The integrated spintronic functionalities of an individual high-spin state spin-crossover molecule between graphene nanoribbon electrodes.

The spin-polarized transport properties of a high-spin-state spin-crossover molecular junction with zigzag-edge graphene nanoribbon electrodes have been studied using density functional theory combined with the nonequilibrium Green's-function formalism. The molecular junction presents integrated spintronic functionalities such as negative differential resistance behavior, spin filter and the spin rectifying effect, associated with the giant magnetoresistance effect by tuning the external magnetic field. Furthermore, the transport properties are almost unaffected by the electrode temperature. The microscopic mechanism of these functionalities is discussed. These results represent a step toward multifunctional molecular spintronic devices on the level of the individual spin-crossover molecule.

Protective Effects of Total Glucosides of Paeony on N-nitrosodiethylamine-induced Hepatocellular Carcinoma in Rats via Down-regulation of Regulatory B Cells.

Total glucoside of paeony (TGP), extracted from the root of Paeonia Lactiflora, has been known to show anti-inflammatory, anti-oxidative, hepato-protective and immuno-regulatory activities. The aim of this present study was to determine the anti-tumor effect of TGP against N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) in rats, and to find the related mechanisms. Rat HCC model was established by intragastrically administrating with DEN (8 mg/kg). We found the number of tumor nodules and the index of liver and spleen were increased in the model group compared with the normal group, and was significantly decreased by TGP. Additionally, TGP obviously improved the hepatic pathological lesions induced by DEN, and decreased the elevated levels of serum alanine aminotransferase (ALT), glutamic oxalacetic transaminase (AST), alkaline phosphatase (ALP) and alpha fetoprotein (AFP) by DEN. Moreover, TGP decreased the level of B cell-activating factor (BAFF) and the proportion of IL-10-producing regulatory B cells (Bregs), and the decrease of BAFF by TGP is positively correlated to the decrease of IL-10-producing Bregs by TGP. These results suggest that TGP had a good therapeutic action on DEN-induced HCC rats, which might be due to its down-regulation of Bregs through reducing the level of BAFF.

TGF-ß favors bone marrow-derived dendritic cells to acquire tolerogenic properties.

Dendritic cells (DCs) are the most powerful antigen-presenting cells that have an important role in the immunity and immune tolerance. Transforming growth factor ß (TGF-ß) is a pleiotropic cytokine widely expressing in various tissues and cells, which regulates cellular proliferation, differentiation and apoptosis of several immune cells and is considered to be a key factor in inducing immune tolerance. The effect of TGF-ß on DCs is very complex. In this study, we further investigated the effect of TGF-ß on inducing immune tolerance of DCs. DCs were differentiated from mice bone marrow cells in the absence or presence of TGF-ß. The phenotype as well as function was studied in detail. We found that TGF-ß limited the expression of CD40, CD83, CD86 and MHCII in DCs, increased CD45RB and indoleamine 2, 3-dioxygenase (IDO) expression in DCs, promoted IL-10 and limited IL-12 secretion by DCs. Moreover, TGF-ß increased the endocytosis ability of DCs and limited the ability of DCs in activating T cells. These results suggest that TGF-ß affects the immunity of DCs and enhances their tolerogenicity.

Paeoniflorin inhibited the tumor invasion and metastasis in human hepatocellular carcinoma cells.

OBJECTIVE: Evidence suggests that paeoniflorin may be involved in anticancer activities. Here, we have investigated the effects of paeoniflorin and correlative mechanisms on anti-invasion and anti-metastasis in human hepatocellular carcinoma (HCC) cell lines. MATERIALS AND METHODS: In the current study, we have applied 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay to determine the proliferative effect of HepG2 and Bel-7402, two human hepatoma cell lines, and we have established a boyden chamber assay, a wound healing assay and cell adhesion assay to detect and quantify the invasion, metastasis and adhesion of both HepG2 and Bel-7402. In addition, we have analyzed the protein expression of matrix metalloproteinas (MMP)-9, E-cadherin (E-cad) and extracellular signal-regulated kinase (ERK) in both cell lines through western blot analysis. RESULTS: Paeoniflorin (6. 25-200 µM) had inhibitory effect on the growth of HepG2 and Bel-7402 cell lines, and reduced significantly invasion, metastasis and adhesion of HCC cell lines. In addition, paeoniflorin decreased the expression of MMP-9 and ERK in HepG2 and Bel-7402 cells, and increased expression of E-cad in both cell lines. CONCLUSIONS: Paeoniflorin is effective anti-metastatic and anti-invasive agent for suppressing HCC invasion and metastasis (Fig. 5, Ref. 30).

Next-generation sequencing for disorders of low and high bone mineral density.

UNLABELLED: To achieve an efficient molecular diagnosis of osteogenesis imperfecta (OI), Ehlers-Danlos syndrome (EDS), and osteopetrosis (OPT), we designed a next-generation sequencing (NGS) platform to sequence 34 genes. We validated this platform on known cases and have successfully identified the causative mutation in most patients without a prior molecular diagnosis. INTRODUCTION: Osteogenesis imperfecta, Ehlers-Danlos syndrome, and osteopetrosis are collectively common inherited skeletal diseases. Evaluation of subjects with these conditions often includes molecular testing which has important counseling and therapeutic and sometimes legal implications. Since several different genes have been implicated in these conditions, Sanger sequencing of each gene can be a prohibitively expensive and time-consuming way to reach a molecular diagnosis. METHODS: In order to circumvent these problems, we have designed and tested a NGS platform that would allow simultaneous sequencing on a single diagnostic platform of different genes implicated in OI, OPT, EDS, and other inherited conditions, leading to low or high bone mineral density. We used a liquid-phase probe library that captures 602 exons (~100 kb) of 34 selected genes and have applied it to test clinical samples from patients with bone disorders. RESULTS: NGS of the captured exons by Illumina HiSeq 2000 resulted in an average coverage of over 900X. The platform was successfully validated by identifying mutations in six patients with known mutations. Moreover, in four patients with OI or OPT without a prior molecular diagnosis, the assay was able to detect the causative mutations. CONCLUSIONS: In conclusion, our NGS panel provides a fast and accurate method to arrive at a molecular diagnosis in most patients with inherited high or low bone mineral density disorders.

Light emission probing quantum shot noise and charge fluctuations at a biased molecular junction.

The emission of plasmonic light from a single C(60) molecule on Cu(111) is probed in a scanning tunneling microscope from the weak-coupling, tunneling range to strong coupling of the molecule to the electrodes at contact. At positive sample voltage the photon yield decreases owing to shot-noise suppression in an increasingly transparent quantum contact. At reversed bias an unexpected nonlinear increase occurs. First-principles transport calculations reveal that ultrafast charge fluctuations on the molecule give rise to additional noise at optical frequencies beyond the shot noise of the current that is injected to the tip.

Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

Coupled electron-phonon transport from molecular dynamics with quantum baths.

Based on generalized quantum Langevin equations for the tight-binding wavefunction amplitudes and lattice displacements, electron and phonon quantum transport are obtained exactly using molecular dynamics (MD) in the ballistic regime. The electron-phonon interactions can be handled with a quasi-classical approximation. Both charge and energy transport and their interplay can be studied. We compare the MD results with those of a fully quantum mechanical nonequilibrium Green's function (NEGF) approach for the electron currents. We find a ballistic to diffusive transition of the electron conduction in one-dimensional chains as the chain length increases.

Mechanism of LncRNA FOXC2-AC1 promoting lung cancer metastasis by regulating miR-107.

OBJECTIVE: Previous studies have shown that long non-coding RNA (lncRNA) FOXC2-AC1 is one of cancer-promoting genes. However, the role of FOXC2-AC1 in lung cancer (LCa) has not been reported. This study aimed to investigate the expression characteristics of FOXC2-AC1 in LCa, and to further explore the mechanism by which it accelerates the metastasis of LCa. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction (qRT-PCR) was used to detect the level of FOXC2-AC1 in 62 pairs of LCa tissues and adjacent normal tissues, and the relationship between FOXC2-AC1 and LCa pathological parameters as well as the prognosis of patients were analyzed. Meanwhile, FOXC2-AC1 level was further verified in LCa cells by qRT-PCR. In addition, FOXC2-AC1 knockdown and overexpression models were constructed using lentivirus in LCa cell lines including H1299 and SPCA1, and the effect of FOXC2-AC1 on the biological function of LCa cells was analyzed by cell counting kit-8 (CCK-8) test along with transwell invasion and migration assay. Finally, the potential mechanism was explored using Western blotting assay. RESULTS: In this study, qRT-PCR results indicated that the expression level of FOXC2-AC1 in LCa was considerably higher than that in normal tissues, with statistically significant differences. Compared with patients with low expression of FOXC2-AC1, patients with high expression of FOXC2-AC1 had higher incidence of distant metastasis and lower overall survival rate. Compared with the control group, the cell proliferation, invasion and metastasis capacities of FOXC2-AC1 overexpressing group were considerably enhanced, while opposite results were observed in the FOXC2-AC1 silencing group. In addition, miR-107 expression was found significantly reduced no matter in LCa cell lines or in tissues and showed a negative correlation with FOXC2-AC1. Subsequently, luciferase reporter gene assay demonstrated that overexpression of miR-107 significantly attenuated the luciferase activity of the wild-type FOXC2-AC1 vector without reducing the activity of the mutant vector or empty vector, further proving that FOXC2-AC1 could be targeted by miR-107 through this binding site. In addition, rescue experiment also found that FOXC2-AC1 and miR-107 have mutual regulation, which jointly affected the malignant progression of LCa. CONCLUSIONS: These studies indicate that LncRNA FOXC2-AC1 is notably upregulated in LCa and is significantly correlated with LCa distant metastasis as well as poor prognosis. Therefore, it is suggested that lncRNA FOXC2-AC1 may promote malignant progression of LCa through the mutual regulation of miR-107.

Spectroscopy of transmission resonances through a C60 junction.

Electron transport through a single C60 molecule on Cu(1 1 1) has been investigated with a scanning tunnelling microscope in tunnelling and contact ranges. Single-C60 junctions have been fabricated by establishing a contact between the molecule and the tip, which is reflected by a down-shift in the lowest unoccupied molecular orbital resonance. These junctions are stable even at elevated bias voltages enabling conductance measurements at high voltages and nonlinear conductance spectroscopy in tunnelling and contact ranges. Spectroscopy and first principles transport calculations clarify the relation between molecular orbital resonances and the junction conductance. Due to the strong molecule-electrode coupling the simple picture of electron transport through individual orbitals does not hold.

NAMPT inhibitor and metabolite protect mouse brain from cryoinjury through distinct mechanisms.

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD). In the brain, NAMPT is primarily expressed in neurons and can prevent neuronal degeneration. NAMPT is also highly expressed in inflammatory cells, and is responsible for their activation. Since inflammation following traumatic brain injury enhances neuronal damage, we assessed the effects of nicotinamide mononucleotide (NMN), the direct NAMPT metabolite, and FK866, a potent NAMPT inhibitor, on brain injury in a cryoinjury mouse model. Twenty-four hours after brain cryoinjury, the density of neuron and the level of NAD decreased. Both NMN and FK866 alleviated the neuronal loss and decreased the lesion volume. NMN prevented the cryoinjury-induced decrease of NAD level, and FK866 decreased it further. On day 14 after cryoinjury, further neuronal loss occurred, astrocytes and Iba1-positive macrophage/microglia activated, and the NAD level increased. At this time-point, NAMPT expression was strongly induced in Iba1-positive macrophages/microglia in the lesion core. NMN and FK866 also alleviated the neuronal loss and decreased the lesion volume. In addition, FK866 significantly attenuated the activation of astrocytes and Iba1-positive macrophages/microglia, and decreased the NAD, while NMN had no such effects. Taken together, both FK866 and NMN attenuate traumatic brain injury. However, FK866 acts via the inhibition of the NAMPT activity in inflammatory cells resulting in the inhibition of inflammation, whereas NMN is effective via replenishing NAD.

Development of the neuromuscular junction: genetic analysis in mice.

Formation of the skeletal neuromuscular junction is a multi-step process that requires communication between the nerve and muscle. Studies in many laboratories have led to identification of factors that seem likely to mediate these interactions. 'Knock-out' mice have now been generated with mutations in several genes that encode candidate transsynaptic messengers and components of their effector mechanisms. Using these mice, it is possible to test hypotheses about the control of synaptogenesis. Here, we review our studies on neuromuscular development in mutant mice lacking agrin alpha CGRP, rapsyn, MuSK, dystrophin, dystrobrevin, utrophin, laminin alpha 5, laminin beta 2, collagen alpha 3 (IV), the acetylcholine receptor epsilon subunit, the collagenous tail of acetylcholinesterase, fibroblast growth factor-5, the neural cell adhesion molecule, and tenascin-C.

Blockade effects of (Nphe1)Nociceptin(1-13)-NH(2) on anti-nociception induced by intrathecal administration of nociceptin in rats.

The present study investigated the roles of the opioid-receptor-like (ORL1) receptor and its endogenous ligand nociceptin on nociception in the spinal cord of rats. Intrathecal administration of 10 nmol of nociceptin produced significant increases in hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulation. There were no significant changes of average maximum angles in inclined plane tests after intrathecal injection of 10 nmol of nociceptin in rats. The intrathecal nociceptin-induced increases in HWL were antagonized by intrathecal administration of (Nphe1)Nociceptin(1-13)-NH(2), a selective antagonist of ORL1 receptor, in a dose-dependent manner. The results demonstrated that ORL1 receptor is involved in the nociceptin-induced anti-nociceptive effect in the spinal cord of rats.

Bending and twisting of an in vivo coronary artery at a bifurcation.

Dynamic changes in the geometric shape and dimensions of a left coronary artery tree were extracted from the computer-tomographically reconstructed three-dimensional images of an in situ beating heart of an anesthetized dog. Wireframe models of the left coronary artery tree at 16 different instants of a cardiac cycle were constructed for the study of its flexing motion. For quantifying the local bending and twisting of the left coronary artery tree, the anatomic landmarks of the bifurcation points are selected as focussed locations. At these points, the space curves of the tree at different cardiac instants were first derived in parametric forms. Curvature and torsion expressions are next obtained in terms of the derivatives with respect to the parameter. This analysis revealed that during the initial contraction of the heart wall, a 2% reduction per millisecond in the radius of curvature occurred near the bifurcation point where the left circumflex coronary artery descends toward the apex of the heart. When the left ventricular chamber reached a maximum value, the radius of curvature was found to decrease at a rate of 2.3% ms-1. At the end of diastole, an increase in the radius of curvature at a rate of 5.7% ms-1 was observed. The twisting rates per unit length of artery near the bifurcation point of the selected artery were found to range from -0.62 to 0.63 degrees ms-1.

Liquid crystals of gold(I) N-heterocyclic carbene complexes.

Three types of Au(I) N-heterocyclic carbene (NHC) and imidazole (Im) complexes, namely [Au(NHC)Cl], [Au(NHC)(Im)][NO(3)], and [Au(NHC)(2)][NO(3)], with two-, three-, and four-N-long alkyl chains, respectively, were synthesized and their mesomorphic properties investigated. Only the [Au(NHC)(Im)][NO(3)] series of compounds, adopting an m-shaped conformation in the solid state, showed liquid crystalline properties. For the molecules with three alkyl chains in particular, the Coulombic and hydrogen bonding interactions between the cationic head core and anionic NO(3)(-), and the hydrophobic chain-chain interactions facilitate in sustaining the partially ordered motion, which is not observed for those with two and four arms. These complexes were employed for preparation of stable nanomaterials in organic solvents.

[Bacteriological analysis of chronic sinusitis in school-age children (36 cases report)].

OBJECTIVE: To research the bacteriological characters of chronic sinusitis in school-age children and to provide basis for clinical treatment. METHOD: The purrent discharges taken from middle meatus of 36 patients were cultured for bacteria and the antimicrobial suscepility was determined. RESULT: The positive rate of bacteria culture was 83.3%, the compound infection rate was 36.1%. Aerobic bacteria were present in 76.7%, anaerobic bacteria were present in 55.6%. The result of antimicrobial susceptibility test was scattered. CONCLUSION: Infection rate of anaerobic bacteria was high in chronic sinusitis in school-age children and result of antimicrobial susceptibility was scattered. It was important to have anti-anaerobic treatment in chronic sinusitis in school-age children and to take an antimicrobial susceptibility test before medical treatment.

Antinociceptive effect of astragalosides and its mechanism of action.

AIM: To study the effect and mechanism of astragalosides (AST) related to the antinociceptive activity. METHODS: The standardized formalin test was performed to induce the direct stimulation of nociceptors followed by inflammatory process in the Kunming strain mice. The involvement of opioid and nitric oxide was studied by subcutaneous injection of morphine with/without naloxone 30 min before formalin test, or peritoneal injection of L-arginine with/without L-NAME 20 min before formalin. RESULTS: AST 20, 40, and 80 mg/kg significantly lowered pain score of the second phase of formalin response as compared with control group (P<0.01). The maximum analgesic effect of AST 40 mg/kg was found at 4 h after the administration of AST (34.4 % inhibition at the second phase). Injection of morphine 5 mg/kg significantly inhibited pain response of both phases (P<0.01) and this was reversed by naloxone 2 mg/kg (P<0.01). However, naloxone did not alter the effect of AST on the second phase. Antinociceptive effect of AST 40 mg/kg was partially blocked by L-arginine 400 or 800 mg/kg (P<0.01). CONCLUSION: AST has an antinociceptive effect on formalin test in mice that is not mediated by the endogenous opioid system but related to its inhibitory effect on the production of NO.

Identification, molecular cloning, and distribution of a short variant of the 5-hydroxytryptamine2C receptor produced by alternative splicing.

The actions of the neurotransmitter 5-hydroxytryptamine (5-HT) (serotonin) are mediated by multiple receptor subtypes. One of the prominent serotonin receptors in the brain is the 5-HT2C receptor (5-HT2C-R). We report the occurrence of a second 5-HT2C-R transcript, first identified using S1 nuclease protection of total RNA isolated from the choroid plexus. Analyses of the distribution of these two RNAs revealed that the short form is expressed in the same structures as the 5-HT2C-R mRNA, including choroid plexus, striatum, hippocampus, hypothalamus, olfactory tubercles, and spinal cord. Cloning and sequence analyses revealed a second cDNA with a 95-nt deletion in the region coding for the putative second intracellular loop and the fourth transmembrane domain of the 5-HT2C-R. This deletion leads to a frameshift in the coding sequence and the introduction of a premature stop codon. The predicted truncated protein (5-HT2C-tr) contains 172 amino acids, with 153 residues at the amino terminus, identical to the 5-HT2C-R, and 19 carboxyl-terminal amino acids that are unique. Although antibodies specific to the 5-HT2C-tr protein showed that the truncated form is expressed in a transfected fibroblast cell model system, there was no serotonergic ligand binding activity or phosphoinositide hydrolysis. Analyses of the 5-HT2C-R gene revealed that the two transcripts arise from a single gene by differential splicing using alternative donor sites and a common 3'-splice acceptor. Polymerase chain reaction amplification of mouse and human brain cDNAs demonstrated the occurrence of the same splicing patterns in these species. Although this study demonstrates tissue-specific expression of two 5-HT2C mRNA splice variants in rat, mouse, and human, the significance of the truncated form in these three species remains to be established.

Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development.

alpha-Calcitonin gene-related peptide (alphaCGRP) is a pleiotropic peptide neuromodulator that is widely expressed throughout the Central and peripheral nervous systems. CGRP has been implicated in a variety of physiological processes including peripheral vasodilation, cardiac acceleration nicotinic acetylcholine receptor (AChR) synthesis and function, testicular descent, nociception, carbohydrate metabolism, gastrointestinal motility, neurogenic inflammation, and gastric acid secretion. To provide a better understanding of the physiological role(s) mediated by this peptide neurotransmitter, we have generated alphaCGRP-null mice by targeted modification in embryonic stem cells. Mice lacking alpha CGRP expression demonstrate no obvious phenotypic differences from their wild-type littermates. Detailed analysis of systemic cardiovascular function revealed no differences between control and mutant mice regarding heart rate and blood pressure under basal or exercise-induced conditions and subsequent to pharmacological manipulation. Characterization of neuromuscular junction in morphology including nicotinic receptor localization, terminal sprouting in response to denervation, developmental regulation of AChR subunit expression, and synapse elimination also revealed no differences in alphaCGRP-deficient animals. These results suggest that alphaCGRP is not required for the systemic regulation of cardiovascular hemodynamics or development of the neuromuscular junction.