs from those proposed in the Leg 151 (Hole 907A) and 162 (Holes 907B and 907C) Initial Reports volumes. An important hiatus in the 7-10 Ma interval at Site 907 caused sedimentation to slow or cease for ~2.7 m.y. We have revised the shipboard correlation among the three holes at Site 907, resulting in a new composite section splice and recalculation of composite depths. For Site 985, magnetostratigraphic interpretation is possible down to ~150 meters below seafloor (mbsf) (C3An/C3Ar) at ~6 Ma. There are no useful biostratigraphic datums from Site 985 to support this interpretation; however, the interpretation is supported by the correlation of Sites 985 and 907 using natural gamma data from the shipboard multisensor track. Below ~150 mbsf at Site 985, drilling-related deformation at the onset of extended core barrel drilling precluded magnetostratigraphic interpretation.

Age tie points and geochemistry of sediment cores from the Antarctic continental margin

Few high-latitude terrestrial records document the timing and nature of the Cenozoic "Greenhouse" to "Icehouse" transition. Here we exploit the bulk geochemistry of marine siliciclastic sediments from drill cores on Antarctica's continental margin to extract a unique semiquantitative temperature and precipitation record for Eocene to mid-Miocene (~54-13 Ma). Alkaline elements are strongly enriched in the detrital mineral fraction in fine-grained siliciclastic marine sediments and only occur as trace metals in the biogenic fraction. Hence, terrestrial climofunctions similar to the chemical index of alteration (CIA) can be applied to the alkaline major element geochemistry of marine sediments on continental margins in order to reconstruct changes in precipitation and temperature. We validate this approach by comparison with published paleotemperature and precipitation records derived from fossil wood, leaves, and pollen and find remarkable agreement, despite uncertainties in the calibrations of the different proxies. A long-term cooling on the order of >=8°C is observed between the Early Eocene Climatic Optimum (~54-52 Ma) and the middle Miocene (~15-13 Ma) with the onset of transient cooling episodes in the middle Eocene at ~46-45 Ma. High-latitude stratigraphic records currently exhibit insufficient temporal resolution to reconstruct continental aridity and inferred ice-sheet development during the middle to late Eocene (~45-37 Ma). However, we find an abrupt aridification of East Antarctica near the Eocene-Oligocene transition (~34 Ma), which suggests that ice coverage influenced high-latitude atmospheric circulation patterns through albedo effects from the earliest Oligocene onward.

Composite depth scale, tie points and magnetic susceptibilities of ODP Site 178-1098 sediments

Multiple holes were cored at Ocean Drilling Program Leg 178 Sites 1098 and 1099 in two subbasins of the Palmer Deep in order to recover complete and continuous records of sedimentation. By correlating measured properties of cores from different holes at a site, we have established a common depth scale, referred to as the meters composite depth scale (mcd), for all cores from Site 1098. For Site 1098, distinct similarities in the magnetic susceptibility records obtained from three holes provide tight constraints on between-hole correlation. Additional constraints come from lithologic features. Specific intervals from other data sets, particularly gamma-ray attenuation bulk density, magnetic intensity, and color reflectance, contain distinctive anomalies that correlate well when placed into the preferred composite depth scale, confirming that the scale is accurate. Coring in two holes at Site 1099 provides only a few meters of overlap. None of the data sets within this limited overlap region provide convincing correlations. Thus, the preferred composite depth scale for Site 1099 is the existing depth scale in meters below seafloor (mbsf).