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Revisiting FrankâStarling: regulatory light chain phosphorylation alters the rate of force redevelopment (k<inf>tr</inf>) in a length-dependent fashion
© 2016 Wellcome Trust. Key points: Regulatory light chain (RLC) phosphorylation has been shown to alter the ability of muscle to produce force and power during shortening and to alter the rate of force redevelopment (ktr) at submaximal [Ca2+]. Increasing RLC phosphorylation âŒ50% from the in vivo level in maximally [Ca2+]-activated cardiac trabecula accelerates ktr. Decreasing RLC phosphorylation to âŒ70% of the in vivo control level slows ktr and reduces force generation. ktr is dependent on sarcomere length in the physiological range 1.85â1.94 Όm and RLC phosphorylation modulates this response. We demonstrate that FrankâStarling is evident at maximal [Ca2+] activation and therefore does not necessarily require length-dependent change in [Ca2+]-sensitivity of thin filament activation. The stretch response is modulated by changes in RLC phosphorylation, pinpointing RLC phosphorylation as a modulator of the FrankâStarling law in the heart. These data provide an explanation for slowed systolic function in the intact heart in response to RLC phosphorylation reduction. Abstract: Force and power in cardiac muscle have a known dependence on phosphorylation of the myosin-associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (ktr) in maximally activating [Ca2+]. Activation was achieved by rapidly increasing the temperature (temperature-jump of 0.5â20ÂșC) of permeabilized trabeculae over a physiological range of sarcomere lengths (1.85â1.94 Όm). The trabeculae were subjected to shortening ramps over a range of velocities and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC-exchange technique, which avoids changes in the phosphorylation level of other proteins. The results show that increasing RLC phosphorylation by 50% accelerates ktr by âŒ50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows ktr by âŒ50%, relative to the ktr obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of ktr following step shortening or ramp shortening. Using a two-state model, we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross-bridges. In summary, RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca2+] and are not explained by changes in the Ca2+-sensitivity of acto-myosin interactions. The length-dependence of the rate of force redevelopment, together with the modulation by the state of RLC phosphorylation, suggests that these effects play a role in the FrankâStarling law of the heart.Wellcome Trust Grant 091460/Z/10/Z
Effectiveness of training stop-smoking advisers to deliver cessation support to the UK national proposed standard versus usual care in Malaysia: a two-arm cluster randomised controlled trial
AIMS: To assess the effectiveness of training stop smoking services providers in Malaysia to deliver support for smoking cessation based on the UK National Centre for Smoking Cessation and Training (NCSCT) standard treatment programme compared with usual care. DESIGN: Twoâarm clusterârandomized controlled effectiveness trial across 19 sites with followâup at 4âweek, 3âmonth, and 6âmonth. SETTING: Stop smoking services operating in public hospitals in Malaysia. PARTICIPANTS: Five hundred and two smokers [mean ± standard deviation (SD), age 45.6 (13.4) years; 97.4% male] attending stop smoking services in hospital settings in Malaysia: 330 in 10 hospitals in the intervention condition and 172 in nine hospitals in the control condition. INTERVENTION AND COMPARATOR: The intervention consisted of training stopâsmoking practitioners to deliver support and followâup according to the NCSCT Standard Treatment Programme. The comparator was usual care (brief support and followâup). MEASUREMENTS: The primary outcome was continuous tobacco smoking abstinence up to 6 months in smokers who received smoking cessation treatment, verified by expiredâair carbon monoxide (CO) concentration. Secondary outcomes were continuous COâverified tobacco smoking abstinence up to 4 weeks and 3 months. RESULTS: Followâup rates at 4 weeks, 3 months and 6 months were 80.0, 70.6 and 53.3%, respectively, in the intervention group and 48.8, 30.8 and 23.3%, respectively, in the control group. At 6âmonth followâup, 93 participants in the intervention group and 19 participants in the control group were abstinent from smoking, representing 28.2 versus 11.0% in an intentionâtoâtreat (ITT) analysis assuming that participants with missing data had resumed smoking, and 52.8 versus 47.5% in a followâupâonly (FUO) analysis. Unadjusted odds ratios (accounting for clustering) were 5.04, (95% confidence interval (CI) = 1.22â20.77, P = 0.025) and 1.70, (95% CI = 0.25â11.53, P = 0.589) in the ITT and FUO analyses, respectively. Abstinence rates at 4 week and 3 month followâups were significantly higher in the intervention versus control group in the ITT but not the FUO analysis. CONCLUSIONS: On an intentionâtoâtreat analysis with missingâequalsâsmoking imputation, training Malaysian stop smoking service providers in the UK National Centre for Smoking Cessation and Training standard treatment programme appeared to increase 6 month continuous abstinence rates in smokers seeking help with stopping compared with usual care. However, the effect may have been due to increasing followâup rates
Volatility forecasting in the Chinese commodity futures market with intraday data
Given the unique institutional regulations in the Chinese commodity futures market as well as the characteristics of the data it generates, we utilize contracts with three months to delivery, the most liquid contract series, to systematically explore volatility forecasting for aluminum, copper, fuel oil, and sugar at the daily and three intraday sampling frequencies. We adopt popular volatility models in the literature and assess the forecasts obtained via these models against alternative proxies for the true volatility. Our results suggest that the long memory property is an essential feature in the commodity futures volatility dynamics and that the ARFIMA model consistently produces the best forecasts or forecasts not inferior to the best in statistical terms
Generating MHV super-vertices in light-cone gauge
We constructe the SYM lagrangian in light-cone gauge using
chiral superfields instead of the standard vector superfield approach and
derive the MHV lagrangian. The canonical transformations of the gauge field and
gaugino fields are summarised by the transformation condition of chiral
superfields. We show that MHV super-vertices can be described
by a formula similar to that of the MHV super-amplitude. In the
discussions we briefly remark on how to derive Nair's formula for
SYM theory directly from light-cone lagrangian.Comment: 25 pages, 7 figures, JHEP3 style; v2: references added, some typos
corrected; Clarification on the condition used to remove one Grassmann
variabl
Asymmetry, realised volatility and stock return risk estimates
In this paper we estimate minimum capital risk requirements for short and long positions with three investment horizons, using the traditional GARCH model and two other GARCH-type models that incorporate the possibility of asymmetric responses of volatility to price changes. We also address the problem of the extremely high estimated persistence of the GARCH model to generate observed volatility patterns by including realised volatility as an explanatory variable into the modelâs variance equation. The results suggest that the inclusion of realised volatility improves the GARCH forecastability as well as its ability to calculate accurate minimum capital risk requirements and makes it quite competitive when compared with asymmetric conditional heteroscedastic models such as the GJR and the EGARCH.info:eu-repo/semantics/publishedVersio
Biologic Rhythms Derived from Siberian Mammoths' Hairs
Hair is preserved for millennia in permafrost; it enshrines a record of biologic rhythms and offers a glimpse at chronobiology as it was in extinct animals. Here we compare biologic rhythms gleaned from mammoth's hairs with those of modern human hair. Four mammoths' hairs came from varying locations in Siberia 4600 km, four time zones, apart ranging in age between 18,000 and 20,000 years before present. We used two contemporaneous human hairs for comparison. Power spectra derived from hydrogen isotope ratios along the length of the hairs gave insight into biologic rhythms, which were different in the mammoths depending on location and differed from humans. Hair growth for mammoths was âŒ31 cms/year and âŒ16 cms/year for humans. Recurrent annual rhythms of slow and fast growth varying from 3.4 weeks/cycles to 8.7 weeks/cycles for slow periods and 1.2 weeks/cycles to 2.2 weeks/cycles for fast periods were identified in mammoth's hairs. The mineral content of mammoth's hairs was measured by electron microprobe analysis (k-ratios), which showed no differences in sulfur amongst the mammoth hairs but significantly more iron then in human hair. The fractal nature of the data derived from the hairs became evident in Mandelbrot sets derived from hydrogen isotope ratios, mineral content and geographic location. Confocal microscopy and scanning electron microscopy showed varied degrees of preservation of the cuticle largely independent of age but not location of the specimens. X-ray fluorescence microprobe and fluorescence computed micro-tomography analyses allowed evaluation of metal distribution and visualization of hollow tubes in the mammoth's hairs. Seasonal variations in iron and copper content combined with spectral analyses gave insights into variation in food intake of the animals. Biologic rhythms gleaned from power spectral plots obtained by modern methods revealed life style and behavior of extinct mega-fauna
The Global Burden of Trachoma: A Review
Trachoma is the commonest infectious cause of blindness worldwide. Recurrent infection of the ocular surface by Chlamydia trachomatis, the causative agent, leads to inturning of the eyelashes (trichiasis) and blinding corneal opacification. Trachoma is endemic in more than 50 countries. It is currently estimated that there are about 1.3 million people blind from the disease and a further 8.2 million have trichiasis. Several estimates for the burden of disease from trachoma have been made, giving quite variable results. The variation is partly because different prevalence data have been used and partly because different sequelae have been included. The most recent estimate from the WHO placed it at around 1.3 million Disability-Adjusted Life Years (DALYs). A key issue in producing a reliable estimate of the global burden of trachoma is the limited amount of reliable survey data from endemic regions
A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone
Recommended standardized procedures for determining exhaled lower respiratory
nitric oxide and nasal nitric oxide have been developed by task forces of the
European Respiratory Society and the American Thoracic Society. These
recommendations have paved the way for the measurement of nitric oxide to
become a diagnostic tool for specific clinical applications. It would be
desirable to develop similar guidelines for the sampling of other trace gases
in exhaled breath, especially volatile organic compounds (VOCs) which reflect
ongoing metabolism. The concentrations of water-soluble, blood-borne substances
in exhaled breath are influenced by: (i) breathing patterns affecting gas
exchange in the conducting airways; (ii) the concentrations in the
tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations
of the compound. The classical Farhi equation takes only the alveolar
concentrations into account. Real-time measurements of acetone in end-tidal
breath under an ergometer challenge show characteristics which cannot be
explained within the Farhi setting. Here we develop a compartment model that
reliably captures these profiles and is capable of relating breath to the
systemic concentrations of acetone. By comparison with experimental data it is
inferred that the major part of variability in breath acetone concentrations
(e.g., in response to moderate exercise or altered breathing patterns) can be
attributed to airway gas exchange, with minimal changes of the underlying blood
and tissue concentrations. Moreover, it is deduced that measured end-tidal
breath concentrations of acetone determined during resting conditions and free
breathing will be rather poor indicators for endogenous levels. Particularly,
the current formulation includes the classical Farhi and the Scheid series
inhomogeneity model as special limiting cases.Comment: 38 page
Effects of insurance status on children's access to specialty care: a systematic review of the literature
<p>Abstract</p> <p>Background</p> <p>The current climate of rising health care costs has led many health insurance programs to limit benefits, which may be problematic for children needing specialty care. Findings from pediatric primary care may not transfer to pediatric specialty care because pediatric specialists are often located in academic medical centers where institutional rules determine accepted insurance. Furthermore, coverage for pediatric specialty care may vary more widely due to systematic differences in inclusion on preferred provider lists, lack of availability in staff model HMOs, and requirements for referral. Our objective was to review the literature on the effects of insurance status on children's access to specialty care.</p> <p>Methods</p> <p>We conducted a systematic review of original research published between January 1, 1992 and July 31, 2006. Searches were performed using Pubmed.</p> <p>Results</p> <p>Of 30 articles identified, the majority use number of specialty visits or referrals to measure access. Uninsured children have poorer access to specialty care than insured children. Children with public coverage have better access to specialty care than uninsured children, but poorer access compared to privately insured children. Findings on the effects of managed care are mixed.</p> <p>Conclusion</p> <p>Insurance coverage is clearly an important factor in children's access to specialty care. However, we cannot determine the structure of insurance that leads to the best use of appropriate, quality care by children. Research about specific characteristics of health plans and effects on health outcomes is needed to determine a structure of insurance coverage that provides optimal access to specialty care for children.</p
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