A New Concept to Reveal Protein Dynamics Based on Energy Dissipation

Protein dynamics is essential for its function, especially for intramolecular signal transduction. In this work we propose a new concept, energy dissipation model, to systematically reveal protein dynamics upon effector binding and energy perturbation. The concept is applied to better understand the intramolecular signal transduction during allostery of enzymes. The E. coli allosteric enzyme, aspartokinase III, is used as a model system and special molecular dynamics simulations are designed and carried out. Computational results indicate that the number of residues affected by external energy perturbation (i.e. caused by a ligand binding) during the energy dissipation process shows a sigmoid pattern. Using the two-state Boltzmann equation, we define two parameters, the half response time and the dissipation rate constant, which can be used to well characterize the energy dissipation process. For the allostery of aspartokinase III, the residue response time indicates that besides the ACT2 signal transduction pathway, there is another pathway between the regulatory site and the catalytic site, which is suggested to be the β15-αK loop of ACT1. We further introduce the term “protein dynamical modules” based on the residue response time. Different from the protein structural modules which merely provide information about the structural stability of proteins, protein dynamical modules could reveal protein characteristics from the perspective of dynamics. Finally, the energy dissipation model is applied to investigate E. coli aspartokinase III mutations to better understand the desensitization of product feedback inhibition via allostery. In conclusion, the new concept proposed in this paper gives a novel holistic view of protein dynamics, a key question in biology with high impacts for both biotechnology and biomedicine

Differences in tissue distribution ability of evodiamine and dehydroevodiamine are due to the dihedral angle of the molecule stereo-structure

Introduction: This researcher focused at the evodiamine and dehydroevodiamine tissue distribution and structure-pharmacokinetics (PK) relationship after intravenous injection in mice.Methods: Using a transmembrane transport experiment, the permeability of evodiamine and dehydroevodiamine on Caco-2 cells was evaluated. The tissue distribution and pharmacokinetics (PK) of evodiamine and dehydroevodiamine in mice were studied. To comprehend the connection between structure and tissue distribution, physicochemical property evaluations and molecular electrostatic potential (MEP) calculations were performed.Results: Dehydroevodiamine’s Papp values in vitro were 10−5 cm/s, whereas evodiamine’s were 10−6 cm/s. At a dose of 5 mg/kg, the brain concentration of dehydroevodiamine was 6.44 times more than that of evodiamine. By MEP or physicochemical measures, the permeability difference between evodiamine and dehydroevodiamine is unaffected. The dihedral angle of the stereo-structure appears to be the main cause of the difference in tissue distribution ability between evodiamine and dehydroevodiamine.Discussion: Dehydroevodiamine has a dihedral angle of 3.71° compared to 82.34° for evodiamine. Dehydroevodiamine can more easily pass through the phospholipid bilayer than evodiamine because it has a more planar stereo-structure. Dehydroevodiamine is therefore more likely to pass cross the blood-brain barrier and enter the brain in a tissue-specific manner

Forgotten joint score associated with prosthesis weight in cementless total hip arthroplasty: a prospective clinical study

BackgroundThis prospective study aimed to investigate the influence of weight difference between implanted prosthesis and removed bone in cementless total hip arthroplasty (THA) on hip awareness and patient-reported outcomes.MethodsA total of 48 patients (56 hips) who underwent primary THA were prospectively enrolled. Implanted prosthesis and removed bone were weighed intraoperatively. Forgotten Joint Score (FJS) and Western Ontario and McMaster Universities (WOMAC) scores were obtained before and at 1 and 3 months after surgery. Patients were divided into groups A, B, and C according to the percentile of the weight difference.ResultsThe mean weight difference of the implanted prosthesis and removed bone was 117.97 ± 47.35 g. A negative correlation was found among the weight differences of the three groups and 1- and 3-month postoperative FJS (correlation coefficients, −0.331 and −0.734, respectively). A positive correlation was found among the weight difference of the three groups and 3-month postoperative WOMAC (correlation coefficient, 0.403). A significant difference in 3-month postoperative FJS and WOMAC scores was found among the three groups. The mean 3-month postoperative FJS (79.00) of group C was significantly lower than that of group A (93.32) (P < 0.05). The mean WOMAC score (15.83) of group A was significantly lower than that of group C (23.67) (P < 0.05).ConclusionThe implanted prosthesis is larger than the removed bone in cementless THA. The weight difference is negatively correlated with hip function. The weight difference should be minimized to achieve optimal hip joint awareness

MiR-455 targeting SOCS3 improve liver lipid disorders in diabetic mice

MiR-455 has been verified a key regulator of brown adipose tissue and adipose tissue-specific overexpression of miR-455 (ap2-miR-455) mice could combat high-fat-diet-induced obesity. This study is to verify overexpression of miR-455 could ameliorate the lipid accumulation and metabolism in the liver of db/db diabetic mice and explore the potential mechanisms. Diabetic mice (db/db) and control mice (db/m) were randomly divided into four groups. After overexpression of miR-455 in the liver of db/db mice, the triglycerides level in both serum and liver decreased, the lipid deposit in liver was improved, the expression of fatty acid synthase, stearoyl-CoA desaturase 1, sterol regulatory element binding protein 1c (SREBP-1c) and acetyl-CoA carboxylase (ACCα) was also significantly down-regulated. TargetScan indicated that suppressor of cytokine signalling 3 (SOCS3) is predicated to target miR-455 and the protein of SOCS3 in the liver of db/db mice after intervention was significantly decreased. The dual luciferase reporter assay showed that SOCS3 was target gene of miR-455. In vitro, in Palmitate (PA)-stimulated human normal liver (LO2) cells, transfected miR-455 mimic could significantly inhibit the expression of SOCS3, while transfected miR-455 inhibitor could up-regulate the expression of SOCS3. Transfecting LO2 cells with siRNA of SOCS3 could significantly down-regulate the protein expression of SREBP-1c and ACCα. Our study showed that overexpression of miR-455 in the liver could improve lipid metabolism in diabetic mice by down-regulating its target gene SOCS3

Insight into Proton Transfer in Phosphotungstic Acid Functionalized Mesoporous Silica-Based Proton Exchange Membrane Fuel Cells

We have developed for fuel cells a novel proton exchange membrane (PEM) using inorganic phosphotungstic acid (HPW) as proton carrier and mesoporous silica as matrix (HPW-meso-silica) . The proton conductivity measured by electrochemical impedance spectroscopy is 0.11 S cm^(–1) at 90 °C and 100% relative humidity (RH) with a low activation energy of 14 kJ mol^(–1). In order to determine the energetics associated with proton migration within the HPW-meso-silica PEM and to determine the mechanism of proton hopping, we report density functional theory (DFT) calculations using the generalized gradient approximation (GGA). These DFT calculations revealed that the proton transfer process involves both intramolecular and intermolecular proton transfer pathways. When the adjacent HPWs are close (less than 17.0 Å apart), the calculated activation energy for intramolecular proton transfer within a HPW molecule is higher (29.1–18.8 kJ/mol) than the barrier for intermolecular proton transfer along the hydrogen bond. We find that the overall barrier for proton movement within the HPW-meso-silica membranes is determined by the intramolecular proton transfer pathway, which explains why the proton conductivity remains unchanged when the weight percentage of HPW on meso-silica is above 67 wt %. In contrast, the activation energy of proton transfer on a clean SiO_2 (111) surface is computed to be as high as 40 kJ mol^(–1), confirming the very low proton conductivity on clean silica surfaces observed experimentally

ANTIOXIDANT AND SGC-7901 CELL INHIBITION ACTIVITIES OF RHIZOMA DIOSCOREAE BULBIFERAE. ETHANOL EXTRACTS

The objective of this research was to study the pharmacology of Dioscorea bulbifera L. on antioxidant and anticancer activity. Alcohol extracts of Dioscorea bulbifera L. were made out by different concentration alcohol; they were tested by Hydroxyl radical scavenging test, reducing capacity test and total antioxidant capacity test. In the anticancer test, MTT test was used to study the inhibition rate. The results told that 70% ethanol extracts could scavenge most DPPH• at 2mg/ml. The rate was 55.2%; 80% ethanol extract could clear the most •OH. The clearance rate was 51.2%. 80% ethanol crude extracts possessed the strongest reducing ability per gram of the extract equal to 49.3μmol Fe2 +. Different concentrations of the extracts could inhibit the proliferation of line SGC-7901, and with the concentration increased, the inhibition rate was gradually increased

Ice-nucleating particles from multiple aerosol sources in the urban environment of Beijing under mixed-phase cloud conditions

Ice crystals occurring in mixed-phase clouds play a vital role in global precipitation and energy balance because of the unstable equilibrium between coexistent liquid droplets and ice crystals, which affects cloud lifetime and radiative properties, as well as precipitation formation. Satellite observations proved that immersion freezing, i.e., ice formation on particles immersed within aqueous droplets, is the dominant ice nucleation (IN) pathway in mixed-phase clouds. However, the impact of anthropogenic emissions on atmospheric IN in the urban environment remains ambiguous. In this study, we present in situ observations of ambient ice-nucleating particle number concentration (NINP) measured at mixed-phase cloud conditions (−30 ∘C, relative humidity with respect to liquid water RHw= 104 %) and the physicochemical properties of ambient aerosol, including chemical composition and size distribution, at an urban site in Beijing during the traditional Chinese Spring Festival. The impact of multiple aerosol sources such as firework emissions, local traffic emissions, mineral dust, and urban secondary aerosols on NINP is investigated. The results show that NINP during the dust event reaches up to 160 # L−1 (where “#” represents number of particles), with an activation fraction (AF) of 0.0036 % ± 0.0011 %. During the rest of the observation, NINP is on the order of 10−1 to 10 # L−1, with an average AF between 0.0001 % and 0.0002 %. No obvious dependence of NINP on the number concentration of particles larger than 500 nm (N500) or black carbon (BC) mass concentration (mBC) is found throughout the field observation. The results indicate a substantial NINP increase during the dust event, although the observation took place at an urban site with high background aerosol concentration. Meanwhile, the presence of atmospheric BC from firework and traffic emissions, along with urban aerosols formed via secondary transformation during heavily polluted periods, does not influence the observed INP concentration. Our study corroborates previous laboratory and field findings that anthropogenic BC emission has a negligible effect on NINP and that NINP is unaffected by heavy pollution in the urban environment under mixed-phase cloud conditions.</p

VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancers

<p>Abstract</p> <p>Background</p> <p>VHZ is a VH1-like (member Z) dual specific protein phosphatase encoded by DUSP23 gene. Some of the dual specific protein phosphatases (DSPs) play an important role in cell cycle control and have shown to be associated with carcinogenesis. Here, the expression of VHZ associated with cell growth and human cancers was investigated.</p> <p>Results</p> <p>We generated a mouse monoclonal antibody (mAb clone#209) and rabbit polyclonal antibodies (rAb) against VHZ. We performed cell proliferation assay to learn how VHZ is associated with cell cycle by retroviral transduction to express VHZ, VHZ(C95S), and control vector in MCF-7 cells. Overexpression of VHZ [but not VHZ(C95S)] in MCF-7 cells promoted cell proliferation compared to control cells. shRNA-mediated knockdown of VHZ in MCF-7 cells showed that reduction of VHZ resulted in increased G1 but decreased S phase cell populations. Using indirect immunofluorescence, we showed that both exogenous and endogenous VHZ protein was localized at the centrosome in addition to its cytoplasmic distribution. Furthermore, using immunohistochemistry, we revealed that VHZ protein was overexpressed either in enlarged centrosomes (VHZ-centrosomal-stain) of some invasive ductal carcinomas (IDC) Stage I (8/65 cases) or in entire cytoplasm (VHZ-cytosol-stain) of invasive epithelia of some IDC Stage II/III (11/47 cases) of breast cancers examined. More importantly, upregulation of VHZ protein is also associated with numerous types of human cancer, in particular breast cancer. VHZ mAb may be useful as a reagent in clinical diagnosis for assessing VHZ positive tumors.</p> <p>Conclusions</p> <p>We generated a VHZ-specific mAb to reveal that VHZ has a novel subcellular localization, namely the centrosome. VHZ is able to facilitate G1/S cell cycle transition in a PTP activity-dependent manner. The upregulation of its protein levels in primary human cancers supports the clinical relevance of the protein in cancers.</p