Physiology and pathophysiology of excitation–contraction coupling in skeletal muscle: the functional role of ryanodine receptor

Calcium (Ca2+) release from intracellular stores plays a key role in the regulation of skeletal muscle contraction. The type 1 ryanodine receptors (RyR1) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) of myocytes in skeletal muscle and is required for excitation–contraction (E–C) coupling. This article explores the role of RyR1 in the skeletal muscle physiology and pathophysiology

Systematic review and meta-analysis of serotonin transporter genotype and discontinuation from antidepressant treatment

AbstractThere is evidence that 5-HTTLPR is associated with response following treatment from selective serotonin reuptake inhibitors (SSRIs). The short (S) allele has reduced serotonin transporter expression, compared to the long (L) allele, and has been reported to be associated with poorer response in Europeans, with the effect in other populations unclear. However the published literature is inconsistent. A systematic review and meta-analysis was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data were obtained from 17 studies including 4309 participants. The principal outcome measure was the allelic odds ratio (OR) for the 5-HTTLPR S allele and discontinuation status. A random effects meta-analysis provided no evidence that the S allele was associated with increased odds of discontinuation from SSRIs in Europeans (OR 1.09, 95% CI 0.83–1.42, p=0.53; 10 studies, n=2504) but in East Asians there was evidence of a reduced odds of discontinuation (OR 0.28, 95% CI 0.12–0.64, p=0.002; 2 studies, n=136). There was a suggestion of small study bias (p=0.05). This meta-analysis provides no evidence of an association between 5-HTTLPR and discontinuation from antidepressant treatment in Europeans. The low number of studies in East Asian samples using SSRIs reduces confidence in our evidence that the S allele decreases the odds of discontinuation in this population. At present, there is no evidence of an association between 5-HTTLPR and discontinuation from SSRI treatment in a European population with further studies required to investigate its effects in different populations

Palmitoylation of Desmoglein 2 Is a Regulator of Assembly Dynamics and Protein Turnover.

Desmosomes are prominent adhesive junctions present between many epithelial cells as well as cardiomyocytes. The mechanisms controlling desmosome assembly and remodeling in epithelial and cardiac tissue are poorly understood. We recently identified protein palmitoylation as a mechanism regulating desmosome dynamics. In this study, we have focused on the palmitoylation of the desmosomal cadherin desmoglein-2 (Dsg2) and characterized the role that palmitoylation of Dsg2 plays in its localization and stability in cultured cells. We identified two cysteine residues in the juxtamembrane (intracellular anchor) domain of Dsg2 that, when mutated, eliminate its palmitoylation. These cysteine residues are conserved in all four desmoglein family members. Although mutant Dsg2 localizes to endogenous desmosomes, there is a significant delay in its incorporation into junctions, and the mutant is also present in a cytoplasmic pool. Triton X-100 solubility assays demonstrate that mutant Dsg2 is more soluble than wild-type protein. Interestingly, trafficking of the mutant Dsg2 to the cell surface was delayed, and a pool of the non-palmitoylated Dsg2 co-localized with lysosomal markers. Taken together, these data suggest that palmitoylation of Dsg2 regulates protein transport to the plasma membrane. Modulation of the palmitoylation status of desmosomal cadherins can affect desmosome dynamics

Follow-up services for improving long-term outcomes in intensive care unit (ICU) survivors

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: Our main objective is to assess the effectiveness of follow-up services for ICU survivors that aim to identify and address unmet health needs related to the ICU period. We aim to assess the effectiveness in relation to health-related quality of life, mortality, depression and anxiety, post-traumatic stress disorder, physical function, cognitive function, ability to return to work or education and adverse events. Our secondary objectives are, in general, to examine both the various ways that follow-up services are provided and any major influencing factors. Specifically, we aim to explore: the effectiveness of service organisation (physician versus nurse led, face to face versus remote, timing of follow-up service); possible differences in services related to country (developed versus developing country); and whether participants had delirium within the ICU setting

The SDSS-2MASS-WISE Ten Dimensional Stellar Color Locus

We present the fiducial main sequence stellar locus traced by 10 photometric colors observed by SDSS, 2MASS, and WISE. Median colors are determined using 1,052,793 stars with r-band extinction less than 0.125. We use this locus to measure the dust extinction curve relative to the r-band, which is consistent with previous measurements in the SDSS and 2MASS bands. The WISE band extinction coefficients are larger than predicted by standard extinction models. Using 13 lines of sight, we find variations in the extinction curve in H, Ks, and WISE bandpasses. Relative extinction decreases towards Galactic anti-center, in agreement with prior studies. Relative extinction increases with Galactic latitude, in contrast to previous observations. This indicates a universal mid-IR extinction law does not exist due to variations in dust grain size and chemistry with Galactocentric position. A preliminary search for outliers due to warm circumstellar dust is also presented, using stars with high signal-to-noise in the W3-band. We find 199 such outliers, identified by excess emission in Ks-W3. Inspection of SDSS images for these outliers reveals a large number of contaminants due to nearby galaxies. Six sources appear to be genuine dust candidates, yielding a fraction of systems with infrared excess of 0.12$\pm$0.05%.Comment: 11 pages, 10 figures, MNRAS Accepted. Tables 1 and 2 available online: https://github.com/jradavenport/wise_locu

Water Oxidation by a Cytochrome P450: Mechanism and Function of the Reaction

P450cam (CYP101A1) is a bacterial monooxygenase that is known to catalyze the oxidation of camphor, the first committed step in camphor degradation, with simultaneous reduction of oxygen (O2). We report that P450cam catalysis is controlled by oxygen levels: at high O2 concentration, P450cam catalyzes the known oxidation reaction, whereas at low O2 concentration the enzyme catalyzes the reduction of camphor to borneol. We confirmed, using 17O and 2H NMR, that the hydrogen atom added to camphor comes from water, which is oxidized to hydrogen peroxide (H2O2). This is the first time a cytochrome P450 has been observed to catalyze oxidation of water to H2O2, a difficult reaction to catalyze due to its high barrier. The reduction of camphor and simultaneous oxidation of water are likely catalyzed by the iron-oxo intermediate of P450cam, and we present a plausible mechanism that accounts for the 1:1 borneol:H2O2 stoichiometry we observed. This reaction has an adaptive value to bacteria that express this camphor catabolism pathway, which requires O2, for two reasons: 1) the borneol and H2O2 mixture generated is toxic to other bacteria and 2) borneol down-regulates the expression of P450cam and its electron transfer partners. Since the reaction described here only occurs under low O2 conditions, the down-regulation only occurs when O2 is scarce

Toward a new Homestead Act: Designing a farmstead transfer and leasing program for high-value farming and farmstead preservation

Finding ways to make farming more accessible for would-be farmers involves working with existing landowners and potential tenants/buyers to educate both groups on the possibilities open to them. Surveys, focus groups and personal interviews were used to determine what tactics would be more effective in engaging both groups

Excitation functions for (p,x) reactions of niobium in the energy range of Ep_{\text{p}} = 40-90 MeV

A stack of thin Nb foils was irradiated with the 100 MeV proton beam at Los Alamos National Laboratory's Isotope Production Facility, to investigate the $^{93}$Nb(p,4n)$^{90}$Mo nuclear reaction as a monitor for intermediate energy proton experiments and to benchmark state-of-the-art reaction model codes. A set of 38 measured cross sections for $^{\text{nat}}$Nb(p,x) and $^{\text{nat}}$Cu(p,x) reactions between 40-90 MeV, as well as 5 independent measurements of isomer branching ratios, are reported. These are useful in medical and basic science radionuclide productions at intermediate energies. The $^{\text{nat}}$Cu(p,x)$^{56}$Co, $^{\text{nat}}$Cu(p,x)$^{62}$Zn, and $^{\text{nat}}$Cu(p,x)$^{65}$Zn reactions were used to determine proton fluence, and all activities were quantified using HPGe spectrometry. Variance minimization techniques were employed to reduce systematic uncertainties in proton energy and fluence, improving the reliability of these measurements. The measured cross sections are shown to be in excellent agreement with literature values, and have been measured with improved precision compared with previous measurements. This work also reports the first measurement of the $^{\text{nat}}$Nb(p,x)$^{82\text{m}}$Rb reaction, and of the independent cross sections for $^{\text{nat}}$Cu(p,x)$^{52\text{g}}$Mn and $^{\text{nat}}$Nb(p,x)$^{85\text{g}}$Y in the 40-90 MeV region. The effects of $^{\text{nat}}$Si(p,x)$^{22,24}$Na contamination, arising from silicone adhesive in the Kapton tape used to encapsulate the aluminum monitor foils, is also discussed as a cautionary note to future stacked-target cross section measurements. \emph{A priori} predictions of the reaction modeling codes CoH, EMPIRE, and TALYS are compared with experimentally measured values and used to explore the differences between codes for the $^{\text{nat}}$Nb(p,x) and $^{\text{nat}}$Cu(p,x) reactions.Comment: 34 pages, submitted to NIM-