The distributions of the initial main-sequence binary parameters are one of the key ingredients in obtaining evolutionary predictions for compact binary (BH–BH/BH–NS/NS–NS) merger rates. Until now, ...such calculations were done under the assumption that initial binary parameter distributions were independent. For the first time, we implement empirically derived inter-correlated distributions of initial binary parameters primary mass (M1), mass ratio (q), orbital period (P), and eccentricity (e). Unexpectedly, the introduction of inter-correlated initial binary parameters leads to only a small decrease in the predicted merger rates by a factor of ≲2–3 relative to the previously used non-correlated initial distributions. The formation of compact object mergers in the isolated classical binary evolution favours initial binaries with stars of comparable masses (q ≈ 0.5–1) at intermediate orbital periods (log P (days) = 2–4). New distributions slightly shift the mass ratios towards lower values with respect to the previously used flat q distribution, which is the dominant effect decreasing the rates. New orbital periods (∼1.3 more initial systems within log P (days) = 2–4), together with new eccentricities (higher), only negligibly increase the number of progenitors of compact binary mergers. Additionally, we discuss the uncertainty of merger rate predictions associated with possible variations of the massive-star initial mass function (IMF). We argue that evolutionary calculations should be normalized to a star formation rate (SFR) that is obtained from the observed amount of UV light at wavelength 1500 Å (an SFR indicator). In this case, contrary to recent reports, the uncertainty of the IMF does not affect the rates by more than a factor of ∼2. Any change to the IMF slope for massive stars requires a change of SFR in a way that counteracts the impact of IMF variations on compact object merger rates. In contrast, we suggest that the uncertainty in cosmic SFR at low metallicity can be a significant factor at play.
Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia. Resistance is characterized by significantly delayed clearance ...of parasites following artemisinin treatment. Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries.
A non-randomized, single-arm, open-label clinical trial of artesunate monotherapy (4 mg/kg daily for seven days) was conducted in adults with acute blood-smear positive P. falciparum malaria in Kawthaung, southern Myanmar. Parasite density was measured every 12 hours until two consecutive negative smears were obtained. Participants were followed weekly at the study clinic for three additional weeks. Co-primary endpoints included parasite clearance time (the time required for complete clearance of initial parasitemia), parasite clearance half-life (the time required for parasitemia to decrease by 50% based on the linear portion of the parasite clearance slope), and detectable parasitemia 72 hours after commencement of artesunate treatment. Drug pharmacokinetics were measured to rule out delayed clearance due to suboptimal drug levels.
The median (range) parasite clearance half-life and time were 4.8 (2.1-9.7) and 60 (24-96) hours, respectively. The frequency distributions of parasite clearance half-life and time were bimodal, with very slow parasite clearance characteristic of the slowest-clearing Cambodian parasites (half-life longer than 6.2 hours) in approximately 1/3 of infections. Fourteen of 52 participants (26.9%) had a measurable parasitemia 72 hours after initiating artesunate treatment. Parasite clearance was not associated with drug pharmacokinetics.
A subset of P. falciparum infections in southern Myanmar displayed markedly delayed clearance following artemisinin treatment, suggesting either emergence of artemisinin resistance in southern Myanmar or spread to this location from its site of origin in western Cambodia. Resistance containment efforts are underway in Myanmar.
Australian New Zealand Clinical Trials Registry ACTRN12610000896077.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Animal cell cytokinesis results from patterned activation of the small GTPase Rho, which directs assembly of actomyosin in the equatorial cortex. Cytokinesis is restricted to a portion of the cell ...cycle following anaphase onset in which the cortex is responsive to signals from the spindle. We show that shortly after anaphase onset oocytes and embryonic cells of frogs and echinoderms exhibit cortical waves of Rho activity and F-actin polymerization. The waves are modulated by cyclin-dependent kinase 1 (Cdk1) activity and require the Rho GEF (guanine nucleotide exchange factor), Ect2. Surprisingly, during wave propagation, although Rho activity elicits F-actin assembly, F-actin subsequently inactivates Rho. Experimental and modelling results show that waves represent excitable dynamics of a reaction-diffusion system with Rho as the activator and F-actin the inhibitor. We propose that cortical excitability explains fundamental features of cytokinesis including its cell cycle regulation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Vascular calcification is common in chronic kidney disease and associated with increased morbidity and mortality. Its mechanism is multifactorial and incompletely understood. Patients with chronic ...kidney disease are at risk for vascular calcification because of multiple risk factors that induce vascular smooth muscle cells to change into a chondrocyte or osteoblast-like cell; high total body burden of calcium and phosphorus due to abnormal bone metabolism; low levels of circulating and locally produced inhibitors; impaired renal excretion; and current therapies. Together these factors increase risk and complicate the management of vascular calcification.
Background The management of chronic kidney disease–mineral and bone disorder requires the assessment of bone turnover, which most often is based on parathyroid hormone (PTH) concentration, the ...utility of which remains controversial. Study Design Cross-sectional retrospective diagnostic test study. Setting & Participants 492 dialysis patients from Brazil, Portugal, Turkey, and Venezuela with prior bone biopsy and stored (−20°C) serum. Index Tests Samples were analyzed for PTH (intact iPTH and whole PTH), bone-specific alkaline phosphatase (bALP), and amino-terminal propeptide of type 1 procollagen (P1NP). Reference Test Bone histomorphometric assessment of turnover (bone formation rate/bone surface BFR/BS) and receiver operating characteristic curves for discriminating diagnostic ability. Results The biomarkers iPTH and bALP or combinations thereof allowed discrimination of low from nonlow and high from nonhigh BFR/BS, with an area under the receiver operating characteristic curve > 0.70 but < 0.80. Using iPTH level, the best cutoff to discriminate low from nonlow BFR/BS was <103.8 pg/mL, and to discriminate high from nonhigh BFR/BS was >323.0 pg/mL. The best cutoff for bALP to discriminate low from nonlow BFR/BS was <33.1 U/L, and for high from nonhigh BFR/BS, 42.1 U/L. Using the KDIGO practice guideline PTH values of greater than 2 but less than 9 times the upper limit of normal, sensitivity and specificity of iPTH level to discriminate low from nonlow turnover bone disease were 65.7% and 65.3%, and to discriminate high from nonhigh were 37.0% and 85.8%, respectively. Limitations Cross-sectional design without consideration of therapy. Potential limited generalizability with samples from 4 countries. Conclusions The serum biomarkers iPTH, whole PTH, and bALP were able to discriminate low from nonlow BFR/BS, whereas iPTH and bALP were able to discriminate high from nonhigh BFR/BS. Prospective studies are required to determine whether evaluating trends in biomarker concentrations could guide therapeutic decisions.
In patients with chronic kidney and end-stage renal diseases, the major risk factor for progression of arterial calcification is the presence of existing (baseline) calcification. Here, we tested ...whether calcification of arteries is extended from calcified vascular smooth muscle cells (VSMCs) to adjacent normal cells by matrix vesicle–induced alteration of cell signaling. Matrix vesicles isolated from VSMC of rats with chronic kidney disease were co-cultured with VSMCs from normal littermates. Endocytosis of vesicles by recipient cells was confirmed by confocal microscopy. The addition of cellular matrix vesicles with characteristics of exosomes and low fetuin-A content enhanced the calcification of recipient VSMC. Further, only cellular-derived matrix vesicles induced an increase in intracellular calcium ion concentration, NOX1 (NADPH oxidase) and the anti-oxidant superoxide dismutase-2 in recipient normal VSMC. The increase in intracellular calcium ion concentration was due to release from endoplasmic reticulum and partially attributed to the activation of both NOX1 and mitogen-activated protein kinase (MEK1 and Erk1/2) signaling, since inhibiting both pathways blocked the increase in intracellular calcium ion in recipient VSMC. In contrast, matrix vesicles isolated from the media had no effect on the intracellular calcium ion concentration or MEK1 signaling, and did not induce calcification. However, media matrix vesicles did increase Erk1/2, although not to the level of cellular matrix vesicles, and NOX1 expression. Blockade of NOX activity further inhibited the cellular matrix vesicle–induced accelerated calcification of recipient VSMC, suggesting a potential therapeutic role of such inhibition. Thus, addition of cellular-derived matrix vesicles from calcifying VSMC can accelerate calcification by inducing cell signaling changes and phenotypic alteration of recipient VSMC.
Fibroblast growth factor-23 (FGF-23) has been hypothesized to play a role in the increased risk of cardiovascular disease in patients with CKD.
We identified prospective studies reporting ...associations between FGF-23 concentration and risk of cardiovascular events. Maximally adjusted risk ratios (RRs) were extracted for each outcome and scaled to a comparison of the top versus bottom third of the baseline FGF-23 concentration, and the results aggregated.
Depending on the assay used, median FGF-23 concentrations were 43-74 RU/ml and 38-47 pg/ml in 17 general population cohorts; 102-392 RU/ml in nine cohorts of patients with CKD not requiring dialysis; and 79-4212 RU/ml and 2526-5555 pg/ml in eight cohorts of patients on dialysis. Overall, comparing participants in the top and bottom FGF-23 concentration thirds, the summary RRs (95% confidence intervals 95% CIs) were 1.33 (1.12 to 1.58) for myocardial infarction, 1.26 (1.13 to 1.41) for stroke, 1.48 (1.29 to 1.69) for heart failure, 1.42 (1.27 to 1.60) for cardiovascular mortality, and 1.70 (1.52 to 1.91) for all-cause mortality. The summary RR for noncardiovascular mortality, calculated indirectly, was 1.52 (95% CI, 1.28 to 1.79). When studies were ordered by average differences in FGF-23 concentration between the top and bottom thirds, there was no trend in RRs across the studies.
The similarly-sized associations between increased FGF-23 concentration and cardiovascular (atherosclerotic and nonatherosclerotic) and noncardiovascular outcomes, together with the absence of any exposure-response relationship, suggest that the relationship between FGF-23 and cardiovascular disease risk may be noncausal.
Abstract Disordered calcium balance and homeostasis are common in patients with chronic kidney disease. Such alterations are commonly associated with abnormal bone remodeling, directly and ...indirectly. Similarly, positive calcium balance may also be a factor in the pathogenesis of extra skeletal soft tissue and arterial calcification. Calcium may directly affect cardiac structure and function through direct effects to alter cell signaling due to abnormal intracellular calcium homeostasis 2) extra-skeletal deposition of calcium and phosphate in the myocardium and small cardiac arterioles, 3) inducing cardiomyocyte hypertrophy through calcium and hormone activation of NFAT signaling mechanisms, and 4) increased aorta calcification resulting in chronic increased afterload leading to hypertrophy. Similarly, calcium may alter vascular smooth muscle cell function and affect cell signaling which may predispose to a proliferative phenotype important in arteriosclerosis and arterial calcification. Thus, disorders of calcium balance and homeostasis due to CKD-MBD may play a role in the high cardiovascular burden observed in patients with CKD.
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► Coupled micro- and macro-cell corrosion process is numerically simulated. ► Oxygen is a crucial factor influencing corrosion rate under cracked concrete cover. ► Microcell corrosion ...dominates corrosion process after concrete cover cracking. ► Corrosion-induced longitudinal crack accelerates subsequent deterioration process.
Chloride-induced corrosion of steel reinforcement in concrete may cause severe damage to RC structures. This paper examines the interaction between corrosion-induced cover crack growth and corrosion propagation. The coupled micro- and macro-cell corrosion process involved in a typical chloride-induced corrosion is numerically simulated. Both oxygen concentration and electrical potential distribution within concrete cover are considered in the electrochemical analysis. A uniform thick-walled cylinder model is formulated to simulate the cover surface crack width evolution. Results show that macrocell corrosion rate may not change so much while microcell corrosion rate increases a lot as oxygen permeability increases with corrosion-induced cover crack.
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