Averaging Generalized Scalar Field Cosmologies II: Locally Rotationally Symmetric Bianchi I and flat Friedmann-Lema\^itre-Robertson-Walker models

Scalar field cosmologies with a generalized harmonic potential and a matter fluid with a barotropic Equation of State (EoS) with barotropic index $\gamma$ for the Locally Rotationally Symmetric (LRS) Bianchi I and flat Friedmann-Lema\^itre-Robertson-Walker (FLRW) metrics are investigated. Methods from the theory of averaging of nonlinear dynamical systems are used to prove that time-dependent systems and their corresponding time-averaged versions have the same late-time dynamics. Therefore, the simplest time-averaged system determines the future asymptotic behavior. Depending on the values of $\gamma$, the late-time attractors of physical interests are flat quintessence dominated FLRW universe and Einstein-de Sitter solution. With this approach, the oscillations entering the system through the Klein-Gordon (KG) equation can be controlled and smoothed out as the Hubble parameter $H$ - acting as time-dependent perturbation parameter - tends monotonically to zero. Numerical simulations are presented as evidence of such behavior.Comment: Research Program Averaging Generalized Scalar Field Cosmologies, part II. 27 pages, 7 compound figures. Minor revision. References updated. Discussion improve

Averaging Generalized Scalar Field Cosmologies I: Locally Rotationally Symmetric Bianchi III and open Friedmann-Lema\^itre-Robertson-Walker models

Scalar field cosmologies with a generalized harmonic potential and a matter fluid with a barotropic Equation of State (EoS) with barotropic index $\gamma$ for Locally Rotationally Symmetric (LRS) Bianchi III metric and open Friedmann-Lema\^itre-Robertson-Walker (FLRW) metric are investigated. Methods from the theory of averaging of nonlinear dynamical systems are used to prove that time-dependent systems and their corresponding time-averaged versions have the same late-time dynamics. Therefore, simple time-averaged systems determine the future asymptotic behavior. Depending on values of barotropic index $\gamma$ late-time attractors of physical interests for LRS Bianchi III metric are Bianchi III flat spacetime, matter dominated FLRW universe (mimicking de Sitter, quintessence or zero acceleration solutions) and matter-curvature scaling solution. For open FLRW metric late-time attractors are a matter dominated FLRW universe and Milne solution. With this approach, oscillations entering nonlinear system through Klein-Gordon (KG) equation can be controlled and smoothed out as the Hubble factor $H$ - acting as a time-dependent perturbation parameter - tends monotonically to zero. Numerical simulations are presented as evidence of such behaviour.Comment: Research Program Averaging Generalized Scalar Field Cosmologies, part I. 48 pages, 24 compound figures. Minor revision. References adde

DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts

High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. The exact nature of the breaks, and their location, has not been entirely clear, and it has not been evident how cells survive, replicate, and maintain genome integrity in environments like the renal inner medulla in which cells are constantly exposed to high NaCl concentration. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (γH2AX), which occurs around DNA double-strand breaks and contributes to their repair. Here, we confirm by specific comet assay and pulsed-field electrophoresis that cells adapted to high NaCl have increased levels of double-strand breaks. Importantly, γH2AX foci that occur during repair of the breaks are nonrandomly distributed in the mouse genome. By chromatin immunoprecipitation using anti-γH2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of double-strand breaks induced by high NaCl, γH2AX is predominantly localized to regions of the genome devoid of genes (“gene deserts”), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation, and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes

Sustained hyperosmolarity increses TGF-beta1 and Egr-1 expression in the rat renal medulla.

BACKGROUND: Although TGF-ss and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-ss and Egr-1 expression. METHODS: Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. RESULTS: Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p < 0.05). Gene expression of TGF-ss and Egr-1 increased by 1.9-fold and 7-fold in the hypertonic medulla, respectively (p < 0.05), accompanied by 6-fold and 2-fold increased c-Fos and TIMP-1 expression, respectively (p < 0.05) and positive immunostaining for TGF-ss and Egr-1 (p < 0.05). Similarly, hyperosmolarity led to overexpression of TGF-ss and Egr-1 mRNA in IMCD cells (2.5-fold and 3.5-fold increase from 330 to 900 mOsm, respectively (p < 0.05)) accompanied by significant c-Fos and c-Jun overexpressions (p < 0.01), and increased Col3a1 and Col4a1 mRNA expression. CONCLUSION: We conclude that both TGF-ss and Egr-1 are upregulated by sustained hyperosmolarity in the rat renal medulla, and it favors the expression of extracellular matrix components

Moderate Antiproteinuric Effect of Add-On Aldosterone Blockade with Eplerenone in Non-Diabetic Chronic Kidney Disease. A Randomized Cross-Over Study

Reduction of proteinuria and blood pressure (BP) with blockers of the renin-angiotensin system (RAS) impairs the progression of chronic kidney disease (CKD). The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD.Open randomized cross-over trial.Forty patients with non-diabetic CKD and urinary albumin excretion greater than 300 mg/24 hours.Eight weeks of once-daily administration of add-on 25–50 mg eplerenone to stable standard antihypertensive treatment including RAS-blockade.24 hour urinary albumin excretion, BP, p-potassium, and creatinine clearance.The mean urinary albumin excretion was 22% [CI: 14,28], P<0.001, lower during treatment with eplerenone. Mean systolic BP was 4 mmHg [CI: 2,6], P = 0.002, diastolic BP was 2 mmHg [CI: 0,4], P = 0.02, creatinine clearance was 5% [CI: 2,8], P = 0.005, lower during eplerenone treatment. After correction for BP and creatinine clearance differences between the study periods, the mean urinary albumin excretion was 14% [CI: 4,24], P = 0.008 lower during treatment. Mean p-potassium was 0.1 mEq/L [CI: 0.1,0.2] higher during eplerenone treatment, P<0.001. Eplerenone was thus well tolerated and no patients were withdrawn due to hyperkalaemia.Open label, no wash-out period and a moderate sample size.In non-diabetic CKD patients, the addition of eplerenone to standard antihypertensive treatment including RAS-blockade caused a moderate BP independent fall in albuminuria, a minor fall in creatinine clearance and a 0.1 mEq/L increase in p-potassium

Why are mineralocorticoid receptor antagonists cardioprotective?

Two clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effect could not be attributed solely to blockade of the renal MR-mediated effects on blood pressure, and it has therefore been proposed that aldosterone, the endogenous MR agonist, also acts extrarenally, in particular in the heart. Indeed, MR are present in cardiac tissue, and possibly aldosterone synthesis occurs in the heart. This review critically addresses the following questions: (1) is aldosterone synthesized at cardiac tissue sites, (2) what agonist stimulates cardiac MR normally, and (3) what effects are mediated by aldosterone/MR in the heart that could explain the beneficial effects of MR blockade in heart failure? Conclusions are that most, if not all, of cardiac aldosterone originates in the circulation (i.e., is of adrenal origin), and that glucocorticoids, in addition to aldosterone, may serve as the endogenous agonist of cardiac MR. MR-mediated effects in the heart include effects on endothelial function, cardiac fibrosis and hypertrophy, oxidative stress, cardiac inotropy, coronary flow, and arrhythmias. Some of these effects occur via or in synergy with angiotensin II, and involve a non-MR-mediated mechanism. This raises the possibility that aldosterone synthase inhibitors might exert beneficial effects on top of MR blockade

Averaging generalized scalar-field cosmologies III: Kantowski–Sachs and closed Friedmann–Lemaître–Robertson–Walker models

Scalar-field cosmologies with a generalized harmonic potential and matter with energy density $$\rho _m$$, pressure $$p_m$$, and barotropic equation of state (EoS) $$p_m=(\gamma -1)\rho _m, \; \gamma \in [0,2]$$ in Kantowski–Sachs (KS) and closed Friedmann–Lemaître–Robertson–Walker (FLRW) metrics are investigated. We use methods from non-linear dynamical systems theory and averaging theory considering a time-dependent perturbation function D. We define a regular dynamical system over a compact phase space, obtaining global results. That is, for KS metric the global late-time attractors of full and time-averaged systems are two anisotropic contracting solutions, which are non-flat locally rotationally symmetric (LRS) Kasner and Taub (flat LRS Kasner) for $$0\le \gamma \le 2$$, and flat FLRW matter-dominated universe if $$0\le \gamma \le \frac{2}{3}$$. For closed FLRW metric late-time attractors of full and averaged systems are a flat matter-dominated FLRW universe for $$0\le \gamma \le \frac{2}{3}$$ as in KS and Einstein–de Sitter solution for $$0\le \gamma <1$$. Therefore, a time-averaged system determines future asymptotics of the full system. Also, oscillations entering the system through Klein–Gordon (KG) equation can be controlled and smoothed out when D goes monotonically to zero, and incidentally for the whole D-range for KS and closed FLRW (if $$0\le \gamma < 1$$) too. However, for $$\gamma \ge 1$$ closed FLRW solutions of the full system depart from the solutions of the averaged system as D is large. Our results are supported by numerical simulations