Structural aspects of postnatal lung development - alveolar formation and growth

The human lung is born with a fraction of the adult complement of alveoli. The postnatal stages of human lung development comprise an alveolar stage, a stage of microvascular maturation, and very likely a stage of late alveolarization. The characteristic structural features of the alveolar stage are well known; they are very alike in human and rat lungs. The bases for alveolar formation are represented by immature inter-airspace walls with two capillary layers with a central sheet of connective tissue. Interalveolar septa are formed by folding up of one of the two capillary layers. In the alveolar stage, alveolar formation occurs rapidly and is typically very conspicuous in both species; it has therefore been termed 'bulk alveolarization'. During and after alveolarization the septa with double capillary networks are restructured to the mature form with a single network. This happens in the stage of microvascular maturation. After these steps the lung proceeds to a phase of growth during which capillary growth by intussusception plays an important role in supporting gas exchange. In view of reports that alveoli are added after the stage of microvascular maturation, the question arises whether the present concept of alveolar formation needs revision. On the basis of morphological and experimental findings we can state that mature lungs contain all the features needed for 'late alveolarization' by the classical septation process. Because of the high plasticity of the lung tissues, late alveolarization or some forms of compensatory alveolar formation may be considered for the human lung.

Cyclooxygenase-2 inhibition selectively attenuates bone morphogenetic protein-6 synthesis and bone formation during guided tissue regeneration in a rat model

OBJECTIVES: Bone formation during guided tissue regeneration is a tightly regulated process involving cells, extracellular matrix and growth factors. The aims of this study were (i) to examine the expression of cyclooxygenase-2 (COX-2) during bone regeneration and (ii) the effects of selective COX-2 inhibition on osseous regeneration and growth factor expression in the rodent femur model. MATERIAL AND METHODS: A standardized transcortical defect of 5 x 1.5 mm was prepared in the femur of 12 male rats and a closed half-cylindrical titanium chamber was placed over the defect. The expression of COX-2 and of platelet-derived growth factor-B (PDGF-B), bone morphogenetic protein-6 (BMP-6) and insulin-like growth factor-I/II (IGF-I/II) was analyzed at Days 3, 7, 21 and 28 semiquantitatively by reverse transcriptase-polymerase chain reaction and immunohistochemistry. The effects of COX-2 inhibition by intraperitoneal injection of NS-398 (3 mg/kg/day) were analyzed in five additional animals sacrificed at Day 14. RESULTS: Histomorphometry revealed that new bone formation occurred in the cortical defect area as well as in the supracortical region, i.e. region within the chamber by Day 7 and increased through Day 28. Immunohistochemical evidence of COX-2 and PDGF-B levels were observed early (i.e. Day 3) and decreased rapidly by Day 7. BMP-6 expression was maximal at Day 3 and slowly declined by Day 28. In contrast, IGF-I/II expression gradually increased during the 28-day period. Systemic administration NS-398 caused a statistically significant reduction (P<0.05) in new bone formation (25-30%) and was associated with a statistically significant reduction in BMP-6 protein and mRNA expression (50% and 65% at P<0.05 and P<0.01, respectively). PDGF-B mRNA or protein expression was not affected by NS-398 treatment. CONCLUSION: COX-2 inhibition resulted in reduced BMP-6 expression and impaired osseous regeneration suggesting an important role for COX-2-induced signaling in BMP synthesis and new bone formation.

Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group

BACKGROUND AND OBJECTIVES: There are no widely accepted criteria for the definition of hematopoietic stem cell transplant -associated microangiopathy (TAM). An International Working Group was formed to develop a consensus formulation of criteria for diagnosing clinically significant TAM. DESIGN AND METHODS: The participants proposed a list of candidate criteria, selected those considered necessary, and ranked those considered optional to identify a core set of criteria. Three obligatory criteria and four optional criteria that ranked highest formed a core set. In an appropriateness panel process, the participants scored the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts' ratings on the patient profiles as a gold standard, the sensitivity and specificity of 24 candidate definitions of the disorder developed from the core set of criteria were evaluated. A nominal group technique was used to facilitate consensus formation. The definition of TAM with the highest score formed the final PROPOSAL. RESULTS: The Working Group proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: (i) >4% schistocytes in blood; (ii) de novo, prolonged or progressive thrombocytopenia (platelet count <50 x 109/L or 50% or greater reduction from previous counts); (iii) sudden and persistent increase in lactate dehydrogenase concentration; (iv) decrease in hemoglobin concentration or increased transfusion requirement; and (v) decrease in serum haptoglobin. The sensitivity and specificity of this definition exceed 80%. INTERPRETATION AND CONCLUSIONS: The Working Group recommends that the presented criteria of TAM be adopted in clinical use, especially in scientific trials.

Sodium retention and ascites formation in a cholestatic mice model: role of aldosterone and mineralocorticoid receptor?

Renal sodium retention in experimental liver cirrhosis originates from the distal nephron sensitive to aldosterone. The aims of this study were to (1) determine the exact site of sodium retention along the aldosterone-sensitive distal nephron, and (2) to evaluate the role of aldosterone and mineralocorticoid receptor activation in this process. Liver cirrhosis was induced by bile duct ligation in either adrenal-intact or corticosteroid-clamped mice. Corticosteroid-clamp was achieved through adrenalectomy and corticosteroid supplementation with aldosterone and dexamethasone via osmotic minipumps. 24-hours renal sodium balance was evaluated in metabolic cages. Activity and expression of sodium- and potassium-dependent adenosine triphosphatase were determined in microdissected segments of nephron. Within 4-5 weeks, cirrhosis induced sodium retention in adrenal-intact mice and formation of ascites in 50% of mice. At that time, sodium- and potassium-dependent adenosine triphosphatase activity increased specifically in cortical collecting ducts. Hyperaldosteronemia was indicated by increases in urinary aldosterone excretion and in sgk1 (serum- and glucocorticoid-regulated kinase 1) mRNA expression in collecting ducts. Corticosteroid-clamp prevented induction of sgk1 but not cirrhosis-induced sodium retention, formation of ascites and stimulation of sodium- and potassium-dependent adenosine triphosphatase activity and expression (mRNA and protein) in collecting duct. These findings demonstrate that sodium retention in cirrhosis is independent of hyperaldosteronemia and of the activation of mineralocorticoid receptor. CONCLUSION: Bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of sodium- and potassium-dependent adenosine triphosphatase in cortical collecting ducts, to renal sodium retention and to the formation of ascites. Sodium retention, ascites formation and induction of sodium- and potassium-dependent adenosine triphosphatase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids.

SOLUTE-DERIVED THERMAL STABILITY OF NANOCRYSTALLINE ALUMINUM AND PROCESSING FACTOR INFLUENCE ON THE FORMATION OF AL6MN QUASICRYSTALS IN MELT-SPINNING

Thermal stability of nanograined metals can be difficult to attain due to the large driving force for grain growth that arises from the significant boundary area constituted by the nanostructure. Kinetic approaches for stabilization of the nanostructure effective at low homologous temperatures often fail at higher homologous temperatures. Thermodynamic approaches for thermal stabilization may offer higher temperature stability. In this research, modest alloying of aluminum with solute (1 at.% Sc, Yb, or Sr) was examined as a means to thermodynamically stabilize a bulk nanostructure at elevated temperatures. After using melt-spinning and ball-milling to create an extended solid-solution and nanostructure with average grain size on the order of 30-45 nm, 1 h annealing treatments at 673 K (0.72 Tm) , 773 K (0.83 Tm) , and 873 K (0.94 Tm) were applied. The alloys remain nanocrystalline (<100 nm) as measured by Warren-Averbach Fourier analysis of x-ray diffraction peaks and direct observation of TEM dark field micrographs, with the efficacy of stabilization: Sr>Yb>Sc. Disappearance of intermetallic phases in the Sr and Yb alloys in the x-ray diffraction spectra are observed to occur coincident with the stabilization after annealing, suggesting that precipitates dissolve and the boundaries are enriched with solute. Melt-spinning has also been shown to be an effective process to produce a class of ordered, but non-periodic crystals called quasicrystals. However, many of the factors related to the creation of the quasicrystals through melt-spinning are not optimized for specific chemistries and alloy systems. In a related but separate aspect of this research, meltspinning was utilized to create metastable quasicrystalline Al6Mn in an α-Al matrix through rapid solidification of Al-8Mn (by mol) and Al-10Mn (by mol) alloys. Wheel speed of the melt-spinning wheel and orifice diameter of the tube reservoir were varied to determine their effect on the resulting volume proportions of the resultant phases using integrated areas of collected x-ray diffraction spectra. The data were then used to extrapolate parameters for the Al-10Mn alloy which consistently produced Al6Mn quasicrystal with almost complete suppression of the equilibrium Al6Mn orthorhombic phase.

MODELING DYNAMICS OF OZONE AND NITROGEN OXIDES AT SUMMIT, GREENLAND WITH A 1-D PROCESS-SCALE MODEL

This work presents a 1-D process scale model used to investigate the chemical dynamics and temporal variability of nitrogen oxides (NOx) and ozone (O3) within and above snowpack at Summit, Greenland for March-May 2009 and estimates surface exchange of NOx between the snowpack and surface layer in April-May 2009. The model assumes the surface of snowflakes have a Liquid Like Layer (LLL) where aqueous chemistry occurs and interacts with the interstitial air of the snowpack. Model parameters and initialization are physically and chemically representative of snowpack at Summit, Greenland and model results are compared to measurements of NOx and O3 collected by our group at Summit, Greenland from 2008-2010. The model paired with measurements confirmed the main hypothesis in literature that photolysis of nitrate on the surface of snowflakes is responsible for nitrogen dioxide (NO2) production in the top ~50 cm of the snowpack at solar noon for March – May time periods in 2009. Nighttime peaks of NO2 in the snowpack for April and May were reproduced with aqueous formation of peroxynitric acid (HNO4) in the top ~50 cm of the snowpack with subsequent mass transfer to the gas phase, decomposition to form NO2 at nighttime, and transportation of the NO2 to depths of 2 meters. Modeled production of HNO4 was hindered in March 2009 due to the low production of its precursor, hydroperoxy radical, resulting in underestimation of nighttime NO2 in the snowpack for March 2009. The aqueous reaction of O3 with formic acid was the major sync of O3 in the snowpack for March-May, 2009. Nitrogen monoxide (NO) production in the top ~50 cm of the snowpack is related to the photolysis of NO2, which underrepresents NO in May of 2009. Modeled surface exchange of NOx in April and May are on the order of 1011 molecules m-2 s-1. Removal of measured downward fluxes of NO and NO2 in measured fluxes resulted in agreement between measured NOx fluxes and modeled surface exchange in April and an order of magnitude deviation in May. Modeled transport of NOx above the snowpack in May shows an order of magnitude increase of NOx fluxes in the first 50 cm of the snowpack and is attributed to the production of NO2 during the day from the thermal decomposition and photolysis of peroxynitric acid with minor contributions of NO from HONO photolysis in the early morning.

Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension

BACKGROUND/AIMS: Angiogenesis is a pathological hallmark of portal hypertension. Although VEGF is considered to be the most important proangiogenic factor in neoangiogenesis, this process requires the coordinated action of a variety of factors. Identification of novel molecules involved in angiogenesis is highly relevant, since they may represent potential new targets to suppress pathological neovascularization in angiogenesis-related diseases like portal hypertension. The apelin/APJ signaling pathway plays a crucial role in angiogenesis. Therefore, we determined whether the apelin system modulates angiogenesis-driven processes in portal hypertension. METHODS: Partial portal vein-ligated rats were treated with the APJ antagonist F13A for seven days. Splanchnic neovascularization and expression of angiogenesis mediators (Western blotting) was determined. Portosystemic collateral formation (microspheres), and hemodynamic parameters (flowmetry) were also assessed. RESULTS: Apelin and its receptor APJ were overexpressed in the splanchnic vasculature of portal hypertensive rats. F13A effectively decreased, by 52%, splanchnic neovascularization and expression of proangiogenic factors VEGF, PDGF and angiopoietin-2 in portal hypertensive rats. F13A also reduced, by 35%, the formation of portosystemic collateral vessels. CONCLUSIONS: This study provides the first experimental evidence showing that the apelin/APJ system contributes to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats, presenting a potential novel therapeutic target for portal hypertension.

The etiology of cleft palate formation in BMP7-deficient mice

Palatogenesis is a complex process implying growth, elevation and fusion of the two lateral palatal shelves during embryogenesis. This process is tightly controlled by genetic and mechanistic cues that also coordinate the growth of other orofacial structures. Failure at any of these steps can result in cleft palate, which is a frequent craniofacial malformation in humans. To understand the etiology of cleft palate linked to the BMP signaling pathway, we studied palatogenesis in Bmp7-deficient mouse embryos. Bmp7 expression was found in several orofacial structures including the edges of the palatal shelves prior and during their fusion. Bmp7 deletion resulted in a general alteration of oral cavity morphology, unpaired palatal shelf elevation, delayed shelf approximation, and subsequent lack of fusion. Cell proliferation and expression of specific genes involved in palatogenesis were not altered in Bmp7-deficient embryos. Conditional ablation of Bmp7 with Keratin14-Cre or Wnt1-Cre revealed that neither epithelial nor neural crest-specific loss of Bmp7 alone could recapitulate the cleft palate phenotype. Palatal shelves from mutant embryos were able to fuse when cultured in vitro as isolated shelves in proximity, but not when cultured as whole upper jaw explants. Thus, deformations in the oral cavity of Bmp7-deficient embryos such as the shorter and wider mandible were not solely responsible for cleft palate formation. These findings indicate a requirement for Bmp7 for the coordination of both developmental and mechanistic aspects of palatogenesis.

Intussusceptive angiogenesis: its role in embryonic vascular network formation

Intussusceptive angiogenesis is a novel mode of blood vessel formation and remodeling, which occurs by internal division of the preexisting capillary plexus without sprouting. In this study, the process is demonstrated in developing chicken eye vasculature and in the chorioallantoic membrane by methylmethacrylate (Mercox) casting, transmission electron microscopy, and in vivo observation. In a first step of intussusceptive angiogenesis, the capillary plexus expands by insertion of numerous transcapillary tissue pillars, ie, by intussusceptive microvascular growth. In a subsequent step, a vascular tree arises from the primitive capillary plexus as a result of intussusceptive pillar formation and pillar fusions, a process we termed "intussusceptive arborization." On the basis of the morphological observations, a 4-step model for intussusceptive arborization is proposed, as follows: phase I, numerous circular pillars are formed in rows, thus demarcating future vessels; phase II, formation of narrow tissue septa by pillar reshaping and pillar fusions; phase III, delineation, segregation, growth, and extraction of the new vascular entity by merging of septa; and phase IV, formation of new branching generations by successively repeating the process, complemented by growth and maturation of all components. In contrast to sprouting, intussusceptive angiogenesis does not require intense local endothelial cell proliferation; it is implemented primarily by rearrangement and attenuation of the endothelial cell plates. In summary, transcapillary pillar formation, ie, intussusception, is a central and probably widespread process, which plays a role not only in capillary network growth and expansion (intussusceptive microvascular growth), but also in vascular plexus remodeling and tree formation (intussusceptive arborization).

Assay of β-hematin formation by malaria parasite

Novel leads are urgently required for designing antimalarials due to the reduced efficacy of presently available drugs. The malaria parasite has a unique reaction of heme polymerization, which has attracted much attention in the recent past as a target for the design of antimalarial drugs. The process is hampered by non-availability of a proper assay method. Currently available methods are cumbersome and require advanced instrumentation or radioactive substrates. Here, we are describing an assay for hemozoin formation that is simple and reproducible. This assay has routinely been used by us for the identification of potential compounds with antimalarial activity.

Formation of haemozoin/β-haematin under physiological conditions is not spontaneous

Malaria parasite detoxifies free haem, released as a result of haemoglobin digestion, by converting it into an stable, crystalline, black brown pigment known as 'malaria pigment' or 'haemozoin'. Earlier studies have demonstrated the involvement of a parasite-specific enzyme 'haem polymerase' in the formation of haemozoin. However, recently it has been proposed that the polymerization of haem may be a spontaneous process that could take place by incubation of haematin with carboxylic acids (pH 4.2-5.0) even without presence of any parasitic or biological component (FEBS Letters, 352, 54-57 (1994). Here we report that no spontaneous haem polymerization occurs at physiological conditions and the product described in the study mentioned above is not haemozoin/beta-haematin (haem polymer) as characterized by us on the basis of solubility characteristics and thin layer chromatography. The infra-red spectroscopic analysis of the product formed though exhibits the bands corresponding to formation of iron-carboxylate bond, similar to that in haemozoin/beta-haematin, but was identified as haem-acid adduct. Thus polymerization of haem may not occur spontaneously under the reaction conditions corresponding to food vacuoles of the malarial parasite, the physiological site of haemozoin formation.

A Process Model of Complementarity and Substitution of Contractual and Relational Governance in IS Outsourcing

This paper develops a process model of how and why complementarity and substitution form over time between contractual and relational governance in the context of information systems outsourcing. Our analysis identifies four distinct process patterns that explain this formation as the outcome of interaction processes between key elements of both contractual and relational governance. These patterns unveil the dynamic nature of complementarity and substitution. In particular, we show that the relationship between contractual and relational governance oscillates between complementarity and substitution. Those oscillations are triggered mainly by three types of contextual events (goal fuzziness, goal conflict, and goal misalignment). Surprisingly, substitution of informal control did not occur as an immediate reaction to external events but emerged as a consequence of preceding complementarity. Thus, our study challenges the prevailing view of an either/or dichotomy of complementarity and substitution by showing that they are causally connected over time.

Planet formation models: the interplay with the planetesimal disc

Context. According to the sequential accretion model (or core-nucleated accretion model), giant planet formation is based first on the formation of a solid core which, when massive enough, can gravitationally bind gas from the nebula to form the envelope. The most critical part of the model is the formation time of the core: to trigger the accretion of gas, the core has to grow up to several Earth masses before the gas component of the protoplanetary disc dissipates. Aims: We calculate planetary formation models including a detailed description of the dynamics of the planetesimal disc, taking into account both gas drag and excitation of forming planets. Methods: We computed the formation of planets, considering the oligarchic regime for the growth of the solid core. Embryos growing in the disc stir their neighbour planetesimals, exciting their relative velocities, which makes accretion more difficult. Here we introduce a more realistic treatment for the evolution of planetesimals' relative velocities, which directly impact on the formation timescale. For this, we computed the excitation state of planetesimals, as a result of stirring by forming planets, and gas-solid interactions. Results: We find that the formation of giant planets is favoured by the accretion of small planetesimals, as their random velocities are more easily damped by the gas drag of the nebula. Moreover, the capture radius of a protoplanet with a (tiny) envelope is also larger for small planetesimals. However, planets migrate as a result of disc-planet angular momentum exchange, with important consequences for their survival: due to the slow growth of a protoplanet in the oligarchic regime, rapid inward type I migration has important implications on intermediate-mass planets that have not yet started their runaway accretion phase of gas. Most of these planets are lost in the central star. Surviving planets have masses either below 10 M⊕ or above several Jupiter masses. Conclusions: To form giant planets before the dissipation of the disc, small planetesimals (~0.1 km) have to be the major contributors of the solid accretion process. However, the combination of oligarchic growth and fast inward migration leads to the absence of intermediate-mass planets. Other processes must therefore be at work to explain the population of extrasolar planets that are presently known.

It’s all about networking! Empirical investigation of social capital formation on social network sites

As Social Network Sites (SNS) permeate our daily routines, the question whether participation results in value for SNS users becomes particularly acute. This study adopts a 'participation-source-outcome' perspective to explore how distinct uses of SNS generate various types of social capital benefits. Building on existing research, extensive qualitative findings and an empirical study with 253 Facebook users, we uncover the process of social capital formation on SNS. We find that even though active communication is an important prerequisite, it is the diversified network structure and the increased social connectedness that are responsible for the attainment of the four benefits of social capital on SNS: emotional support, networking value, horizon broadening and offline participation. Moreover, we propose and validate scales to measure social capital benefits in the novel context of SNS.

Characterisation of Gas Transport Properties of the Opalinus Clay, a Potential Host Rock Formation for Radioactive Waste Disposal

The Opalinus Clay in Northern Switzerland has been identified as a potential host rock formation for the disposal of radioactive waste. Comprehensive understanding of gas transport processes through this low-permeability formation forms a key issue in the assessment of repository performance. Field investigations and laboratory experiments suggest an intrinsic permeability of the Opalinus Clay in the order of 10(-20) to 10(-21) m(2) and a moderate anisotropy ratio < 10. Porosity depends on clay content and burial depth; values of similar to 0.12 are reported for the region of interest. Porosimetry indicates that about 10-30 of voids can be classed as macropores, corresponding to an equivalent pore radius > 25 nm. The determined entry pressures are in the range of 0.4-10 MPa and exhibit a marked dependence on intrinsic permeability. Both in situ gas tests and gas permeameter tests on drillcores demonstrate that gas transport through the rock is accompanied by porewater displacement, suggesting that classical flow concepts of immiscible displacement in porous media can be applied when the gas entry pressure (i.e. capillary threshold pressure) is less than the minimum principal stress acting within the rock. Essentially, the pore space accessible to gas flow is restricted to the network of connected macropores, which implies a very low degree of desaturation of the rock during the gas imbibition process. At elevated gas pressures (i.e. when gas pressure approaches the level of total stress that acts on the rock body), evidence was seen for dilatancy controlled gas transport mechanisms. Further field experiments were aimed at creating extended tensile fractures with high fracture transmissivity (hydro- or gasfracs). The test results lead to the conclusion that gas fracturing can be largely ruled out as a risk for post-closure repository performance.