Estimates of the effects of physical activity on osteoporosis using multivariable Mendelian randomization analysis.

This study estimates causality of physical activity (PA) on bone mineral density (BMD) by conducting multivariable Mendelian randomization (MR). The findings suggest that habitual vigorous PA increases lumbar spine BMD, and higher overall acceleration average would improve forearm BMD. The results could promote PA intervention targeting individuals with optimized type. INTRODUCTION: Evidence from epidemiologic studies showed type, frequency, and duration of PA influenced BMD. However, these observational studies may be confounded by many factors, resulting in spurious associations. We aimed to conduct multivariable MR to estimate the causal effect of self-reported and device-measured PA on osteoporosis. METHODS: Three self-reported and two device-measured PA-related traits were selected as exposures. Outcomes were BMD at different skeletal sites: femoral neck BMD (FN BMD), lumbar spine BMD (LS BMD), and forearm BMD (FA BMD). Exposure datasets were obtained from UK Biobank with total 377,234 subjects. Outcome datasets were obtained from GEFOS consortium with 53,236 subjects. Standard MR analysis and multivariable MR were conducted to assess the total and direct causal effect of PA on BMD. RESULTS: For self-reported PA, inverse-normalized moderate-to-vigorous had a direct causal effect on FN BMD independently (ß = - 1.116 (95% confidence interval, 95%CI: - 2.210, - 0.023), P = 0.045); vigorous PA showed a direct effect (ß = 3.592 (95%CI: 0.310, 6.874), P = 0.032) on LS BMD independently. While overall acceleration average and fraction of accelerations both had a direct causal effect on FA BMD independently. CONCLUSIONS: Habitual vigorous PA could increase LS BMD. Individuals with higher overall acceleration average would have a higher FA BMD.

Detecting causal relationship between metabolic traits and osteoporosis using multivariable Mendelian randomization.

By adopting the extension approaches of Mendelian randomization, we successfully detected and prioritized the potential causal risk factors for BMD traits, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases. INTRODUCTION: Osteoporosis (OP) is a common metabolic skeletal disease characterized by reduced bone mineral density (BMD). The identified SNPs for BMD can only explain approximately 10% of the variability, and very few causal factors have been identified so far. METHODS: The Mendelian randomization (MR) approach enables us to assess the potential causal effect of a risk factor on the outcome by using genetic IVs. By using extension methods of MR-multivariable MR (mvMR) and MR based on Bayesian model averaging (MR-BMA)-we intend to estimate the causal relationship between fifteen metabolic risk factors for BMD and try to prioritize the most potential causal risk factors for BMD. RESULTS: Our analysis identified three risk factors T2D, FG, and HCadjBMI for FN BMD; four risk factors FI, T2D, HCadjBMI, and WCadjBMI for FA BMD; and three risk factors FI, T2D, and HDL cholesterol for LS BMD, and all risk factors were causally associated with heel BMD except for triglycerides and WCadjBMI. Consistent with the mvMR results, MR-BMA confirmed those risk factors as top risk factors for each BMD trait individually. CONCLUSIONS: By combining MR approaches, we identified the potential causal risk factors for FN, FA, LS, and heel BMD individually and we also prioritized and ranked the potential causal risk factors for BMD, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases.

Systematic review: exosomal microRNAs associated with pancreatic cancer for early detection and prognosis.

OBJECTIVE: Pancreatic cancer (PC) is one of the most common malignant tumors of the digestive system with a high degree of malignancy. Currently, there have been many studies on exosomal microRNAs (miRNAs) discovery in pancreatic cancer. This systematic review aimed to give an overview about known exosomal miRNAs and discuss their diagnostic performance, as well as prognostic value in PC. MATERIALS AND METHODS: PubMed and Web of Science were used for systematic literature research for this review. This literature research was mainly to identify studies that performed plasmatic and serological testing for exosomal miRNAs in pancreatic cancer patients and controls. Two independent reviewers separately extracted data on study characteristics and results. RESULTS: In total, nine prior studies were included in this review. Of which, eleven different single exosomal miRNAs and three exosomal miRNA panels were reported. CONCLUSIONS: When single exosomal miRNA was used as a diagnostic tool, the specificity is generally high, but the sensitivity is commonly low. When multiple of exosomal miRNAs were used simultaneously, higher sensitivities can be obtained at relatively reasonable specificity levels with certain miRNA combinations. Developing a combination of miRNA markers may be a promising approach for early detection of pancreatic cancer.

[Research advances in the mammalian target of rapamycin signaling pathway and its inhibitors in treatment of hepatocellular carcinoma].

Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase in the downstream of the phosphatidylinositol 3-kinases (PI3K) family. This kinase plays an important role in the development and progression of hepatocellular carcinoma (HCC). Preclinical data demonstrate that 40%-50% of HCC patients have dysregulated expression of the effectors of the mTOR signaling pathway, and the activation of the mTOR pathway is associated with poorly differentiated tumors, early tumor recurrence, and poor survival/prognosis. This article reviews the research advances in the potential role of the mTOR signaling pathway and its inhibitors in the treatment of HCC.

The role of Notch1 genes in lung cancer A594 cells and the impact on chemosensitivity.

OBJECTIVE: Expression of Notch1 gene in lung cancer A549 cells was reduced using small interfering RNA (small interfering RNA, siRNA) and the effect of Notch1 gene on proliferation and chemo sensitivity of lung cancer A549 cells was studied. MATERIALS AND METHODS: The Notch1 siRNA was transfected into A549 cells by liposome to inhibit the expressions of Notch1 gene in A549 cells. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to detect the expression of Notch1 gene and protein. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the proliferation of A549 cells. After transfection of Notch1-siRNA, cisplatin was added to each group at a concentration of 4 µg/ml, and cultured for 48 h. MTT assay and 4',6-diamidino-2-phenylindole (DAPI) staining was used to evaluate the change of apoptosis and sensitivity to chemotherapy. RESULTS: Notch1 gene expression of A594 cells, detected by RT-PCR and Western blot was significantly reduced in transfected cells when compared with the control group (p<0.05). Inhibition of A594 cell proliferation was significantly decreased as detected by MTT (p<0.05), and the MTT assay and DAPI staining showed that Notch1 gene silencing can significantly improve the sensitivity of A549 cells to chemotherapeutic drugs. CONCLUSIONS: The Notch1 siRNA can effectively inhibit the expression of Notch1 gene, inhibit the proliferation of lung cancer A549 cells and increase the sensitivity to chemotherapeutic drugs.

Characterizing and marker-assisting a novel chili pepper (Capsicum annuum L.) yellow bud mutant with cytoplasmic male sterility.

Cytoplasmic male sterility (CMS) in pepper is a better way to produce hybrid seeds compared to manual production. We used the two sequence characterized amplified region (SCAR) markers (CRF-SCAR and CMS-SCAR130) in CMS pepper, to identify the genotype. We assembled two CMS yellow bud mutants (YBM; YBM12-A and YBM12-B). This mutation in leaf color is controlled by a single dominant nuclear gene. The aim was to create a new hybrid seed production method that reduces the costs and increases F1 hybrid seed purity. The results suggest that the CRF-SCAR and CMS-SCAR130 markers can be used together in multiple generations to screen for restorer or maintainer genes. We found the marker linked to the restorer gene (Rf) in the C-line and F1 hybrids, as well as partially in the F2 generation, whereas it was not found in the sterile YBM12-A or the maintainer line YBM12-B. In the F2 population, sterility and fertility segregated at a 3:1 ratio based on the CRF-SCAR marker. A 130 bp fragment was produced in the YBM12-A, F1, and F2 populations, suggesting that these lines contained sterile cytoplasm. A 140 bp fragment present in the YBM12-B and C-line indicated that these lines contained normal cytoplasm. In addition, we identified some morphological characters distinguishing sterile and fertile buds and flowers that may be linked to the sterility gene. If more restorer lines are identified, CMS expressing the YBM trait can be used in hybrid seed production.

Two Dimensional Antiferromagnetic Chern Insulator: NiRuCl6.

Density functional theory (DFT) and Berry curvature calculations show that quantum anomalous Hall effect (QAHE) can be realized in two-dimensional(2D) antiferromagnetic (AFM) NiRuCl6. The results indicate that NiRuCl6 behaves as an AFM Chern insulator and its spin-polarized electronic structure and strong spin-orbit coupling (SOC) are responsible for the QAHE. By tuning SOC, we found that the topological property of NiRuCl6 arises from its energy band inversion. Considering the compatibility between the AFM and insulators, AFM Chern insulator provides a new way to archive high temperature QAHE in experiments due to its different magnetic coupling mechanism from that of ferromagnetic (FM) Chern insulator.

Modulation of electronic properties from stacking orders and spin-orbit coupling for 3R-type MoS2.

Two-dimensional crystals stacked by van der Waals coupling, such as twisted graphene and coupled graphene-BN layers with unusual phenomena have been a focus of research recently. As a typical representative, with the modulation of structural symmetry, stacking orders and spin-orbit coupling, transitional metal dichalcogenides have shown a lot of fascinating properties. Here we reveal the effect of stacking orders with spin-orbit coupling on the electronic properties of few-layer 3R-type MoS2 by first principles methods. We analyze the splitting of states at the top of valence band and the bottom of conduction band, following the change of stacking order. We find that regardless of stacking orders and layers' number, the spin-up and spin-down channels are evidently separated and can be as a basis for the valley dependent spin polarization. With a model Hamiltonian about the layer's coupling, the band splitting can be effectively analyzed by the coupling parameters. It is found that the stacking sequences, such as abc and abca, have the stronger nearest-neighbor coupling which imply the popular of periodic abc stacking sequence in natural growth of MoS2.

Band gap engineering of early transition-metal-doped anatase TiO2: first principles calculations.

The thermal stability and electronic structures of anatase TiO2 doped with early transition metals (TM) (group III-B = Sc, Y and La; group IV-B = Zr and Hf; group V-B = V, Nb and Ta) have been studied using first principles calculations. It was found that all doped systems are thermodynamically stable, and their band gaps were reduced by 1-1.3 eV compared to pure TiO2. Doping with transition metals affects the strength of the hybrid orbital of TM-O bonding, and the band gap increases approximately linearly with the MP value of TM-O bonding.

Correlation between the band gap, elastic modulus, Raman shift and melting point of CdS, ZnS, and CdSe semiconductors and their size dependency.

With structural miniaturization down to the nanoscale, the detectable quantities of solid materials no longer remain constant but become tunable. For the II-VI semiconductors example, the band gap expands, the elastic modulus increases, the melting point drops, and the Raman optical phonons experience red shift associated with creation of low frequency Raman acoustic modes that undergo blue shift with decreasing the dimensional scale. In order to understand the common origin of the size dependency of these seemingly irrelevant properties, we formulated these quantities for CdS, ZnS, and CdSe semiconductors from the perspectives of bond order-length-strength correlation and the local bond averaging approach. Consistency between the theory predictions and the measured size dependence of these quantities clarified that the undercoordination-induced local strain and quantum entrapment and the varied fraction of undercoordinated atoms of the entire solid correlate these quantities and dominate their size effect.

Size-suppressed dielectrics of Ge nanocrystals: skin-deep quantum entrapment.

Although the dielectric behavior of nanostructured semiconductors has been intensively investigated, the physics behind observations remains disputed with possible mechanisms such as quantum confinement and dangling bond polarization. Here we show that theoretical reproduction of the measured dielectric suppression of Ge nanocrystals asserts that the dielectric suppression originates from the shorter and stronger bonds at the skin-deep surface, the associated local densification and quantum entrapment of energy. Coordination-imperfection induced local quantum entrapment perturbs the Hamiltonian that determines the band gap and hence, the process of electron polarization consequently.

Porcine bocaviruses: genetic analysis and prevalence in Chinese swine population.

In members of the Bocavirus genus, that contain three open reading frames (ORFs) of the Parvovirinae subfamily, porcine bocaviruses (PoBoVs) exhibit the most genetic diversity. Based on the ORF2-encoded viral protein (VP1) classification, the six reported porcine bocaviruses were grouped into four species: PoBoV1 (porcine boca-like virus or PBoLV), PoBoV2 (porcine parvovirus 4 or PPV4), PoBoV3 (PBoV1/PBoV2) and PoBoV4 (6V/7V), with PoBoV3 and PoBoV4 each having two genotype viruses. All four PoBoV species were detected in the 166 samples collected in 2010 from swine herds located in ten provinces of China. The detection rates for PoBoV1-4 were 28·9%, 6·6%, 19·3% and 39·7%, respectively. The co-infection combinations involving these six porcine bocaviruses in the collected samples were very complex. Furthermore, mixed infections with viruses from other families (porcine reproductive and respiratory syndrome virus, classic swine fever virus and porcine circovirus type 2) were also detected.

Atomistic origin of lattice strain on stiffness of nanoparticles.

Lattice strain plays a crucial role on the properties of nanoparticles. Although the effect of lattice strain on nanoparticles has been widely studied in experimental measurements and calculations, its physical mechanism from the perfective of bond identities is still poorly understood. Herein we put forward an analytical solution of the size effect and external stimuli such as pressure and temperature dependence of lattice strain and bulk modulus of a nanoparticle from the perspective of atomistic origin. A shell-core configuration has been considered for the nanoparticle structure. It has been found that the lattice strain as well as quantum trapping and energy storage exerted by the compressive stress and thermal stress would be responsible for the mechanical behavior of nanoparticles. The theoretical predictions were well consistent with the experimental data and ab initio calculations, implying that the model could be expected to be a general approach to understand mechanical behavior in nanomaterials.

Mechanically stiffened and thermally softened Raman modes of ZnO crystal.

An analytical form connecting the energy shift of Raman modes directly to the bonding identities (order, nature, length, energy) of a specimen and the response of the bonding identities to the applied stimuli of temperature and pressure was presented for a deeper understanding of the atomistic origin of the ZnO Raman shift. Theoretical reproduction based on the BOLS correlation theory [Sun, C. Q. Prog. Solid State Chem. 2007, 35, 1] and the local bond average (LBA) approach [Sun, C. Q. Prog. Mater. Sci. 2009, 54, 179] of the measurements revealed that the thermally softened ZnO Raman modes arise from bond expansion and bond weakening due to vibration and that the pressure-stiffened Raman modes result from bond compression and bond strengthening due to mechanical work hardening. The developed approach could be useful in generalizing the lattice dynamics directly to the process of vibration and relaxation of a representative bond of the specimen under external stimuli.

Energy shifts of Si oxidation states in the system of Si nanocrystals embedded in SiO2 matrix.

Energy shifts in the Si 2p levels of the five Si oxidation states Sin+ (n = 0, 1, 2, 3, 4) in the system of Si nanocrystals embedded in SiO2 matrix have been determined. The thermal annealing effect on the energy shifts has been studied. The result suggests that the Si nanocrystals and the SiO2 are thermally stable but the annealing can cause some structural deformations such as changes in the bond lengths and bond angles for the suboxides Si2O and SiO. The energy shifts generally show a linear dependence on the oxidation state n, suggesting that the energy shifts could be mainly determined by the nearest-neighbor oxygen atoms. It is shown that the chemical structures of the system are similar to those of the conventional SiO2/Si system in terms of the energy shifts.

Long terminal repeats are not the sole determinants of virulence for equine infectious anemia virus.

The long terminal repeats (LTRs) of equine infectious anemia virus donkey leukocyte-attenuated virus (EIAV-DLA) were substituted with those of the wild-type EIAV-L (wt EIAV-L, the parent virus of EIAV-DLA). The resulting chimeric plasmid was designated pOK-LTR DLA/L. Purified pOK-LTR DLA/L was transfected into monocyte-derived macrophage (MDM) cultures prepared from EIAV-negative, heparinized whole blood from a donkey. Eighth-passage cell cultures developed the typical cytopathogenic effects (CPE) of EIAV infection, and virions with typical EIAV profiles were observed with an electron microscope. Horses were inoculated with the chimeric virus or EIAV-DLA and challenged with the wt EIAV-L strain six months later. All of the horses inoculated with either the chimeric virus or EIAV-DLA were protected from disease, whereas the control horses died with typical EIA symptoms.

Impedance labelless detection-based polypyrrole protein biosensor.

A simple and sensitive electrochemical immunosensor with impedance labelless detection and novel data processing method was investigated. One-step copolymerization was used to electrochemically deposit an antibody impregnated polypyrrole film on a glassy carbon electrode surface for the immunosensor. Impedance measurements provided a labelless or reporterless method to detect antibody (Ab)-antigen (Ag) interactions. Dimensionless analysis was employed to successfully process the measured impedance data. Since the method derived unit impedance change to eliminate or reduce the variation of the bulk electronic properties of Ab/polypyrrole films, the signal to noise ratio (S/N) was significantly improved for high sensitivity and specificity. Nonspecific binding effect was studied by array electrode chips and was found out that the polypyrrole electrode without antibody attachment had much stronger nonspecific binding effect than the Ab/polypyrrole electrode; incubation followed by thoroughly washing significantly reduced the nonspecific interference. 10 pg/ml detection limit and superior specificity were achieved by the method, demonstrating a highly sensitive labelless immunosensor in comparison with the detection limit of ng -microgram/ml for the reported polypyrrole based immunosensors. The electrochemical immunosensors presented in this paper, due to its simplicity, low cost, high sensitivity and superior specificity, could be an invaluable tool for clinical diagnostics and could have potential applications in drug discovery, environmental and food analysis.

Impedance labelless detection-based polypyrrole DNA biosensor.

Microelectrodes were fabricated to study impedance labelless detection of DNA hybridization. The probe molecule was attached onto the platinum microelectrode surface by electrochemically copolymerizing pyrrole and the probe oligonucleotides. Measured impedance complexes showed that an electrochemical redox-reaction occurred and the electron-transfer resistance increased after DNA hybridization. It was proposed that the hybridization of DNA in the conductive polymer matrix slowed down the anionic doping/undoping process, resulting impedance changes for the target DNA detection. Impedance measurements were conducted at the complementarily hybridized probe oilgomer-attached polypyrrole film electrodes in different anionic solutions to exam the anionic effects. Results showed that higher concentration and smaller size of anions had the lower electron-transfer resistance. The results not only provide further evidence to support the detection mechanism proposed, but also offer a method to improve the signal to noise ratio for the DNA biosensor. The research also tested the specificity of the methods and experimental results, indicating good specificity of the method. A concept array chip was fabricated and used to demonstrate the capability of the labelless detection method. Nano-Molar concentrations were detected and showed fairly linear responses versus the target molecule concentrations. The method is simple and inexpensive. The technique based genosensors could have potential applications in clinical diagnosis, drug discovery, environmental and food analysis.

BMS-201620: a selective beta 3 agonist.

A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.

Microsomal triglyceride transfer protein inhibitors: discovery and synthesis of alkyl phosphonates as potent MTP inhibitors and cholesterol lowering agents.

A series of newly synthesized phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP). The most potent compounds were evaluated for their ability to inhibit lipoprotein secretion in HepG2 cells and to affect VLDL secretion in rats. These inhibitors were also found to lower serum cholesterol levels in a hamster model upon oral dosing.