(R)-[(R)-3-Benzyl-2-oxooxazolidin-4-yl][4-(methyl-sulfon-yl)phen-yl]methyl acetate.

The structure of the title compound, C20H21NO6S, is of inter-est with respect to its anti-bacterial properties. The oxazolidine ring makes dihedral angles of 79.63 (14) and 56.16 (12)° with the phenyl and benzene rings, respectively, while the phenyl and benzene rings make a dihedral angle of 64.37 (13)°. In the crystal, non-classical C-H⋯O hydrogen bonds link adjacent mol-ecules along the c axis.

The Incidences and Related CT Features of Vascular Lake Phenomenon on Angiography Before Chemoembolization.

PURPOSE: To elucidate incidence rates of vascular lake phenomenon (VLP) in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatic metastasis (HMT) on transarterial angiography before chemoembolization, and to identity CT features predictive for it. MATERIALS AND METHODS: A comprehensive evaluation involved 665 subjects for incidence analysis, comprising 527 of HCC, 33 of ICC and 105 of HMT. VLP was characterized as intratumoral contrast material pool persisting late into venous phase. Incidences were cataloged on both super-selective and common hepatic artery angiography. For CT features analysis, a subset of 182 cases were analyzed. Enhancement ratio served as an index for comparative analysis of nodule enhancement degrees. RESULTS: In HCC, incidence of VLP ascertained via super-selective angiography was 13.5%, whereas it as 7.8% on common hepatic artery angiography. Remarkably, no incidences of VLP were recorded in either ICC or HMT cases. On pre-interventional CT, the prevalence of pseudocapsule was statistically greater in VLP group than Non-VLP group (66.6% vs. 37.6%, P = 0.015). The Houndsfield units (HU) of tumors in plain scan (P = 0.007), arterial phase (P = 0.001), venous phase (P = 0.041), arterial phase enhancement ratio (P < 0.001) were statistically higher in VLP group compared to Non-VLP group. Arterial phase enhancement ratio (P = 0.025), presence of pseudocapsule (P = 0.001), HU of tumor in plain scan (P = 0.035) serve as independent risk factors for VLP manifestation. CONCLUSION: VLP is a distinct angiography phenomenon uniquely associated with HCC. High arterial phase enhancement ratio, presence of pseudocapsule, high HU of tumor in plain scan are independent risk factors for VLP.

Role of Arg228 in the phosphorylation of galactokinase: the mechanism of GHMP kinases by quantum mechanics/molecular mechanics studies.

GHMP kinases are a group of structurally related small molecule kinases. They have been found in all kingdoms of life and are mostly responsible for catalyzing the ATP-dependent phosphorylation of intermediary metabolites. Although the GHMP kinases are of clinical, pharmaceutical, and biotechnological importance, the mechanism of GHMP kinases is controversial. A catalytic base mechanism was suggested for mevalonate kinase that has a structural feature of the γ-phosphate of ATP close to an aspartate residue; however, for one GHMP family member, homoserine kinase, where the residue acting as general base is absent, a direct phosphorylation mechanism was suggested. Furthermore, it was proposed by some authors that all the GHMP kinases function by a similar mechanism. This controversy in mechanism has limited our ability to exploit these enzymes as drug targets and in biotechnology. Here the phosphorylation reaction mechanism of the human galactokinase, a member of the GHMP kinase family, was investigated using molecular dynamics simulations and density functional theory-based quantum mechanics/molecular mechanics calculations (B3LYP-D/AMBER99). The reaction coordinates were localized by potential energy scan using an adiabatic mapping method. Our results indicate that a highly conserved Glu174 captures Arg105 in the proximity of the α-phosphate of ATP, forming a H-bond network; therefore, the mobility of ATP in the large oxyanion hole is restricted. Arg228 functions to stabilize the negative charge developed at the ß,γ-bridging oxygen of the ATP during bond cleavage. The reaction occurs via a direct phosphorylation mechanism, and the Asp186 in the proximity of ATP does not directly participate in the reaction pathway. Because Arg228 is not conserved among GHMP kinases, reagents which form interactions with Arg228, and therefore can interrupt its function in phosphorylation, may be developed into potential selective inhibitors for galactokinase.

[Curative effects on standardized management of community patients with coronary heart disease complicated with chronic heart failure].

OBJECTIVE: To explore the effects on the standardized management of patients with coronary atherosclerotic heart disease complicated with chronic heart failure. METHODS: A total of 823 patients discharged from our department were randomly enrolled. Among 734 patients with follow-up consents, they were divided into management and control groups (n = 440, 294). The management group received standardized out-of-hospital management, regular health education and follow-ups of telephone and outpatient visits. RESULTS: Compared with the control group, the management group had lower rates of all-cause mortality, cardiac death and readmission due to cardiovascular events (CVE) declining by 26.5%, 32.2% and 57.0% respectively. Over a 4-year period, the annular survival rate of management group was 92%, 85%, 83% and 82% while that of control group 95%, 89%, 82% and 75% respectively. Patient compliance of digoxin and diuretics in the control group was inferior to that in the management group. CONCLUSION: Through standardized out-of-hospital management, the patients with coronary atherosclerotic heart disease plus chronic heart failure may achieve significant benefits through reducing the rates of all-cause mortality, cardiac death and readmission due to CVE and improving survival rate.

Gas-to-ionic liquid partition: QSPR modeling and mechanistic interpretation.

The present work was devoted to explore the quantitative structure-property relationships for gas-to-ionic liquid partition coefficients (log KILA ). A series of linear models were first established for the representative dataset (IL01). The optimal model was a four-parameter equation (1Ed) consisting of two electrostatic potential-based descriptors ( Σ V s , i n d - ${{\rm { \Sigma }}{V}_{s,ind}^{-}}$ and Vs,max ), one 2D matrix-based descriptor (J_D/Dt) and dipole moment (µ). All of the four descriptors introduced in the model can find the corresponding parameters, directly or indirectly, from Abraham's linear solvation energy relationship (LSER) or its theoretical alternatives, which endows the model good interpretability. Gaussian process was utilized to build the nonlinear model. Systematical validations, including 5-fold cross-validation for the training set, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. Applicability domain of the model was evaluated, and the Williams plot revealed that the model can be used to predict the log KILA values of structurally diverse solutes. The other 13 datasets were also processed in the same way, and all of the linear models with expressions similar to equation 1Ed were obtained. These models, whether linear of nonlinear, represent satisfactory statistical results, which confirms the universality of the method adopted in this study in QSPR modeling of gas-to-IL partition.

Effect of double mutations K214/A-E215/Q of FRATide on GSK3ß: insights from molecular dynamics simulation and normal mode analysis.

Glycogen synthase kinase 3ß (GSK3ß) is a multifunctional serine/threonine protein kinase that is involved in several biological processes including insulin and Wnt signaling pathways. The Wnt signaling via FRAT-mediated displacement of axin inhibits GSK3ß activity toward non-primed substrates without affecting its activity toward primed substrates. Herein, molecular dynamics simulation, molecular mechanics generalized Born/surface area (MM_GBSA) calculation, and normal mode analysis are performed to explore the structural influence of the double mutations K214/A-E215/Q of FRATide on the GSK3ß-FRATide complex. The results reveal that the priming phosphate-binding site, the primed substrate-binding site, the alignment of the critical active site residues in the ATP-binding site, as well as the periodic open-closed conformational change of the ATP-binding site, which are critical for the catalytic activity of GSK3ß, are negligibly influenced in the mutated system compared with the wild-type (WT) system. This indicates that FRATide does not inhibit the GSK3ß activity toward primed substrates. Additionally, MM_GBSA calculation indicates that the less energy-favorable GSK3ß-FRATide complex is observed in the mutant than in the WT complex.

A quantitative structure-property relationship analysis of soot-water partition coefficients for persistent organic pollutants.

Geometrical optimization and electrostatic potential calculations have been performed at the HF/6-31G level of theory for investigated persistent organic pollutants (POPs). A number of statistically based parameters have been obtained. Relationship between soot-water partition coefficients (logK(SC)) of POPs and the structural descriptors has been established by the multiple linear regression method. The result shows that the quantities derived from electrostatic potential V(s)(-)¯ and V(s,max), together with molecular surface area (A(S)) and the energy of the highest occupied molecular orbital (E(HOMO)) can be well used to express the quantitative relationship between structure and logK(SC) (QSPR) of POPs. Predictive capability of the model has been demonstrated by leave-one-out cross-validation with the cross-validated correlation coefficient of 0.9797. Furthermore, the predictive power of this model was further examined for the external test set with the correlation coefficient of 0.9811 between observed and predicted logK(SC), validating the robustness and good predictive ability of our model. Furthermore, in order to further investigate the applicability of these parameters derived from electrostatic potential in prediction of soot-water partition coefficient for organic pollutants, eleven polycyclic aromatic hydrocarbons (PAHs), eleven polychlorinated biphenyls (PCBs) and nine phenyl urea herbicides (PUHs) from other source have also been studied. The QSPR models established may provide a new powerful method for predicting soot-water partition coefficients (logK(SC)) of organic pollutants.

QSPR study on Hydrophobicity of Pt(II) complexes with surface electrostatic potential-based descriptors.

Pt(II) complexes play an important role in bioinorganic chemistry due to their antitumor activities. In the present study, we focused on building predictive models for the hydrophobicity of Pt(II) complexes. A five-parameter model, integrating frontier orbital energies (EHOMO, ELUMO) and descriptors derived from electrostatic potentials on molecular surface, was firstly constructed by using multiple linear regression (MLR) method. Mechanistic interpretations of the introduced descriptors were elucidated in terms of intermolecular interactions in the n-octanol/water partition system. Then, four up-to-date modeling methods, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a very rigorous Monte Carlo cross-validation (MCCV) were performed to verify the reliability of the constructed models. The peak, median and integralRext2 values of the best GP model are 0.88, 0.86 and 0.84, respectively. The root mean squared errors for the test set (RMSEP) of the MLR, SVM, LSSVM and GP models fall in the range of 0.62-0.71. Although they are not superior to prior models built with the use of a number of descriptors, the results are satisfactory. Applicability domain of the model was evaluated.

Water-soluble bright NIR AIEgens with hybrid ROS for wash-free mitochondrial "off-on" imaging and photodynamic therapy.

Several aggregation-induced emission luminogens (AIEgens) with excellent water-solubility and near-infrared emission were designed and synthesized for wash-free "off-on" mitochondrial imaging and photodynamic therapy of HeLa cells. The AIEgen TEPP exhibits both bright near-infrared emission (φF = 17.8%) and high hybrid ROS productivity (including OH˙ and 1O2).

Molecularly engineered AIEgens with enhanced quantum and singlet-oxygen yield for mitochondria-targeted imaging and photodynamic therapy.

Luminogens characteristic of aggregation-induced emission (AIEgens) have been extensively exploited for the development of imaging-guided photodynamic therapeutic (PDT) agents. However, intramolecular rotation of donor-acceptor (D-A) type AIEgens favors non-radiative decay of photonic energy which results in unsatisfactory fluorescence quantum and singlet oxygen yields. To address this issue, we developed several molecularly engineered AIEgens with partially "locked" molecular structures enhancing both fluorescence emission and the production of triplet excitons. A triphenylphosphine group was introduced to form a D-A conjugate, improving water solubility and the capacity for mitochondrial localization of the resulting probes. Experimental and theoretical analyses suggest that the much higher quantum and singlet oxygen yield of a structurally "significantly-locked" probe (LOCK-2) than its "partially locked" (LOCK-1) and "unlocked" equivalent (LOCK-0) is a result of suppressed AIE and twisted intramolecular charge transfer. LOCK-2 was also used for the mitochondrial-targeting, fluorescence image-guided PDT of liver cancer cells.

Role of bridging water molecules in GSK3ß-inhibitor complexes: insights from QM/MM, MD, and molecular docking studies.

The role of water molecules is increasingly gaining interest in drug design, and several studies have highlighted their paramount contributions to the specificity and the affinity of ligand binding. In this study, we employ the two-layer ONIOM-based quantum mechanics/molecular mechanics (QM/MM) calculations, molecular dynamics (MD) simulations, and molecular docking studies to investigate the effect of bridging water molecules at the GSK3ß-inhibitors interfaces. The results obtained from the ONIOM geometry optimization and AIM analysis corroborated the presence of bridging water molecules that form hydrogen bonds with protein side chain of Thr138 and/or backbone of Gln185, and mediate interactions with inhibitors in the 10 selected GSK3ß-inhibitor complexes. Subsequently, MD simulations carried out on a representative system of 1R0E demonstrated that the bridging water molecule is stable at the GSK3ß-inhibitor interface and appears to contribute to the stability of the protein-inhibitor interactions. Furthermore, molecular docking studies of GSK3ß-inhibitor complexes indicated that the inhibitors can increase binding affinities and the better docked conformation of inhibitors can be obtained by inclusion of the bridging water molecules, especially for the flexible inhibitors, in docking experiments into individual protein conformations. Our results elucidate the importance of bridging water molecules at the GSK3ß-inhibitor interfaces and suggest that they might prove useful in rational drug design.

Percutaneous vertebroplasty as a treatment for painful osteoblastic metastatic spinal lesions.

Percutaneous vertebroplasty (PVP) has been used widely to treat pain caused by osteolytic spinal lesions, whereas vertebroplasty for osteoblastic spinal lesions is less known. The purpose of this study is to describe PVP as a highly effective miniinvasive procedure to treat painful osteoblastic metastatic spinal lesions. Four patients with painful osteoblastic metastatic spinal lesions were treated by PVP in the authors' department, and immediately relief of pain was achieved in all of them. The findings from this study may encourage more studies of PVP in palliative treatment of patients with osteoblastic lesions.

Molecular modeling and molecular dynamics simulation studies of the GSK3ß/ATP/substrate complex: understanding the unique P+4 primed phosphorylation specificity for GSK3ß substrates.

Substrate specificity of protein kinases is of fundamental importance for the integrity and fidelity of signaling pathways. Glycogen synthase kinase 3ß (GSK3ß) has a unique substrate specificity that prefers phosphorylation of its substrates at the P+4 serine before it can further phosphorylate the substrate at the P0 serine in the canonical motif SXXXS(p), where S(p) is the primed phosphorylation site. The detailed phosphorylation mechanism, however, is not clearly understood. In this study, a three-dimensional (3D) model of the ternary complex of GSK3ß, ATP, and the phosphorylated glycogen synthase (pGS), termed GSK3ß/ATP/pGS, is constructed using a hierarchical approach and by integrating molecular modeling and molecular dynamics (MD) simulations. Based on the 3D model, the substrate primed phosphorylation mechanism is investigated via two 12 ns comparative MD simulations of the GSK3ß/ATP/pGS and GSK3ß/ATP/GS systems, which differ in the phosphate group bound to the P+4 serine of GS. In agreement with structural analysis, computed binding free energies reveal that the binding of pGS to GSK3ß is favored in the prephosphorylated state compared with the GS native state. More importantly, comparison with the system simulated without primed phosphorylation in the GSK3ß/ATP/GS complex shows that for an optimal phosphorylation reaction to occur, the pGS priming phosphate in the GSK3ß/ATP/pGS system optimizes the proper orientation of the GSK3ß N- and C-terminal domains and clamps the P0 serine of pGS in the appropriate configuration for interaction with the ATP γ-phosphate within the catalytic groove.

Drug metabolism-based design, synthesis, and bioactivities of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) analogs as α1-adrenoceptors antagonists.

1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) is a potent α1-adrenoceptor antagonist that is currently under Phase II clinic trials. However, the fast metabolism has restricted its further use. In this paper, 11 DDPH analogs were designed according to the probable metabolism pathways of DDPH, and featured the structures of halogen, methyl, and cyano groups at the 3-, or 4-position of aromatic ring A to block the hydroxylation, and one hydroxyl group at the 3-, or 4-position of aromatic ring B to extend the duration time. These compounds were synthesized in moderate to good yields from the reductive amination of substituted phenoxyacetones with substituted phenylethylamines, and fully characterized with ¹H NMR, IR, and HRMS. Biological evaluation indicated that most of the compounds exhibited strong blocking and moderate to good antihypertensive activities. It is clear that the compounds having 4-OH/3-OMe on group B exhibited higher blocking activities and longer duration time than their corresponding analogs having 4-OMe/3-OMe (and also 3-OH/4-OMe). Among them, compound 13 having bromo group at the 4-position of ring A and 4-OH/3-OMe on group B, exhibited the highest blocking activity, whereas compound 17 that had a methyl group at the 4-position of ring A and a hydroxyl group at the 4-position of ring B, was more active than potent DDPH in terms of both blocking and antihypertensive activities. In addition, the possible correlations between the blocking and antihypertensive activities are also briefly discussed.

Dissection of the difference between the group I metal ions in inhibiting GSK3ß: a computational study.

Glycogen synthase kinase 3ß (GSK3ß) is a serine/threonine kinase that requires two cofactor Mg(2+) ions for catalysis in regulating many important cellular signals. Experimentally, Li(+) is a competitive inhibitor of GSK3ß relative to Mg(2+), while this mechanism is not experienced with other group I metal ions. Herein, we use native Mg(2)(2+)-Mg(1)(2+) GSK3ß and its Mg(2)(2+)-M(1)(+) (M = Li, Na, K, and Rb) derivatives to investigate the effect of metal ion substitution on the mechanism of inhibition through two-layer ONIOM-based quantum mechanics/molecular mechanics (QM/MM) calculations and molecular dynamics (MD) simulations. The results of ONIOM calculations elucidate that the interaction of Na(+), K(+), and Rb(+) with ATP is weaker compared to that of Mg(2+) and Li(+) with ATP, and the critical triphosphate moiety of ATP undergoes a large conformational change in the Na(+), K(+), and Rb(+) substituted systems. As a result, the three metal ions (Na(+), K(+), and Rb(+)) are not stable and depart from the active site, while Mg(2+) and Li(+) can stabilize in the active site, evident in MD simulations. Comparisons of Mg(2)(2+)-Mg(1)(2+) and Mg(2)(2+)-Li(1)(+) systems reveal that the inline phosphor-transfer of ATP and the two conserved hydrogen bonds between Lys85 and ATP, together with the electrostatic potential at the Li(1)(+) site, are disrupted in the Mg(2)(2+)-Li(1)(+) system. These computational results highlight the possible mechanism why Li(+) inhibits GSK3ß.

Dichloridobis(3-chloro-pyridine-κN)zinc.

In the crystal structure of the title compound, [ZnCl(2)(C(5)H(4)ClN)(2)], discrete complex mol-ecules are found in which the Zn(II) cations are coordinated by two chloride anions and the N atoms of the two 3-chloro-pyridine ligands within a slightly distorted tetra-hedron. Moreover, inter-molecular C-Cl⋯Cl-C halogen inter-actions (Cl⋯Cl = 3.442 Å) are found between the building blocks.

3-(7-Meth-oxy-ß-carbolin-1-yl)propionic acid monohydrate.

In the title compound, C(15)H(14)N(2)O(3)·H(2)O [systematic name: 3-(7-meth-oxy-9H-pyrido[3,4-b]indol-1-yl)propanoic acid monohydrate], the fused rings make dhedral angles of 0.4 (1), 1.1 (2) and 1.4 (2)°. In the crystal, the water mol-ecule is involved in the formation of three independent hydrogen-bonded chains via O-H⋯O and N-H⋯O hydrogen bonds, while the carb-oxy group forms an inter-molecular O-H⋯N hydrogen bond.

Prediction of the hydrophobicity of platinum(IV) complexes based on molecular surface properties.

A quantitative structure-property relationship (QSPR) study was performed for predicting the hydrophobicity of Pt(IV) complexes. Two four-parameter equations, one based solely on structural descriptors derived from electrostatic potentials (ESPs) on molecular surface, and the other integrated ESP descriptors with molecular surface area (AS), were firstly constructed. Mechanistic interpretations of the structural descriptors introduced were elucidated in terms of solute-solvent intermolecular interactions. Subsequently, several up-to-date modeling techniques, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. The predictive performances of the four different nonlinear modeling methods follow the order of LSSVM≈GP > RF > SVM. The pure-ESP-based models are generally inferior to the AS-integrated ones. Comparisons with previous results were made.

[Management of coronary atherosclerotic heart disease through an alliance of community and hospital].

OBJECTIVE: To evaluate the effect of out-hospital normalized management of coronary heart disease (CAD) on the end point events such as mortality, readmission, etc, and on the compliance of patients through normalized management by an alliance of community and hospital. METHODS: The samples were comprised of a total of 2000 patients in 15 communities. And 1642 patients agreed to a follow-up and signed a consent form. Ten communities were chosen as the intensive management group in which community clinicians were trained and the patient management plan was proposed and carried out. The remaining 5 communities were taken as the control group in which the community clinicians were not trained and the patients received only general management. Both groups received a follow-up of 23 months. RESULTS: Compared with the control group, the intensive manage group showed a lower risk of all-cause death, cardiac death and readmission due to cardiovascular events (CVE). They declined by 36.5% (OR 0.635, 95%CI 0.478-0.854), 41.5% (OR 0.585, 95%CI 0.428-0.800) and 56.1% (OR 0.439, 95%CI 0.315-0.612) respectively. The proportion of patients with NYHA III in the intensive management and control groups increased by 3.6% and 7.7% while that of the counterparts of NYHAIV in two groups increased by 1.6% and 6.4% respectively. The cardiac function in the patients of intensive management group was significantly superior to that in control group. Patients in both groups displayed an acceptable compliance to cardiac medications except for aspirin. The proportion of aspirin in the intensive management and control groups increased by 8.4% and 8.7% respectively (P<0.05). CONCLUSION: Through normalized management provided by an alliance of community and hospital, the rates of all-cause death and readmission due to CVE decrease significantly concurrently with an improvement of cardiac function and quality of life in CAD patients.

Spontaneous regression of recurrent hepatocellular carcinoma with multiple lung metastases.

Spontaneous regression (SR) of hepatocellular carcinoma (HCC) is a rare phenomenon but its true incidence is much higher than expected. We report a recurrent HCC who experienced SR both in intrahepatic lesion and lung metastasis. Serum alpha-fetoprotein decreased dramatically from more than 1000 µg/L to normal range. In addition, we reviewed 11 similar case reports published in recent 5 years. We find that the interval from diagnosis to the recognition of SR is very short (4 m, 1-14 m). Therefore, we speculate the mechanism of SR should be a severe systemic reaction, and immune activation is the most likely conjecture.