Transgenic Overexpression of Ephrin B1 in Bone Cells Promotes Bone Formation and an Anabolic Response to Mechanical Loading in Mice

To test if ephrin B1 overexpression enhances bone mass, we generated transgenic mice overexpressing ephrin B1 under the control of a 3.6 kb rat collagen 1A1 promoter (Col3.6-Tg^efnb1). Col3.6-Tg^efnb1 mice express 6-, 12- and 14-fold greater levels of full-length ephrin B1 protein in bone marrow stromal cells, calvarial osteoblasts, and osteoclasts, respectively. The long bones of both genders of Col3.6-Tg^efnb1 mice have increased trabecular bone volume, trabecular number, and trabecular thickness and decreased trabecular separation. Enhanced bone formation and decreased bone resorption contributed to this increase in trabecular bone mass in Col3.6-Tg^efnb1 mice. Consistent with these findings, our in vitro studies showed that overexpression of ephrin B1 increased osteoblast differentiation and mineralization, osterix and collagen 1A1 expression in bone marrow stromal cells. Interaction of ephrin B1 with soluble clustered EphB2-Fc decreased osteoclast precursor differentiation into multinucleated cells. Furthermore, we demonstrated that the mechanical loading-induced increase in EphB2 expression and newly formed bone were significantly greater in the Col3.6-Tg^efnb1 mice than in WT littermate controls. Our findings that overexpression of ephrin B1 in bone cells enhances bone mass and promotes a skeletal anabolic response to mechanical loading suggest that manipulation of ephrin B1 actions in bone may provide a means to sensitize the skeleton to mechanical strain to stimulate new bone formation.     

A mechanism of abiotic immobilization of nitrate in forest ecosystems: the ferrous wheel hypothesis

Forest soils, rather than woody biomass, are the dominant long‐term sink for N in forest fertilization studies and, by inference, for N from atmospheric deposition. Recent evidence of significant abiotic immobilization of inorganic‐N in forest humus layers challenges a previously widely held view that microbial processes are the dominant pathways for N immobilization in soil. Understanding the plant, microbial, and abiotic mechanisms of N immobilization in forest soils has important implications for understanding current and future carbon budgets. Abiotic immobilization of nitrate is particularly perplexing because the thermodynamics of nitrate reduction in soils are not generally favorable under oxic conditions. Here we present preliminary evidence for a testable hypothesis that explains abiotic immobilization of nitrate in forest soils. Because iron (and perhaps manganese) plays a key role as a catalyst, with Fe(II) reducing nitrate and reduced forms of carbon then regenerating Fe(II), we call this ‘the ferrous wheel hypothesis’. After nitrate is reduced to nitrite, we hypothesize that nitrite reacts with dissolved organic matter through nitration and nitrosation of aromatic ring structures, thus producing dissolved organic nitrogen (DON). In addition to ignorance about mechanisms of DON production, little is known about DON dynamics in soil and its fate within ecosystems. Evidence from leaching and watershed studies suggests that DON production and consumption may be largely uncoupled from seasonal biological processes, although biological processes ultimately produce the DOC and reducing power that affect DON formation and the entire N cycle. The ferrous wheel hypothesis includes both biological and abiological processes, but the reducing power of plant‐derived organic matter may build up over seasons and years while the abiotic reduction of nitrate and reaction of organic matter with nitrite may occur in a matter of seconds after nitrate enters the soil solution.     

Considering species richness and rarity when selecting optimal survey traps: comparisons of semiochemical baited flight intercept traps for Cerambycidae in eastern North America

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Effects of glaciers on nutrient concentrations and phytoplankton in lakes within the Northern Cascades Mountains (USA)

We compared nitrate concentrations, phytoplankton biomass, and phytoplankton community structure in lakes fed by glacier melt and snowmelt (GSF lakes) and by snowmelt only (SF lakes) within North Cascades National Park (NOCA) in Washington State, USA. In the U.S. Rocky Mountains, glacier melting has greatly increased nitrate concentrations in GSF lakes (52–236 µg NO₃–N L^?1) relative to SF lakes (1–14 µg NO₃–N L^?1) and thereby stimulated phytoplankton changes in GSF lakes. Considering NOCA contains approximately one-third of the glaciers in the continental U.S., and many mountain lakes that receive glacier meltwater inputs, we hypothesized that NOCA GSF lakes would have greater nitrate concentrations, greater phytoplankton biomass, and greater abundance of nitrogen-sensitive diatom species than NOCA SF lakes. However, at NOCA nitrate concentrations were much lower and differences between lake types were small compared to the Rockies. At NOCA, nitrate concentrations averaged 13 and 5 µg NO₃–N L^?1 in GSF and SF lakes, respectively, and a nitrate difference was not detectable in several individual years. There also was no difference in phytoplankton biomass or abundance of nitrogen-sensitive diatoms between lake types at NOCA. In contrast to the Rockies, there also was not a significant positive relationship between watershed percent glacier area and lake nitrate at NOCA. Results demonstrate that biogeochemical responses to global change in Western U.S. mountain lake watersheds may vary regionally. Regional differences may be affected by differing nitrogen deposition, climate, geology, or microbial processes within glacier environments, and merit further investigation.     

30-Day Survival Probabilities as a Quality Indicator for Norwegian Hospitals: Data Management and Analysis

Background

The Norwegian Knowledge Centre for the Health Services (NOKC) reports 30-day survival as a quality indicator for Norwegian hospitals. The indicators have been published annually since 2011 on the website of the Norwegian Directorate of Health (www.helsenorge.no), as part of the Norwegian Quality Indicator System authorized by the Ministry of Health. Openness regarding calculation of quality indicators is important, as it provides the opportunity to critically review and discuss the method. The purpose of this article is to describe the data collection, data pre-processing, and data analyses, as carried out by NOKC, for the calculation of 30-day risk-adjusted survival probability as a quality indicator.

Methods and Findings

Three diagnosis-specific 30-day survival indicators (first time acute myocardial infarction (AMI), stroke and hip fracture) are estimated based on all-cause deaths, occurring in-hospital or out-of-hospital, within 30 days counting from the first day of hospitalization. Furthermore, a hospital-wide (i.e. overall) 30-day survival indicator is calculated. Patient administrative data from all Norwegian hospitals and information from the Norwegian Population Register are retrieved annually, and linked to datasets for previous years. The outcome (alive/death within 30 days) is attributed to every hospital by the fraction of time spent in each hospital. A logistic regression followed by a hierarchical Bayesian analysis is used for the estimation of risk-adjusted survival probabilities. A multiple testing procedure with a false discovery rate of 5% is used to identify hospitals, hospital trusts and regional health authorities with significantly higher/lower survival than the reference. In addition, estimated risk-adjusted survival probabilities are published per hospital, hospital trust and regional health authority. The variation in risk-adjusted survival probabilities across hospitals for AMI shows a decreasing trend over time: estimated survival probabilities for AMI in 2011 varied from 80.6% (in the hospital with lowest estimated survival) to 91.7% (in the hospital with highest estimated survival), whereas it ranged from 83.8% to 91.2% in 2013.

Conclusions

Since 2011, several hospitals and hospital trusts have initiated quality improvement projects, and some of the hospitals have improved the survival over these years. Public reporting of survival/mortality indicators are increasingly being used as quality measures of health care systems. Openness regarding the methods used to calculate the indicators are important, as it provides the opportunity of critically reviewing and discussing the methods in the literature. In this way, the methods employed for establishing the indicators may be improved.     

4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner

4-1BB (CD137) is a member of the TNFR superfamily (TNFRSF9). T cell expression of 4-1BB is restricted to activated cells, and cross-linking has been shown to deliver a costimulatory signal. Here we have shown that treatment of tumor-bearing mice with agonistic 4-1BB-specific Abs can lead to T cell-mediated tumor rejection. In vivo mAb depletion experiments demonstrated that this rejection requires CD8(+) cells but not CD4(+) or NK cells. Both IFN-gamma- and CD40-mediated signals were also required, because no benefit was observed on treatment with 4-1BB mAb in mice in which the genes for these molecules had been knocked out. Interestingly, 4-1BB-mediated stimulation of immune responses in CD40L(-/-) mice is effective (although at a reduced level), and may suggest the existence of an alternative ligand for CD40. Additional experiments in IL-15(-/-) mice indicate that IL-15 is not required for either the generation of the primary tumor-specific immune response or the maintenance of the memory immune response. In contrast, the presence of CD4 cells during the primary immune response appears to play a significant role in the maintenance of effective antitumor memory. Finally, in mice in which the number of dendritic cells had been expanded by Fms-like tyrosine kinase3 ligand treatment, the antitumor effects of 4-1BB ligation were enhanced.     

Activity of Microorganisms in Acid Mine Water I. Influence of Acid Water on Aerobic Heterotrophs of a Normal Stream

Comparison of microbial content of acid-contaminated and nonacid-contaminated streams from the same geographical area indicated that nonacid streams contained relatively low numbers of acid-tolerant heterotrophic microorganisms. The acid-tolerant aerobes survived when acid entered the stream and actually increased in number to about 2 × 10³ per ml until the pH approached 3.0. The organisms then represented the heterotrophic aerobic microflora of the streams comprised of a mixture of mine drainage and nonacid water. A stream which was entirely acid drainage did not have a similar microflora. Most gram-positive aerobic and anaerobic bacteria died out very rapidly in acidic water, and they comprised a very small percentage of the microbial population of the streams examined. Iron- and sulfur-oxidizing autotrophic bacteria were present wherever mine water entered a stream system. The sulfur-oxidizing bacteria predominated over iron oxidizers. Ecological data from the field were verified by laboratory experiments designed to simulate stream conditions.     

Ontogeny of tracheal system structure: a light and electron-microscopy study of the metathoracic femur of the American locust, Schistocerca americana

Does oxygen delivery become more challenging for insects as they increase in size? To partially test this hypothesis, we used quantitative light and electron microscopy to estimate the oxygen delivery capacity for two steps of tracheal oxygen delivery within the metathoracic femur (jumping leg) for 2nd instar (about 47 mg) and adult (about 1.7 g) locusts, Schistocerca americana. The fractional cross‐sectional areas of the major tracheae running longitudinally along the leg were similar in adults and 2nd instars; however, since the legs of adults are longer, the mass‐specific diffusive conductances of these tracheae were 4‐fold greater in 2nd instars. Diffusive gas exchange longitudinally along the leg is easily possible for 2nd instars but not adults, who have many air sacs within the femur. Mitochondrial content fell proximally to distally within the femur in 2nd instars but not adults, supporting the hypothesis that diffusion was more important for the former. Lateral diffusing capacities of the tracheal walls were 12‐fold greater in adults than 2nd instars. This was primarily due to differences in the smallest tracheal class (tracheoles), which had thinner epidermal and cuticular layers, greater surface to volume ratios, and greater mass‐specific surface areas in adults. Adults also had greater mitochondrial contents, larger cell sizes and more intracellular tracheae. Thus, larger insects do not necessarily face greater problems with oxygen delivery; adult grasshoppers have superior oxygen delivery systems and greater mass‐specific aerobic capacities in their legs than smaller/younger insects. J. Morphol. 262:800–812, 2004. © 2004 Wiley‐Liss, Inc.     

FTIR Spectroscopic Study of Biogenic Mn-Oxide Formation by Pseudomonas putida GB-1

Biomineralization in heterogeneous aqueous systems results from a complex association between pre-existing surfaces, bacterial cells, extracellular biomacromolecules, and neoformed precipitates. Fourier transform infrared (FTIR) spectroscopy was used in several complementary sample introduction modes (attenuated total reflectance [ATR], diffuse reflectance [DRIFT], and transmission) to investigate the processes of cell adhesion, biofilm growth, and biological Mn-oxidation by Pseudomonas putida strain GB-1. Distinct differences in the adhesive properties of GB-1 were observed upon Mn oxidation. No adhesion to the ZnSe crystal surface was observed for planktonic GB-1 cells coated with biogenic MnO _x , whereas cell adhesion was extensive and a GB-1 biofilm was readily grown on ZnSe, CdTe, and Ge crystals prior to Mn-oxidation. IR peak intensity ratios reveal changes in biomolecular (carbohydrate, phosphate, and protein) composition during biologically catalyzed Mn-oxidation. In situ monitoring via ATR-FTIR of an active GB-1 biofilm and DRIFT data revealed an increase in extracellular protein (amide I and II) during Mn(II) oxidation, whereas transmission mode measurements suggest an overall increase in carbohydrate and phosphate moieties. The FTIR spectrum of biogenic Mn oxide comprises Mn-O stretching vibrations characteristic of various known Mn oxides (e.g., “acid” birnessite, romanechite, todorokite), but it is not identical to known synthetic solids, possibly because of solid-phase incorporation of biomolecular constituents. The results suggest that, when biogenic MnO _x accumulates on the surfaces of planktonic cells, adhesion of the bacteria to other negatively charged surfaces is hindered via blocking of surficial proteins.     

Gene order and recombination rate in homologous chromosome regions of the chicken and a passerine bird

Genome structure has been found to be highly conserved between distantly related birds and recent data for a limited part of the genome suggest that this is true also for the gene order (synteny) within chromosomes. Here, we confirm that synteny is maintained for large chromosomal regions in chicken and a passerine bird, the great reed warbler Acrocephalus arundinaceus, with few rearrangements, but in contrast show that the recombination-based linkage map distances differ substantially between these species. We assigned a chromosomal location based on sequence similarity to the chicken genome sequence to a set of microsatellite loci mapped in a pedigree of great reed warblers. We detected homologous loci on 14 different chromosomes corresponding to chicken chromosomes Gga1-5, 7-9, 13, 19, 20, 24, 25, and Z. It is known that 2 passerine macrochromosomes correspond to the chicken chromosome Gga1. Homology of 2 different great reed warbler linkage groups (LG13 and LG5) to Gga1 allowed us to locate the split to a position between 20.8 and 84.8 Mb on Gga1. Data from the 5 chromosomal regions (on Gga1, 2, 3, 5, and Z) with 3 or more homologous loci showed that synteny was conserved with the exception of 2 large previously unreported inversions on Gga1/LG5 and Gga2/LG3, respectively. Recombination data from the 9 chromosomal regions in which we identified 2 or more homologous loci (accounting for the inversions) showed that the linkage map distances in great reed warblers were only 6.3% and 13.3% of those in chickens for males and females, respectively. This is likely to reflect the true interspecific difference in recombination rate because our markers were not located in potentially low-recombining regions: several linkage groups covered a substantial part of their corresponding chicken chromosomes and were not restricted to centromeres. We conclude that recombination rates may differ strongly between bird species with highly conserved genome structure and synteny and that the chicken linkage map may not be suitable, in terms of genetic distances, as a model for all bird species.