Contribution of the gap junction proteins Connexin40 and Connexin43 to the control of blood pressure

Summary Cells in tissues and organs coordinate their activities by communicating with each other through intercellular channels named gap junctions. These channels are conduits between the cytoplasmic compartments of adjacent cells, allowing the exchange of small molecules which may be crucial for hormone secretion. Renin is normally secreted in a regulated manner by specific cells of the juxtaglomerular apparatus located within the renal cortex. Gap junctional communication may be requisite to maintain an accurate functioning in coordination of renin-producing cells, more especially as renin is of paramount importance for the control of blood pressure. Connexin43 (Cx43) and Cx40 form gap junctions that link in vivo the cells of the juxtaglomerular apparatus. Cx43 links the endothelial cells, whereas gap junctions made of Cx40 connect the endothelial cells, the renin secreting cells, as well as the endothelial cells of to the renin-secreting cells of the afferent arteriole. The observation that loss of Cx40 results in chronic hypertension associated with altered vasomotion and signal conduction along arterioles, has lead us to suggest that connexins may contribute to control blood pressure by participating to the integration of various mechanical, osmotic and electrochemical stimuli involved in the control of renin secretion and by mediating the adaptive changes of the vascular wall induced by elevated blood pressure and mechanical stress. We therefore postulated that the absence of Cx40 could have deleterious effects on the coordinated functioning of the renin-containing cells, hence accounting for hypertension. In the first part of my thesis, we reported that Cx40-deficient mice (Cx40) are hypertensive due to increased plasma renin levels and numbers of renin-producing cells. Besides, we demonstrated that prostaglandins and nitric oxide, which are possible mediators in the regulation of renin secretion by the macula densa, exert a critical role in the mechanisms controlling blood pressure ín Cx40 knockout hypertensive mice. In view of previous studies that stated avessel-specifc increase in the expression of Cx43 during renin-dependent hypertension, we hypothesized that Cx43 channels are particularly well-matched to integrate the response of cells constituting the vascular wall to hypertensive conditions. Using transgenic mice in which Cx43 was replaced by Cx32, we revealed that the replacement of Cx43 by Cx32 is associated with decreased expression and secretion of renin and prevent the renin-dependent hypertension which is normally induced in the 2K1C model. To gain insights into the regulation of connexins in two separate tissues exposed to the same fluid pressure, the second part of my thesis work was dedicated to the study of the impact of chronic hypertension and related hypertrophy on the expression of the cardiovascular connexins (Cx40, Cx37, Cx43 and Cx45) in mouse aorta and heart. Our results documented that the expression of connexins is differentially regulated in mouse aorta. according to the models of hypertension. Thus, blood pressure induces mechanical forces that differentially alter the expression of vascular connexins in order to respond to an adaptation of the aortic wall observed under pathological conditions. Altogether these data provide the first evidences that intercellular communication mediated by gap junctions is required for a proper renin secretion from the juxtaglomerular apparatus in order to control blood pressure.

Long-term exercise stabilizes atherosclerotic plaque in apolipoprotein-E deficient mice

PURPOSE: Exercise is known to reduce cardiovascular mortality. However, the precise mechanisms are still unknown. Because atherosclerotic plaque destabilization and rupture leads to dramatic cardiovascular events, stabilization of plaque might be regarded as an important goal of an exercise preventive therapy. The present study examined the plaque-stabilizing effect of long-term exercise in experimental atherosclerosis using apolipoprotein E-deficient mice (ApoE(-/-)). METHODS: ApoE(-/-) mice were subjected to 6 months of swimming exercise. A group of sedentary animals were used as controls. Morphometry and characteristics of atherosclerotic plaque stability were assessed in aortic sinus by immunohistochemistry. Aortic levels of total protein kinase Akt (protein kinase B), phosphorylated Akt at Ser(473) (p-Akt), total endothelial nitric oxide synthase (eNOS), and phosphorylated eNOS at Ser(1177) (p-eNOS) were assessed by Western blotting. RESULTS: Exercised mice developed a more stable plaque phenotype as shown by decreased macrophage and increased smooth muscle cell content. Protein expressions of Akt, p-Akt, eNOS, and p-eNOS were not modulated by exercise. CONCLUSIONS: Long-term exercise promotes plaque stability in ApoE(-/-) mice. The Akt-mediated eNOS phosphorylation pathway seems not to be the primary molecular mechanism.

Effect of fertilization on soil phosphorus in a long-term field experiment in southern Finland

Selostus: Maan fosforitilan muutos pitkäaikaisessa kenttäkokeessa hietamaalla

Semiclassical theory of shot noise in ballistic n+in+ semiconductor structures: relevance of Pauli and long range Coulomb interactions

We work out a semiclassical theory of shot noise in ballistic n+-i-n+ semiconductor structures aiming at studying two fundamental physical correlations coming from Pauli exclusion principle and long-range Coulomb interaction. The theory provides a unifying scheme which, in addition to the current-voltage characteristics, describes the suppression of shot noise due to Pauli and Coulomb correlations in the whole range of system parameters and applied bias. The whole scenario is summarized by a phase diagram in the plane of two dimensionless variables related to the sample length and contact chemical potential. Here different regions of physical interest can be identified where only Coulomb or only Pauli correlations are active, or where both are present with different relevance. The predictions of the theory are proven to be fully corroborated by Monte Carlo simulations.

Determination of the direct band-gap energy of InAlAs matched to InP by photoluminescence excitation spectroscopy

A series of InxAl12xAs samples (0.51,x,0.55) coherently grown on InP was studied in order to measure the band-gap energy of the lattice matched composition. As the substrate is opaque to the relevant photon energies, a method is developed to calculate the optical absorption coefficient from the photoluminescence excitation spectra. The effect of strain on the band-gap energy has been taken into account. For x50.532, at 14 K we have obtained Eg05154966 meV. © 1997 American Institute of Physics.

Phosphorus and root distribution and corn growth as related to long-term tillage systems and fertilizer placement

Soil and fertilizer management during cultivation can affect crop productivity and profitability. Long-term experiments are therefore necessary to determine the dynamics of nutrient and root distribution as related to soil profile, as well as the effects on nutrient uptake and crop growth. An 18-year experiment was conducted at the Federal University of Rio Grande do Sul State (UFRGS), in Eldorado do Sul, Brazil, on Rhodic Paleudult soil. Black oat and vetch were planted in the winter and corn in the summer. The soil management methods were conventional, involving no-tillage and strip tillage techniques and broadcast, row-and strip-applied fertilizer placement (triple superphosphate). Available P (Mehlich-1) and root distribution were determined in soil monoliths during the corn grain filling period. Corn shoot dry matter production and P accumulation during the 2006/2007 growing season were determined and the efficiency of P utilization calculated. Regardless of the degree of soil mobilization, P and roots were accumulated in the fertilized zone with time, mainly in the surface layer (0-10 cm). Root distribution followed P distribution for all tillage systems and fertilizer treatments. Under no-tillage, independent of the fertilizer placement, the corn plants developed more roots than in the other tillage systems. Although soil tillage systems and fertilizer treatments affected P and root distribution throughout the soil profile, as well as P absorption and corn growth, the efficiency of P utilization was not affected.

A comparative long-memory Analysis between Spanish, Mexican and U.S. interest rates

Evidence exists that many natural facts are described better as a fractal. Although fractals are very useful for describing nature, it is also appropiate to review the concept of random fractal in finance. Due to the extraordinary importance of Brownian motion in physics, chemistry or biology, we will consider the generalization that supposes fractional Brownian motion introduced by Mandelbrot.The main goal of this work is to analyse the existence of long range dependence in instantaneous forward rates of different financial markets. Concretelly, we perform an empirical analysis on the Spanish, Mexican and U.S. interbanking interest rate. We work with three time series of daily data corresponding to 1 day operations from 28th March 1996 to 21st May 2002. From among all the existing tests on this matter we apply the methodology proposed in Taqqu, Teverovsky and Willinger (1995).

Agglomeration and labour productivity in Spanish industry: a long-term analysis

This paper analyzes the relationship between spatial density of economic activity and interregional differences in the productivity of industrial labour in Spain during the period 1860-1999. In the spirit of Ciccone and Hall (1996) and Ciccone (2002), we analyze the evolution of this relationship over the long term in Spain. Using data on the period 1860-1999 we show the existence of an agglomeration effect linking the density of economic activity with labour productivity in the industry. This effect was present since the beginning of the industrialization process in the middle of the 19th century but has been decreasing over time. The estimated elasticity of labour productivity with respect to employment density was close to 8% in the subperiod 1860-1900, reduces to a value of around 7% in the subperiod 1914-1930, to 4% in the subperiod 1965-1979 and becomes insignificant in the final subperiod 1985-1999. At the end of the period analyzed there is no evidence of the existence of net agglomeration effects in the industry. This result could be explained by an important increase in the congestion effects in large industrial metropolitan areas that would have compensated the centripetal or agglomeration forces at work. Furthermore, this result is also consistent with the evidence of a dispersion of industrial activity in Spain during the last decades.

External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.

BACKGROUND: We did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results. METHODS: For this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1-2 prostatic adenocarcinoma with WHO histological grade 3 or T3-4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0-2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3·6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082. FINDINGS: Between May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9·1 years (IQR 5·1-12·6). 10-year clinical disease-free survival was 22·7% (95% CI 16·3-29·7) in the radiotherapy-alone group and 47·7% (39·0-56·0) in the combined treatment group (hazard ratio [HR] 0·42, 95% CI 0·33-0·55, p<0·0001). 10-year overall survival was 39·8% (95% CI 31·9-47·5) in patients receiving radiotherapy alone and 58·1% (49·2-66·0) in those allocated combined treatment (HR 0·60, 95% CI 0·45-0·80, p=0·0004), and 10-year prostate-cancer mortality was 30·4% (95% CI 23·2-37·5) and 10·3% (5·1-15·4), respectively (HR 0·38, 95% CI 0·24-0·60, p<0·0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0·60) and in those who did not (14 of 154 vs six of 145; p=0·25). Two fractures were reported in patients allocated combined treatment. INTERPRETATION: In patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity.

Genetic differentiation for size at first reproduction through male versus female functions in the widespread Mediterranean tree Pinus pinaster.

BACKGROUND AND AIMS: The study of local adaptation in plant reproductive traits has received substantial attention in short-lived species, but studies conducted on forest trees are scarce. This lack of research on long-lived species represents an important gap in our knowledge, because inferences about selection on the reproduction and life history of short-lived species cannot necessarily be extrapolated to trees. This study considers whether the size for first reproduction is locally adapted across a broad geographical range of the Mediterranean conifer species Pinus pinaster. In particular, the study investigates whether this monoecious species varies genetically among populations in terms of whether individuals start to reproduce through their male function, their female function or both sexual functions simultaneously. Whether differences among populations could be attributed to local adaptation across a climatic gradient is then considered. METHODS: Male and female reproduction and growth were measured during early stages of sexual maturity of a P. pinaster common garden comprising 23 populations sampled across the species range. Generalized linear mixed models were used to assess genetic variability of early reproductive life-history traits. Environmental correlations with reproductive life-history traits were tested after controlling for neutral genetic structure provided by 12 nuclear simple sequence repeat markers. KEY RESULTS: Trees tended to reproduce first through their male function, at a size (height) that varied little among source populations. The transition to female reproduction was slower, showed higher levels of variability and was negatively correlated with vegetative growth traits. Several female reproductive traits were correlated with a gradient of growth conditions, even after accounting for neutral genetic structure, with populations from more unfavourable sites tending to commence female reproduction at a lower individual size. CONCLUSIONS: The study represents the first report of genetic variability among populations for differences in the threshold size for first reproduction between male and female sexual functions in a tree species. The relatively uniform size at which individuals begin reproducing through their male function probably represents the fact that pollen dispersal is also relatively invariant among sites. However, the genetic variability in the timing of female reproduction probably reflects environment-dependent costs of cone production. The results also suggest that early sex allocation in this species might evolve under constraints that do not apply to other conifers.

Characterization of soil structure and porosity under long-term conventional tillage and no-tillage systems

Different management systems tend to modify soil structure and porosity over the years. The aim of this study was to study modifications in the morphostructure and porosity of dystroferric Red Latosol (Oxisol) under conventional tillage and no-tillage over a 31- year period. The study began with the description of soil profiles based on the cropping profile method, to identify the most compact structures, define sample collection points for physical and chemical analysis, and determine the water retention curve. A forest soil profile was described and used as reference. The results showed that, under conventional tillage, the microaggregate structure of the Oxisol was fragmented between 0 and 0.20 m, and compact (bulk density = 1.52 Mg m-3) in the sub-surface layer between 0.20 and 0.50 m. Under no-tillage, the structure became compacted (bulk density = 1.40 Mg m-3) between 0 and 0.60 m, but contained fissures and biopores. The volume of the class with a pore diameter of > 100 µm under no-tillage was limited, but practically non-existent in the conventional management system. On the other hand, the classes with a pore diameter of < 100 µm were not affected by the type of soil management system.

The psychostimulant modafinil enhances gap junctional communication in cortical astrocytes.

Sleep-wake cycle is characterized by changes in neuronal network activity. However, for the last decade there is increasing evidence that neuroglial interaction may play a role in the modulation of sleep homeostasis and that astrocytes have a critical impact in this process. Interestingly, astrocytes are organized into communicating networks based on their high expression of connexins, which are the molecular constituents of gap junction channels. Thus, neuroglial interactions should also be considered as the result of the interplay between neuronal and astroglial networks. Here, we investigate the effect of modafinil, a wakefulness-promoting agent, on astrocyte gap junctional communication. We report that in the cortex modafinil injection increases the expression of mRNA and protein of connexin 30 but not those of connexin 43, the other major astroglial connexin. These increases are correlated with an enhancement of intercellular dye coupling in cortical astrocytes, which is abolished when neuronal activity is silenced by tetrodotoxin. Moreover, gamma-hydroxybutyric acid, which at a millimolar concentration induces sleep, has an opposite effect on astroglial gap junctions in an activity-independent manner. These results support the proposition that astroglia may play an important role in complex physiological brain functions, such as sleep regulation, and that neuroglial networking interaction is modified during sleep-wake cycle. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.

Evaluation of PCC Long-Term Durability Using Intermediate Sized Gravels to Optimize Mix Gradations, April 2010

With the implementation of the 2000 Q-MC specification, an incentive is provided to produce an optimized gradation to improve placement characteristics. Also, specifications for slip-formed barrier rail have changed to require an optimized gradation. Generally, these optimized gradations have been achieved by blending an intermediate aggregate with the coarse and fine aggregate. The demand for this intermediate aggregate has been satisfied by using crushed limestone chips developed from the crushing of the parent concrete stone. The availability, cost, and physical limitations of crushed limestone chips can be a concern. A viable option in addressing these concerns is the use of gravel as the intermediate aggregate. Unfortunately, gravels of Class 3I durability are limited to a small geographic area in Mississippi river sands north of the Rock River. Class 3 or Class 2 durability gravels are more widely available across the state. The durability classification of gravels is based on the amount and quality of the carbonate fraction of the material. At present, no service histories or research exists to assess the impact of using Class 3 or 2 durability gravels would have on the long-term durability of Portland cement concrete (PCC) pavement requiring Class 3I aggregate.