Proprotein convertases in high-density lipoprotein metabolism

The proprotein convertase subtilisin/kexins (PCSKs) are a serine endopeptidase family. PCSK members cleave amino acid residues and modulate the activity of precursor proteins. Evidence from patients and animal models carrying genetic alterations in PCSK members show that PCSK members are involved in various metabolic processes. These studies further revealed the molecular mechanism by which genetic alteration of some PCSK members impairs normal molecular and physiological functions, which in turn lead to cardiovascular disease. High-density lipoprotein (HDL) is anti-atherogenic as it removes excessive amount of cholesterol from blood and peripheral tissues. Several PCSK members are involved in HDL metabolism. PCSK3, PCSK5, and PCSK6 process two triglyceride lipase family members, endothelial lipase and lipoprotein lipase, which are important for HDL remodeling. Recent studies in our lab found evidence that PCSK1 and PCSK9 are also involved in HDL metabolism. A mouse model carrying an amino acid substitution in PCSK1 showed an increase in serum apolipoprotein A1 (APOA1) level. Another mouse model lacking PCSK9 showed a decrease in APOE-containing HDL. In this review, we summarize the role of the five PCSK members in lipid, glucose, and bile acid (BA) metabolism, each of which can influence HDL metabolism. We propose an integrative model in which PCSK members regulate HDL metabolism through various molecular mechanisms and metabolic processes and genetic variation in some PCSK members may affect the efficiency of reverse cholesterol transport. PCSK members are considered as attractive therapeutic targets. A greater understanding of the molecular and physiological functions of PCSK members will improve therapeutic strategies and drug efficacy for cardiovascular disease where PCSK members play critical role, with fewer adverse effects

Effect of Ag nanoparticle concentration on the electrical and ferroelectric properties of Ag/P(VDF-TrFE) composite films

We investigated the effect of the Ag nanoparticles on the ferroelectric and piezoelectric properties of Ag/poly(vinylidenefluoride-trifluoroethylene) (P(VDF-TrFE)) composite films. We found that the remanent polarization and direct piezoelectric coefficient increased up to 12.14 μC/cm^2 and 20.23 pC/N when the Ag concentration increased up to 0.005 volume percent (v%) and decreased down to 9.38 μC/cm^2 and 13.45 pC/N when it increased up to 0.01 v%. Further increase in Ag concentration resulted in precipitation of Ag phase and significant leakage current that hindered any meaningful measurement of the ferroelectric and piezoelectric properties. 46% increase of the remanent polarization value and 27% increase of the direct piezoelectric coefficient were observed in the film with the 0.005 v% of the Ag nanoparticles added without significant changes to the crystalline structure confirmed by both X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) experiments. These enhancements of both the ferroelectric and piezoelectric properties are attributed to the increase in the effective electric field induced by the reduction in the effective volume of P(VDF-TrFE) that results in more aligned dipoles

Inter- and Intra-Annual Variability of Vegetation in the Northern Hemisphere and Its Association with Precursory Meteorological Factors

Determination of phenological variation is one of the most critical challenges in dynamic vegetation modeling, given the lack of a strong theoretical framework. Previous studies generally focused on the timing of a phenological event (e.g., bud-burst or onset of growing season) and its atmospheric prompts, but not on the interactive variations across phenological stages. This study, therefore, investigated the inter- and intra-annual variability existing in all the phenological stages and the relations of the variability with four meteorological variables (surface temperature (Ts), shortwave radiation (SW ), vapor pressure deficit (VPD), and precipitation (PRCP)) using a 25-year (1982-2006) dataset of leaf area index (LAI) from the Advanced Very High Resolution Radiometer (AVHRR). Our six study sites of each 4 degree x 4 degree grids (mixed forest in China, deciduous needle-leaf forest in Siberia, evergreen needle-leaf forest in western Canada, grass in Gobi, and crops in the Central United States and southeastern Europe) include various vegetation types, local climates, and land-use types in the mid-latitudes of the northern hemisphere. Empirical orthogonal function (EOF) analysis with detrended LAI anomalies identified the two leading EOF modes that account for the amplitude and phase of the monthly LAI variations. The inter-annual correlation between the principle components (PCs) of the two modes and the meteorological variables for spring and summer showed that the amplitude and phase modes (AM and PM, respectively) were affected by different dominant meteorological factors. Over most of the study regions, AM was positively correlated with PRCP and negatively with Ts, SW, and VPD,while PMwas predominantly positively correlated with Ts. The contrasting responses of the two EOFmodes to Ts reflect environmental limitations on plant growth such as early start of growth, but with a reduced value of maximum LAI in a year with a warm spring. In addition, insignificant correlations between AMand PRCP, as well as negative correlations between PM and PRCP, in the crop regions suggest that human interventions such as advanced irrigation systems also play a key role in vegetative activity

Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9.

Background Studies in animals showed that PCSK9 is involved in HDL metabolism. We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and also whether Pcsk9 inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume. Methods Mass spectrometry and western blot were used to analyze the level of apolipoprotein E (APOE) and A1 (APOA1). A mouse model overexpressing human LDLR was used to test the effect of high levels of liver LDLR on the concentration of HDL cholesterol and APOE-containing HDL subfractions. Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation. We also investigated the effects of Pcsk9 inactivation on cholesterol efflux capacity of serum using THP-1 and J774.A1 macrophage foam cells and atherosclerotic fatty streak volume in the aortic sinus of Pcsk9 knockout males fed an atherogenic diet. Results APOE and APOA1 were reduced in the same HDL subfractions of Pcsk9 knockout and human LDLR transgenic male mice. In Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls. In Pcsk9/Apoe double-knockout mice, HDL cholesterol concentration was similar to that of Apoe knockout males. In Pcsk9 knockout males, THP-1 macrophage cholesterol efflux capacity of serum was reduced and the fatty streak lesion volume was similar to wild-type controls. Conclusions In mice, LDLR and APOE are important factors for PCSK9-mediated HDL regulation. Our data suggest that, although LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential. Pcsk9 inactivation decreases the HDL cholesterol concentration and cholesterol efflux capacity in serum, but does not increase atherosclerotic fatty streak volume.This work was supported by HL081162, HL077796 and HL095668 from the National Heart, Lung and Blood Institute and by the Canadian Institutes of Health Research grants 82946 and 102741. The Proteomics Core Facility is supported by the Vermont Genetics Network through NIH grant 8P20GM103449 from the INBRE program of the National Institute of General Medical Sciences (NIGMS) and the National Center for Research Resources (NCRR). BRP thanks the NIH (CA83831) for financial support. AP was supported by the Canadian Institutes of Health Research grants 82946 and 102741

Correlation between Short-Form 36 Scores and Neck Disability Index in Patients Undergoing Anterior Cervical Discectomy and Fusion

Study Design Case control study. Purpose To determine how the Neck Disability Index (NDI), a cervical spine-specific outcome, reflects health-related quality-of-life, and if NDI is correlated to the 36-item Short-Form Health Survey (SF-36) scores. Overview of Literature NDI is a useful tool for assessing health-related quality of life in patients with neck pain. Methods We used the Pearson product-moment correlation coefficient to assess the validity of all items under NDI and SF-36, and the Pearson’s correlation coefficient to assess the correlation between NDI and total SF-36 scores. The primary outcome measures were spine-specific health status- and general health status-measures after spine surgery, and these were evaluated every year for 2 years, using both NDI and SF-36 scores. Results NDI had a strong linear correlation with SF-36 and its two scales, the Physical Component Score (PCS) and the Mental Component Score (MCS), attesting to the validity of these two instruments. Among the eight subscales of SF-36, there was a strong linear correlation between NDI and PCS-physical functioning, PCS-bodily pain, and MCS-role emotional. Further, a moderate linear correlation was observed between NDI and subscales of PCS-role physical, PCS-general health, and MCS-social functioning, and between NDI and MCS-vitality and MCS-mental health. Conclusions Our findings suggest that the NDI adequately reflects the patient’s physical and mental quality of life, implying that the use of NDI to assess functional outcomes can also be ultimately used to evaluate the patient’s quality of life

Plug-in nanoliter pneumatic liquid dispenser with nozzle design flexibility

This paper presents a novel plug-in nanoliter liquid dispensing system with a plugand-play interface for simple and reversible, yet robust integration of the dispenser. A plug-in type dispenser was developed to facilitate assembly and disassembly with an actuating part through efficient modularization. The entire process for assembly and operation of the plug-in dispenser is performed via the plug-and-play interface in less than a minute without loss of dispensing quality. The minimum volume of droplets pneumatically dispensed using the plug-in dispenser was 124 nl with a coefficient of variation of 1.6%. The dispensed volume increased linearly with the nozzle size. Utilizing this linear relationship, two types of multinozzle dispensers consisting of six parallel channels (emerging from an inlet) and six nozzles were developed to demonstrate a novel strategy for volume gradient dispensing at a single operating condition. The droplet volume dispensed from each nozzle also increased linearly with nozzle size, demonstrating that nozzle size is a dominant factor on dispensed volume, even for multinozzle dispensing. Therefore, the proposed plug-in dispenser enables flexible design of nozzles and reversible integration to dispense droplets with different volumes, depending on the application. Furthermore, to demonstrate the practicality of the proposed dispensing system, we developed a pencil-type dispensing system as an alternative to a conventional pipette for rapid and reliable dispensing of minute volume droplets. (C) 2015 AIP Publishing LLC.open114sciescopu

Development and Testing of Thrombolytics in Stroke

Despite recent advances in recanalization therapy, mechanical thrombectomy will never be a treatment for every ischemic stroke because access to mechanical thrombectomy is still limited in many countries. Moreover, many ischemic strokes are caused by occlusion of cerebral arteries that cannot be reached by intra-arterial catheters. Reperfusion using thrombolytic agents will therefore remain an important therapy for hyperacute ischemic stroke. However, thrombolytic drugs have shown limited efficacy and notable hemorrhagic complication rates, leaving room for improvement. A comprehensive understanding of basic and clinical research pipelines as well as the current status of thrombolytic therapy will help facilitate the development of new thrombolytics. Compared with alteplase, an ideal thrombolytic agent is expected to provide faster reperfusion in more patients; prevent re-occlusions; have higher fibrin specificity for selective activation of clot-bound plasminogen to decrease bleeding complications; be retained in the blood for a longer time to minimize dosage and allow administration as a single bolus; be more resistant to inhibitors; and be less antigenic for repetitive usage. Here, we review the currently available thrombolytics, strategies for the development of new clot-dissolving substances, and the assessment of thrombolytic efficacies in vitro and in vivo