Cholesterol promotes interaction of the protein CLIC1 with phospholipid monolayers at the air–water interface

© 2016 by the authors; licensee MDPI, Basel, Switzerland. CLIC1 is a Chloride Intracellular Ion Channel protein that exists either in a soluble state in the cytoplasm or as a membrane bound protein. Members of the CLIC family are largely soluble proteins that possess the intriguing property of spontaneous insertion into phospholipid bilayers to form integral membrane ion channels. The regulatory role of cholesterol in the ion‐channel activity of CLIC1 in tethered lipid bilayers was previously assessed using impedance spectroscopy. Here we extend this investigation by evaluating the influence of cholesterol on the spontaneous membrane insertion of CLIC1 into Langmuir film monolayers prepared using 1‐palmitoyl‐2‐oleoylphosphatidylcholine, 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phospho‐ethanolamine and 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phospho‐L‐serine alone or in combination with cholesterol. The spontaneous membrane insertion of CLIC1 was shown to be dependent on the presence of cholesterol in the membrane. Furthermore, pre‐incubation of CLIC1 with cholesterol prior to its addition to the Langmuir film, showed no membrane insertion even in monolayers containing cholesterol, suggesting the formation of a CLIC1‐cholesterol pre‐complex. Our results therefore suggest that CLIC1 membrane interaction involves CLIC1 binding to cholesterol located in the membrane for its initial docking followed by insertion. Subsequent structural rearrangements of the protein would likely also be required along with oligomerisation to form functional ion channels

Thermorespiratory Response of West African Dwarf Does to Progestagen Injection

The physiological responses in terms of respiration rate (RR) and rectal temperature (RT) of 30 West African Dwarf (WAD) does were monitored after a single im injection of different doses of progestagens meant for synchronising oestrus. The treatments involved im injection of 1) 2 ml of sterile water (Control); 2) 25 mg Medroxy Progesterone Acetate, MPA; 3) 50 mg MPA; 4) 50 mg Progesterone and 5) 100 mg progesterone. The RR and RT of each animal were measured at 9:00, 13:00 and 17:00 h for 21 days after each injection. In all the treatment groups the RT did not change significantly (P> 0.05) during the weeks following treatment. On the contrary the RR was significantly higher (P< 0.05) in the week after injection than in the pre-injection period. Both the RR and the RT were higher at 13:00 h and 17:00 h than at 9:00 h. The RR was more influenced by the animal body size than the RT, while the ambient temperature and humidity affected both the animal's RT and RR. These results indicate that the thermorespiratory function of WAD does under their native humid environment is not negatively affected by injecting ≤ 100 mg progesterone or ≤ 50 mg MPA to synchronize oestrus

SCANNING SPEED INFLUENCE ON THE PHYSICAL PROPERTIES OF LASER METAL DEPOSITION TITANIUM ALLOY

The most commonly used aerospace titanium alloy, Ti6Al4V, was deposited on Ti6Al4V plate of dimension 72 x 72 x5mm. The laser power of 3 kW, powder flow rate of 1.44 g/min and gas flow rate of 4 l/min were used throughout the deposition process. The transverse/ scanning speed was varied between 0.005 to 0.095 m/sec according to established result of the preliminary study that produces full dense and pore free deposits. The mass of the deposited powder was obtained by weighing the substrate before the deposition and reweighing after the deposition. The substrate and the deposits were thoroughly cleaned using wire brush and acetone to remove unmelted powder particles from the surface of the substrate and the deposit. The height and width of the deposits were measured with Venier Caliper and the material efficiencies were determined using developed equations. The objective of this research is to determine the influence of the scanning speed on the material efficiency and deposit height in laser metal deposition of titanium alloy- Ti6Al4V. The results of this study showed that, for the set of processing parameter used in this study, the optimum scanning speed was at 0.015 m/sec with the optimum material utilization efficiency of 83.33% and the deposition height of 1.09 mm.  http://dx.doi.org/10.4314/njt.v36i1.1

Systematic Review and Meta-Analysis: Outcomes of Routine Specialist Mental Health Care for Young People With Depression and/or Anxiety

Objective: Depression and anxiety are the most prevalent mental health problems in youth, yet almost nothing is known about what outcomes are to be expected at the individual level following routine treatment. This paper sets out to address this gap by undertaking a systematic review of outcomes following treatment as usual (TAU) with a particular focus on individual-level outcomes. / Method: MEDLINE, Embase and PsycInfo were searched for articles published between 1980 and January 2019 that assessed TAU outcomes for youth depression and anxiety accessing specialist mental healthcare. Meta-analysis considered change at both group-level pre-post effect size (ES) and individual-level recovery, reliable change and reliable recovery. Temporal analysis considered stability of primary and secondary outcomes over time. Sub-group analysis considered the moderating effect of informant; presenting problem; study design; study year; mean age of youth; use of medication; intervention dosage and type of treatment offered on outcomes. A protocol was pre-registered on PROSPERO (CRD42017063914). / Results: Initial screening of 6,350 publications resulted in 38 which met the inclusion criteria, and which were subsequently included in meta-analyses. This resulted in a final full pooled sample of 11,739 young people (61% of which were female, mean age 13.8 years). The pre-post ES (Hedges’ g) at first/final outcome (13/ 26 weeks) was -0.74/- 0.87. The individual-level change on measures of self-report was 38% reliable improvement, 44% no reliable change and 6% reliable deterioration. Outcomes varied according to moderators, informant, problem type and dosage. / Conclusion: Poor data quantity and quality are limitations, but this is the first study that indicates likely rates of reliable improvement for those accessing TAU. We propose the need for improved reporting of both individual-level metrics and details of TAU to enable greater understanding of likely current outcomes from routine care for youth with depression and anxiety in order to allow the potential for further improvement of impact

What Treatment Outcomes Matter Most? A Q-study of Outcome Priority Profiles Among Youth with Lived Experience of Depression

Objective: Over the past years, interest in youth perspectives on what constitutes an important outcome in the treatment of depression has been growing, but limited attention has been given to heterogeneity in outcome priorities and minority viewpoints. These are important to consider for person-centered outcome tracking in clinical practice, or when conducting clinical trials targeting specific populations. This study used Q-methodology to identify outcome priority profiles among youth with lived experience of service use for depression. / Method: A purposive sample of 28 youth (aged 16–21 years) rank-ordered 35 outcomes by importance and completed brief semi-structured interviews eliciting their sorting rationales. By-person principal component analysis was used to identify outcome priority profiles based on all Q-sort configurations. Priority profiles were described and interpreted with reference to the qualitative interview data. / Results: Four distinct outcome priority profiles were identified: “symptom reduction and enhanced well-being”; “improved coping and self-management”; “better understanding past and present”; and “less interference with daily life”. All four profiles prioritized outcomes related to improved mood and affect over other outcome concepts. Beyond these core outcomes, profiles differed in the level of importance assigned to learning practical coping skills, processing experiences, finding safe ways to articulate emotions, and reduced interference of depression with life and identity. / Conclusion: As part of a person-centered approach to care delivery, care providers should routinely engage young people in conversation and shared decision-making about the types of change they would like to prioritize and track during treatment, beyond a common core of consensus outcomes

Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.

Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in betaAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of betaARK1 or the beta2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP-/- and MLP-/-/beta2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/betaARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/betaARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the betaARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal betaAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit betaARK1 as a novel mode of therapy

Reduction of circulating cholesterol and apolipoprotein levels during sepsis

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed

Design Principles for Plasmonic Nanoparticle Devices

For all applications of plasmonics to technology it is required to tailor the resonance to the optical system in question. This chapter gives an understanding of the design considerations for nanoparticles needed to tune the resonance. First the basic concepts of plasmonics are reviewed with a focus on the physics of nanoparticles. An introduction to the finite element method is given with emphasis on the suitability of the method to nanoplasmonic device simulation. The effects of nanoparticle shape on the spectral position and lineshape of the plasmonic resonance are discussed including retardation and surface curvature effects. The most technologically important plasmonic materials are assessed for device applicability and the importance of substrates in light scattering is explained. Finally the application of plasmonic nanoparticles to photovoltaic devices is discussed.Comment: 29 pages, 15 figures, part of an edited book: "Linear and Non-Linear Nanoplasmonics

Low Blood Lead Levels Do Not Appear to Be Further Reduced by Dietary Supplements

OBJECTIVE: Our objective was to evaluate the association of dietary intakes of selected micronutrients and blood lead (PbB) concentrations in female adults and in children. DESIGN: With longitudinal monitoring, we measured daily intakes of the micronutrients calcium, magnesium, sodium, potassium, barium, strontium, phosphorus, zinc, iron (limited data), and copper from 6-day duplicate diets (2–13 collections per individual) and PbB concentrations. Participants were three groups of females of child-bearing age (one cohort consisting of 21 pregnant subjects and 15 nonpregnant controls, a second cohort of nine pregnant migrants), and one group of 10 children 6–11 years of age. RESULTS: Mean PbB concentrations were < 5 μg/dL. A mixed linear model that included only group and time accounted for 5.9% of the variance of the PbB measurements; neither the effect of time nor the effect of group was significant. The model containing all of the micronutrients (except iron, for which there was a great deal of missing data), along with time and group, accounted for approximately 9.2% of the variance of PbB; this increase was not statistically significant. There was, however, a significant association of PbB with phosphorus, magnesium, and copper when all micronutrients were included in the statistical analysis, perhaps reflecting a synergistic effect. CONCLUSIONS: In contrast to most previous studies, we found no statistically significant relationships between the PbB concentrations and micronutrient intake. In adults and older children with low PbB concentrations and minimal exposure to Pb, micronutrient supplementation is probably unnecessary

An affective disorder in zebrafish with mutation of the glucocorticoid receptor

Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how glucocorticoid signaling is linked to affective disorders. We identified an adult-viable zebrafish mutant in which the negative feedback on the stress response is disrupted, due to abolition of all transcriptional activity of GR. As a consequence, cortisol is elevated, but unable to signal through GR. When placed into an unfamiliar aquarium ('novel tank'), mutant fish become immobile ('freeze'), show reduced exploratory behavior and do not habituate to this stressor upon repeated exposure. Addition of the antidepressant fluoxetine to the holding water and social interactions restore normal behavior, followed by a delayed correction of cortisol levels. Fluoxetine does not affect the overall transcription of CRH, the mineralocorticoid receptor (MR), the serotonin transporter (Serta) or GR itself. Fluoxetine, however, suppresses the stress-induced upregulation of MR and Serta in both wild-type fish and mutants. Our studies show a conserved, protective function of glucocorticoid signaling in the regulation of emotional behavior and reveal novel molecular aspects of how chronic stress impacts vertebrate brain physiology and behavior. Importantly, the zebrafish model opens up the possibility of high-throughput drug screens in search of new classes of antidepressants