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Altered cell metabolism is a characteristic feature of many cancers. Aside from well-described changes in nutrient consumption and waste excretion, altered cancer cell metabolism also results in changes to intracellular metabolite concentrations. Increased levels of metabolites that result directly from genetic mutations and cancer-associated modifications in protein expression can promote cancer initiation and progression. Changes in the levels of specific metabolites, such as 2-hydroxyglutarate, fumarate, succinate, aspartate and reactive oxygen species, can result in altered cell signalling, enzyme activity and/or metabolic flux. In this Review, we discuss the mechanisms that lead to changes in metabolite concentrations in cancer cells, the consequences of these changes for the cells and how they might be exploited to improve cancer therapy.

To investigate the expression of tumor necrosis factor-alpha inducible protein 9 (TNFAIP9) gene in obese children and its clinical significance, 36 simple obese children and 17 non-obese children were recruited as research subjects. The adipose tissue was obtained by abdominal operation. The expression of TNFAIP9 was detected using real-time fluorescence quantitative polymerase chain reaction and western blot. The relationship between the expression of TNFAIP9 and blood lipid, blood glucose, and obesity indexes was analyzed. The levels of TNFAIP9 mRNA and protein in obese children were significantly lower than those in the control group (P < 0.05). The waist circumference (wc), body mass, body mass index (BMI), fat, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), insulin resistance index (HOMA-IR), and endothelin (ET) in obese children were significantly higher than those in the control group. The level of high-density lipoprotein cholesterol (HDL-C) was significantly lower than that in the control group (P < 0.05). The level of TNFAIP9 protein was negatively correlated with the wc, body mass, BMI, fat, TC, TG, LDL-C, HOMA-IR, and ET (P < 0.05) and was positively correlated with the level of HDL-C (P < 0.05). In conclusion, the expression of TNFAIP9 significantly decreased in the adipose tissue of obese children, and its levels are closely related to blood lipid level, insulin resistance, and obesity.

Aims/hypothesis Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. Methods The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10). Conclusions/interpretation We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Effect of microstructure change on the corrosion behaviour of equal channel angular pressed (ECAPed) 304 stainless steel (SS) was investigated. Nanostructure (80–120 nm) was obtained after 4 and 8 passes ECAP and exhibited a higher corrosion resistance than as-received SS. However, thickness and composition of the passive film formed in air at room temperature on both as-received and 8-pass samples show little difference, indicating that Cr diffusion is not enhanced by the formation of nanostructure. The improved corrosion resistance of ECAPed SS is not caused by thickness or composition change, but by compactness and stability improving of the passive film.

Background & Aims Frequent repression of the Socs1 (suppressor of cytokine signaling 1) gene in hepatocellular carcinoma (HCC) and increased susceptibility of SOCS1-deficient mice to hepatocarcinogens suggest a tumor suppressor role for SOCS1 in the liver, but the underlying mechanisms remain unclear. Here we investigated the role of SOCS1 in regulating hepatocyte proliferation following partial hepatectomy and HGF stimulation. Methods Because Socs1 −/− mice die prematurely due to deregulated IFNγ signaling, we used Socs1 −/− Ifng −/− mice to study the role of SOCS1 in liver regeneration following partial hepatectomy. We examined the activation of signaling molecules downstream of IL-6 and hepatocyte growth factor (HGF) receptors in the regenerating liver, primary hepatocytes, and in human hepatoma cells. We examined the interaction between SOCS1 and the HGF receptor c-Met by reciprocal immunoprecipitation. Results Socs1 −/− Ifng −/− mice displayed accelerated liver regeneration with increased DNA synthesis compared to Ifng −/− and wild type mice. The regenerating liver of Socs1 −/− Ifng −/− mice did not show increased IL-6 signaling, but displayed earlier phosphorylation of Gab1, a signaling adaptor downstream of c-Met. Following HGF stimulation, hepatocytes from Socs1 −/− Ifng −/− mice displayed increased phosphorylation of c-Met and Gab1, cell migration and proliferation. Accordingly, SOCS1 overexpression attenuated HGF-induced phosphorylation of c-Met, Gab1, and ERK1/2 in hepatoma cells, and decreased their proliferation and migration. SOCS1 interacted with the Tpr-Met, an oncogenic form of the Met receptor. Conclusions SOCS1 attenuates c-Met signaling and thus negative regulation of HGF signaling could be an important mechanism underlying the anti-tumor role of SOCS1 in the liver.

The microstructure and mechanical properties of 304 stainless steel were investigated which was subjected to equal channel angular pressing (ECAP). Tensile strength, elongation, Vickers hardness of as-ECAPed and annealed ECAPed 304 stainless steel were systematically measured and compared and microstructure evolution during ECAP and ECAP+annealing was observed by OM and TEM. It was found that with the increasing of ECAP passes, the grain size of stainless steel was effectively refined to nanoscale, such as about 50 nm after 8 ECAP-passes. In addition, the dislocation density in ECAPed samplel increased greatly, consequently, the tensile strength and hardness of ECAPed 304 stainless steel increased and elongation decreased remarkably. After annealing at 600°C for 10 min，the ductility of ECAPed stainless steel was improved greatly while grains did not have obvious growth, and strength did not change much. The above results showed that the optimization of strength and ductility in ultra-fined 304 stainless steel can be achieved by appropriate ECAP plus annealing processes.

Four kinds of core–shell structure acrylic impact modifiers (AIMs) with different rubber crosslinking densities were synthesized. The effects of the rubber crosslinking density of the AIMs on the crack initiation and propagation resistance and the mechanical properties of the AIM/poly(methyl methacrylate) (PMMA) blends were investigated, and we found that the maximum stress intensity factor, crack propagation energy, and Izod impact strength reached maximums when the appropriate rubber crosslinking density of AIM, 2.51 × 1025 crosslinks/m3, was adopted. Transmission electron microscopy photographs of the AIM/PMMA blends showed that the AIMs dispersed uniformly in the PMMA matrix. Meanwhile, through the analysis of optical photos and scanning electron microscopy of the impact fracture surface, we found that the deformation mechanism of the AIM/PMMA blends was local matrix shear yielding initiated by rubber particle cavitation of the AIM. The rubber of the AIM, whose crosslinking density was 2.51 × 1025 crosslinks/m3, was beneficial to the formation of intensive voids and initiated the local shear yielding of nearby modifiers of the PMMA matrix effectively in impact tests, which led to higher Izod impact strengths. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Received 27 December 2005; accepted 5 December 2007DOI 10.1002/app.28317Published online 6 May 2008 in Wiley InterScience (www.interscience.wiley.com).ABSTRACT: Molding temperature, molding pressure,and time are three major parameters affecting the curingquality of molding materials. In this article, the effect ofmolding pressure on warpage of HVQFN packages isstudied. The typical map-chips with 65% silica particle-filled epoxy resin are manufactured under five moldingpressure levels from 1.8 to 12.3 MPa. The curvature meas-urements are performed for the packages after demoldingand postcuring, respectively. The viscoelastic tensile relax-ation modulus of molding materials is obtained by usingdynamic mechanical analysis. The characterization of evo-lution of equilibrium moduli is analyzed for future modifi-cation of the model. The experimental results show thatthe molding pressure has a significant effect on the warp-age after molding as well as after postcuring of HVQFNpackages. The curvatures of HVQFN packages at bothlower (1.8 MPa) and higher molding pressures (12.27 MPa)are about 45% less than the average max curvature at 3.6–8.66 MPa. The molding pressure has obvious influences onthe glassy Young’s modulus but has little effects on therubbery modulus and relaxation time of the package mate-rials.

Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism. Keywords: cancer metabolism; metformin; biguanide; NAD+/NADH ratio; drug sensitivity; complex I; mitochondria; aspartate, National Institutes of Health (U.S.) (Grant P30CA1405141), National Institutes of Health (U.S.) (Grant GG006413), National Institutes of Health (U.S.) (Grant R01 CA168653), National Institutes of Health (U.S.) (Grant R01 CA201276)

The SOCS1 gene coding for suppressor of cytokine signaling 1 is frequently repressed in hepatocellular carcinoma (HCC), and hence SOCS1 is considered a tumor suppressor in the liver. However, the tumor-suppressor mechanisms of SOCS1 are not yet well understood. SOCS1 is known to inhibit pro-inflammatory cytokine production and signaling and to promote activation of the p53 tumor suppressor. However, we observed that SOCS1-deficient mice developed numerous and large liver tumor nodules following treatment with the hepatocarcinogen diethylnitrosamine (DEN) without showing increased interleukin-6 production or activation of p53. On the other hand, the livers of DEN-treated Socs1-null mice showed elevated levels of p21(CIP1/WAF1) protein (p21). Even though p21 generally functions as a tumor suppressor, paradoxically many cancers, including HCC, are known to express elevated levels of p21 that correlate with poor prognosis. We observed elevated p21 expression also in the regenerating livers of SOCS1-deficient mice and in cisplatin-treated Socs1-null hepatocytes, wherein the p21 protein showed increased stability. We show that SOCS1 interacts with p21 and promotes its ubiquitination and proteasomal degradation. Besides, the DEN-treated livers of Socs1-null mice showed increased nuclear and cytosolic p21 staining, and the latter was associated with growth factor-induced, phosphatidylinositol 3-kinase-dependent phosphorylation of p21 in SOCS1-deficient hepatocytes. Cytosolic p21 is often associated with malignancy and chemo-resistance in many cancers. Accordingly, SOCS1-deficient hepatocytes showed increased resistance to apoptosis that was reversed by shRNA-mediated p21 knockdown. In the regenerating livers of Socs1-null mice, increased p21 expression coincided with elevated cyclinD levels. Correspondingly, SOCS1-deficient hepatocytes showed increased proliferation to growth factor stimulation that was reversed by p21 knockdown. Overall, our findings indicate that the tumor-suppressor functions of SOCS1 in the liver could be mediated, at least partly, via regulation of the expression, stability and subcellular distribution of p21 and its paradoxical oncogenic functions, namely, resistance to apoptosis and increased proliferation.

Perfringolysin O (PFO) is a member of the cholesterol-dependent cytolysin (CDC) family of bacterial pore-forming proteins, which are highly efficient in delivering exogenous proteins to the cytoplasm. However, the indiscriminate and potent cytotoxicity of PFO limits its practical use as an intracellular delivery system. In this study, we describe the design and engineering of a bispecific, neutralizing antibody against PFO, which targets reversibly attenuated PFO to endocytic compartments via receptor-mediated internalization. This PFO-based system efficiently mediated the endosomal release of a co-targeted gelonin construct with high specificity and minimal toxicity in vitro. Consequently, the therapeutic window of PFO was improved by more than 5 orders of magnitude. Our results demonstrating that the activity of pore-forming proteins can be controlled by antibody-mediated neutralization present a novel strategy for utilizing these potent membrane-lytic agents as a safe and effective intracellular delivery vehicle.

Item does not contain fulltext Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.

Histone deacetylase (HDAC) inhibitors (HDACi) cause cancer cell growth arrest and/or apoptosis in vivo and in vitro . The HDACi suberoylanilide hydroxamic acid (SAHA) is in phase I/II clinical trials showing significant anticancer activity. Despite wide distribution of HDACs in chromatin, SAHA alters the expression of few genes in transformed cells. p21 WAF1 is one of the most commonly induced. SAHA does not alter the expression of p27 KIPI , an actively transcribed gene, or globin, a silent gene, in ARP-1 cells. Here we studied SAHA-induced changes in the p21 WAF1 promoter of ARP-1 cells to better understand the mechanism of HDACi gene activation. Within 1 h, SAHA caused modifications in acetylation and methylation of core histones and increased DNase I sensitivity and restriction enzyme accessibility in the p21 WAF1 promoter. These changes did not occur in the p27 KIPI or ε-globin gene-related histones. The HDACi caused a marked decrease in HDAC1 and Myc and an increase in RNA polymerase II in proteins bound to the p21 WAF1 promoter. Thus, this study identifies effects of SAHA on p21 WAF1 -associated proteins that explain, at least in part, the selective effect of HDACi in altering gene expression.

Eukaryotic cells compartmentalize biochemical processes in different organelles, often relying on metabolic cycles to shuttle reducing equivalents across intracellular membranes. NADPH serves as the electron carrier for the maintenance of redox homeostasis and reductive biosynthesis, with separate cytosolic and mitochondrial pools providing reducing power in each respective location. This cellular organization is critical for numerous functions but complicates analysis of metabolic pathways using available methods. Here we develop an approach to resolve NADP(H)-dependent pathways present within both the cytosol and the mitochondria. By tracing hydrogen in compartmentalized reactions that use NADPH as a cofactor, including the production of 2-hydroxyglutarate by mutant isocitrate dehydrogenase enzymes, we can observe metabolic pathway activity in these distinct cellular compartments. Using this system we determine the direction of serine/glycine interconversion within the mitochondria and cytosol, highlighting the ability of this approach to resolve compartmentalized reactions in intact cells., National Institutes of Health (U.S.) (NIH grant P30CA147882), National Institutes of Health (U.S.) (NIH grant U54- CA121852-09), National Institutes of Health (U.S.) (NIH grant R01CA168653), David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute/DFHCC Bridge Project), David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Frontier Research), Burroughs Wellcome Fund, Damon Runyon Cancer Research Foundation, Kathy and Curt Marble Cancer Research Fund, American Cancer Society (grant IRG #70-002), United States. Department of Defense (DOD grant W81XWH-13-1-0105), University of California, San Diego (University of California Cancer Research Coordinating Committee grant), Searle Scholars Program (Award)

Numerical simulations for desiccation shrinking and cracking in fine-grained soil, based on Distinct Lattice Spring Model by using a new developed micro mechanism, are performed. Negative pore water pressure and air entry value during drying are accountted for through a new introduced suction force constitutive law which describes the mechanical process of desiccation. Drying cracking of heterogeneous soil can be expressed by failure of the suction force at different time and different position where pore draining to dry is happening. The parameters obtained from free drying simulation are used to model the process of constrained drying. Comparisons are made between the simulation results and experimental data highlighting the capability of the model. A good agreement between simulation and exprimental presentation has been reached. In addition, the influences of random ratio and particle size are discussed in this paper as well.

Sidebands of vibration spectrum are sensitive to the fault degree and have been proved to be useful for tooth fault detection and localization. However, the amplitude and frequency modulation due to manufacturing errors (which are inevitable in actual planetary gear system) lead to much more complex sidebands. Thus, in the paper, a lumped parameter model for a typical planetary gear system with various types of errors is established. In the model, the influences of tooth faults on time-varying mesh stiffness and tooth impact force are derived analytically. Numerical methods are then utilized to obtain the response spectra of the system with tooth faults with and without errors. Three system components (including sun, planet, and ring gears) with tooth faults are considered in the discussion, respectively. Through detailed comparisons of spectral sidebands, fault characteristic frequencies of the system are acquired. Dynamic experiments on a planetary gear-box test rig are carried out to verify the simulation results and these results are of great significances for the detection and localization of tooth faults in wind turbines.

The adsorbed kinetics, proton transportation in electrochemical redox process of 4-pyridyl hydroquinone (4PHQ) self-assembled monolayer (SAM) modified Pt electrode were studied by electrochemical quartz crystal microbalance (EQCM) in situ. It proved that the electrode was modified by a monolayer and underwent a rapid electron transfer. It was a slow adsorbed kinetic process. The ion transfer in the electrochemical redox at the SAM-modified electrode surface mainly involved into the hydrate hydrogen ion.

The SOCS1 gene is a frequent target of epigenetic repression in hepatocellular carcinoma. Many other types of cancer also harbor methylated SOCS1 gene. Besides, recent studies implicate microRNAs targeting SOCS1 in cancer progression. These findings suggest a broad tumor suppressor role of SOCS1 and have stimulated the quest to elucidate the underlying molecular mechanisms. The essential physiological function of SOCS1 is to attenuate interferon gamma signaling in immune cells. SOCS1 binds activated JAK kinases and the receptor chains of several cytokines, some of which are implicated in cancer progression. SOCS1 also facilitates ubiquitination and proteasomal degradation of many signaling molecules downstream of cytokine and growth factor receptors. We have shown that SOCS1 inhibits signaling via the hepatocyte growth factor receptor c-MET in hepatocytes. Aberrant MET signaling, implicated in the progression of many types of cancers, also contributes to the development of chemoresistance to tyrosine kinase inhibitors and drugs targeting other oncogenic signaling pathways. Here, we discuss the SOCS1-dependent regulation of MET signaling as an important mechanism underlying the tumor suppressor role of SOCS1 that is relevant not only to hepatocellular carcinoma but also to other types of cancers.

To identify the developmental expression of the ACRV1 gene in humans and mice, testes cDNA samples were collected at different post-natal days (days 4, 9, 18, 35, 54, and 6 months) from Balb/c mice and were hybridised to the mouse whole genome 430 2.0 Array (Affymetrix Inc.) chip. The characteristics of ACRV1 were analysed using various cellular and molecular biotechnologies. The results showed that the expression of mouse ACRV1 was not detected in mouse testes on days 4, 9, and 18 but was present on days 35, 54, and 6 months. Using RT-PCR analysis of mouse ACRV1, we determined that mouse ACRV1 was expressed specifically in the mouse testis, and its expression began at days 35. Western blot analysis demonstrated that human ACRV1 was primarily expressed in human testes, and immunofluorescent and immunohistochemistry staining showed that human ACRV1 protein was predominantly located in round and elongated spermatids in human testes, indicating that ACRV1 may play an important role in mammalian spermatogenesis and may be a target of a contraceptive vaccine.

Potent catalysis by Ru electrodes has been reported by various workers. Reported here are studies of chemisorption, surface vibrational spectroscope and electrochemical reactivity at Ru(001) single-crystal electrode surfaces. Electrochemical oxidation of methane on these Ru electrode surfaces in aqueous electrolytes was investigated. The influence of surface oxide and electrodeposited silver on methane oxidation were explored. Immersion of Ru(001) into pure water at open circuit forms a layer of adsorbed hydrous oxides with an ordered (2 × 2) structure as measured by Auger spectroscopy and low energy electron diffraction (LEED). Anodization of Ru(001) in 1 M HClO 4 produces a disordered Ru O/OH film consisting of several atomic layers. The high resolution energy electron loss spectrum of this O/OH layer exhibits RuO and OH stretching bands, and the layer is not removed by subsequent electrolysis at negative potentials. Various submonolayer and multiple-layer amounts of silver were electrodeposited on Ru(001). A continuous film is formed, based upon attenuation of the substrate Auger signal. The silver layer lacks long-range order, as judged by LEED. Under the present conditions, namely Ru(001) single-crystal surfaces with or without the O/OH and/or silver layers in aqueous electrolytes, the faradaic current due to oxidation of methane is generally less than 1 μA cm −2 . Experiments were performed with Ru(001) surfaces brought to an atomically clean ordered state by Ar + ion bombardment and annealing in UHV. Immersion of Ru(001) into water at open circuit formed a submonolayer of oxide/hydroxide with an ordered (2 × 2) structure and HREELS vibrational bands attributable to RuO and OH libration and traces of adsorbed CO. Cyclic voltammetry of Ru(001) in aqueous KF and HClO 4 electrolytes illustrated the substantial irreversibility of oxide formation—reduction and the near reversibility of hydrogen adsorption—desorption. Electrochemical oxidation of CH 4 in 10 mM KF electrolyte at pH 3 produced an increase in current density equal to 1 μA cm −2 at potentials between − 0.1 and 0.2 V vs. Ag/AgCl. Electrodeposition of Ag onto the bare Ru(001) surface did not alter the current density for CH 4 oxidation significantly. Electrochemical oxidation of the Ru(001) surface to form a (1 × 1) oxide/hydroxide layer decreased the activity of the surface for anodic oxidation of CH 4 in aqueous KF electrolyte. Electrodeposition of a fractional monolayer or multilayer of Ag onto the electrochemically pre-oxidized surface did not detectably influence the rate of CH 4 electrochemical oxidation. The clearly demonstrated catalytic activity of metal-doped Ru oxide electrodes [1–4] is all the more intriguing in the light of the present results which suggest that the observed catalytic behavior is not due primarily to the metallic Ru surface, layers of adsorbed oxide on Ru or electrodeposited metallic Ag.

Four hundred and thirty-eight endosperm-derived plants of kiwifruit (Actinidia chinensis) were observed. The plants were field planted in 1982 and all had flowered annually since 1986. A sample of these plants was assessed for leaf morphology, growth characteristics, flowering, sex expression, chromosome number, and fruit quality characteristics. The chromosome number of the endosperm plants varied from 58 to 146; most were aneuploid. A few triploid plants (2n=3x=87) were obtained; none of these were parthenocarpic. Segregation of sex expression was observed in progeny from one endosperm-derived callus.

Surface electrochemical studies are reported of SCN − at Ag(111) and Pt(111) electrode surfaces in aqueous solutions. Adsorbate packing density and stoichiometry were investigated by use of Auger electron spectroscopy (AES). Adsorbate molecular constitution and surface chemical bonding were characterized by means of high-resolution electron energy-loss spectroscopy (HREELS), which yielded vibrational spectra spanning the entire IR frequency range. Surface electrochemical behavior was explored by cyclic voltammetry (CV). Packing densities of SCN − at Pt and Ag are essentially the saturation values at all practical concentrations, and at all electrode potentials for which the metal surface is stable. The SCN − ion remains intact during adsorption at Pt and Ag surfaces unless the potential is strongly oxidizing. When adsorbed onto Pt(111) at pH 3, SCN − is protonated (SCNH), while at pH 10 it is not protonated (SCN − K + ). Protonation of Pt/SCN − leads to CH and NH vibrational modes in HREELS, suggesting that the adsorbed layer consists of at least two species (PtSCNH and PtNCHS). However, when adsorbed at Ag(111), SCN − is not protonated, even at pH 3. The C:S stoichiometric ratio (evaluated from AES) was essentially 1:1 under all conditions studied; the packing densities were about 0.5 SCN per surface Pt atom, or 0.25 SCN per surface Ag atom. The HREELS spectra suggest that the axis of the SCN moiety is approximately perpendicular to the Pt or Ag surface. Low energy electron diffraction (LEED) studies revealed a Pt(111)(1 × 2)-SCN structure (θ SCN -2~ 0.5), which was converted by heating (700°C) to Pt(111)(2 × 2)-S (θ s -2~ 0.25), and an Ag(111)(2 × 3√3, rectangular)-SCN structure (θ SCN -2 0.25). Adsorption of SCN − at Pt(111) or Ag(111) as a function of electrode potential revealed noticeable changes in the HREELS spectra, including a blue-shift of the CN stretch with increasing potential. Packing densities were virtually independent of potential, except at extremely positive potentials where a separate AgSCN phase is formed or where the Pt/SCN system undergoes extensive oxidation, and the surface becomes disordered as indicated by LEED.

Reported here are surface electrochemical studies of three newly synthesized compounds: (4-pyridyl) hydroquinone (4PHQ), (3-pyridyl) hydroquinone (3PHQ) and (2-pyridyl) hydroquinone (2PHQ). These compounds possess essentially the same electrochemical reactivity in the dissolved form, but exhibit different electron transfer behavior in the adsorbed state. Each chemisorbs at Pt(111) electrode surfaces from aqueous solutions to form a close-packed and highly oriented monolayer which is stable in vacuum and in solution. Molecular packing density (in nanomoles per square centimeter) was measured by means of Auger electron spectroscopy and coulometry. Surface molecular vibrations were determined by use of high resolution electron energy loss spectroscopy (EELS). Electrochemical reactivity was investigated by use of cyclic voltammetry. Long range surface structure was monitored by low energy electron diffraction. The results indicate that 3PHQ and 4PHQ are attached to the platinum surface exclusively through the nitrogen atom with the pyridine ring in a tilted vertical orientation. Such a surface molecular orientation keeps the hydroquinone moiety pendant and thus reversibly electroactive. Since none of the molecular conformations of adsorbed 4PHQ permits direct contact between the hydroquinone moiety and the Pt(111) surface, electron transfer between the hydroquinone moiety and the surface evidently proceeds by electron hopping and/or tunneling through the chemisorbed pyridine ring. In contrast with the behavior of 3PHQ and 4PHQ, the HQ moiety of 2PHQ is directly attached to the Pt(111) surface in addition to the PtN surface bond of the pyridine ring, as required by the 2PHQ molecular structure. Accordingly, adsorbed 2PHQ possesses virtually no reversible electroactivity and only one adsorbed state in the electrode potential range from −0.1 to 0.4 V, based upon EELS spectra.

Reported here are studies in which an oriented single‐crystal, Hg0.8Cd0.2Te (111), was etched with methanolic bromine solution, ion bombarded with Ar+, and annealed in Hg vapor. Both parallel faces of the crystal, the metal‐terminated (111)A surface and the Te‐terminated (111)B surface, were characterized after each of the above stages of preparation by Auger electron spectroscopy (AES), electron energy‐loss spectroscopy (EELS) and low‐energy electron diffraction (LEED). After polishing in air the (111)A and (111)B surfaces were found to be contaminated with C and S‐containing substances, and deficient in Cd; the LEED patterns were diffuse. EELS spectra showed a broad C–H stretching band near 2980 cm−1 and another broad band centered at 1300 cm−1 due to C–H bending and C–C stretching of surface hydrocarbons. Etching with bromine solution in air removed S‐containing surface contaminants, without significantly changing the LEED and EELS results. Argon ion‐bombardment removed the C contamination and increase...

The convenience and advantage of the long optical pathlength thin-layer cell (LOPTLC) for monitoring the follow-up chemical reactions of electrochemically generated species are demonstrated. The hydrolysis rate constants for various electrogenerated o -quinone and p -quinoneimines are determined at both Pt and glassy carbon electrodes. In the case of Pt, adsorption of the organics was prevented by pretreating the electrode with KI so that the surface is covered with a monolayer of iodine. With the glassy carbon electrode, the effect of surface functional groups on the hydrolysis mechanism is observed when the electrode is preoxidized at high anodic potentials. The ability to see the influence of the surface to the rates and mechanisms of the hydrolysis is due to the high surface area to solution volume ratio of the LOPTLC.

Reported here are studies of the chemisorption, surface vibrational spectroscopy, elemental and molecular packing densities, and electrochemical reactivity of three related five-membered heterocycles at Pt(III): pyrrole (PRR), furan (FRN), and thiophene (TPE). Packing density and stoichiometry were investigated by the use of Auger spectroscopy. None of the adsorbed layers exhibited long-range order detectable by LEED. Vibrational spectra of the chemisorbed species were obtained by means of electron energy-loss spectroscopy (EELS), and were compared with infrared spectra of the unadsorbed compounds. Electrochemical oxidation of the adsorbed molecules was explored by the use of cyclic voltammetry (CV). The results reveal that PRR adsorbs at Pt(III) mainly in a horizontal orientation with the ring intact; electrochemical oxidation of adsorbed PRR proceeds completely to NO2 and CO2. However, FRN is converted by hydrolytic, ring-opening isomerization to adsorbed pi-bonded butenoic acid (BTA); electrochemical oxidation of adsorbed BTA proceeds to CO2. TPE forms a mixed layer consisting of S atoms and adsorbed TPE molecules S-bonded and near-vertically oriented; adsorbed TPE is oxidized to CO2 and SO42−.

Surface chemistry studies are described in which molecular layers chemisorbed at well-defined Pt or Ag electrode surfaces from aqueous solutions were characterized by means of ex–situ UHV surface analysis techniques such as Auger electron spectroscopy (AES), electron energy–loss spectroscopy (EELS), and low-energy electron diffraction (LEED), and in–situ electrode–solution interfacial characterization methods such as cyclic voltammetry (CV) and coulometry. Types of compounds studied include alcohols, ethers, aldehydes, ketones, carboxylic acids, amines, amino–acids, amides, cyanides, thiocyanides, halides, mercaptans, thiols, sulfones, sulfonic acids, benzenes, five– and six– membered heterocyclic aromatics, multinitrogen heteroaromatics, fused–ring aromatics, and deuterated molecules. Molecules chemisorbed at electrode surfaces are often not removed by rinsing, facilitating investigation by electrochemical methods, and arc stable also in vacuum, permitting identification and characterization of the adsorbed species by AES, EELS and LEED and related methods. Molecular stoichiometry (elemental composition) and packing density (surface concentration, molecules per unit area) are measured by means of AES. Surface molecular orientation can be deduced from molecular packing densities, supplemented with adsorbate vibrational spectra, electrochemical reactivity, LEED structure and other related observations. Studies of series of related adsorbates offer the advantage that additional insight can be gained from intercomparison of molecular surface behavior as a function of systematic structural and chemical differences. Electrochemical reactivity is found to be a function of molecular orientation: horizontally oriented adsorbates at Pt surfaces in most cases undergo complete electrochemical oxidation to CO2 and other oxides, while vertically oriented adsorbates undergo less extensive oxidation; reversible redox centers such as the hydroquinone and catechol moieties retain their electrochemical reactivity and reversibility at electrode surfaces only when the redox center is pendant, and direct attachment of a redox center at surfaces results in loss of redox electro- activity.Close similarity between adsorbed layer EELS spectra and the IR spectra of the unadsorbed liquid or vapor is usually found for vertically oriented adsorbates for which adsorption docs not substantially perturb the main–frame molecular structure. Surface chemical phenomena involving molecular adsorbates at electrode surfaces, including molecular Packing density, mode of attachment, surface orientation, long–range surface order, molecular structure, spectroscopic behavior, and chemical and electrochemical reactivity, are greatly influenced by factors such as adsorbate molecular structure, electrode material, crystallographic structure of electrode surface, electrode potential, solution pH, adsorbate concentration, and temperature.

The principal aim of this study was to develop an oral microemulsion formulation of berberine in order to improve its bioavailability. The Microemulsion was prepared with pharmaceutically acceptable ingredients such as oleic acid, Tween 80 and PEG400. Phase diagrams were drawn to elucidate the phase behavior of systems, which were composed of Tween 80 as surfactant and PEG400 as cosurfactant. A single isotropic region, considered to be a bicontinuous microemulsion, was detected in the pseudo ternary phase diagrams. The berberine-loaded microemulsion was characterized by viscosity, refractive index, electrical conductivity and particle size. In vivo pharmacokinetic profile and oral bioavailability were also investigated in rats. The optimized formulation was as follows: 15 wt.% oleic acid, 17 wt.% Tween-80, 17 wt.% PEG400, and 51 wt.% water. The formulated microemulsion was found to be relatively uniform in size (24.0 nm). The in vivo study indicated that the bioavailability of the oral berberine-loaded microemulsion formulation was 6.47 times greater than that of the berberine tablet suspensions. The results suggest that the microemulsion is a promising oral drug delivery system for berberine.

Surface electrochemical studies of 2-pyridinethiol (2PyT, 2-mercaptopyridine) and 4-pyridinethiol (4PyT, 4-mercaptopyridine) at Ag(111) single-crystal electrode surfaces in aqueous fluoride solutions are reported. LEED patterns observed for 2PyT adsorbed at Ag(111) from a 1 mM aqueous solution containing 2 mM HF (pH 3) at potentials between −0.54 V and −0.64 V (vs. Ag/AgCl reference) reveal that an ordered layer is formed having a rectangular unit mesh, Ag(111) (2×0.53)R30°-2PyT, containing one molecule of 2PyT. Adsorption at potentials more positive than −0.54 V results in LEED patterns which are relatively diffuse and have not yet been identified. A weak but observable Ag(111) (30.53× 30.53)R30° LEED pattern is obtained for adsorption of 4PyT at −0.40 V from a 1 mM aqueous solution (pH 3). Molecular packing densities (nmolcm2) measured by means of Auger spectroscopy indicate that 2PyT and 4PyT molecules are adsorbed with the pyridine ring perpendicular to the Ag(111) surface. The packing density of these adsorbates is virtually independent of adsorbate concentration from 0.01 mM to near saturation (about 0.2 M) at −0.60 V. Packing density of 2PyT increases slightly but abruptly when the electrode potential is increased above about −0.4 V. The Ag(111) (2×0.53)R30°-2PyT structure contains about 0.57 nmolcm2, slightly less than the saturation packing density, 0.67 nmolcm2, observed at more positive electrode potentials. EELS spectra of adsorbed 2PyT indicate that attachment to the Ag(111) surface at potentials less than −0.2 V occurs primarily through the sulfur atom, with dissociation of the sulfhydryl hydrogen atom. At potentials more positive than 0.0 V, a coupling reaction between an adsorbed 2PyT and a dissolved 2PyT occurs at the Ag(111) surface. The occurrence of this coupling reaction is more apparent for 4PyT at the Ag(111) surface. Amplitudes of the EELS bands due to CH bending and CS stretching depend upon the electrode potential at which adsorption is carried out. EELS spectra of 2PyT adsorbed at Ag(111) at negative potentials (E < −0.4 V) closely resemble the IR spectrum of the unadsorbed compound; the same is true for 4PyT. Apart from potential-dependent adsorption/desorption and coupling reactions, adsorbed 4PyT and 2PyT are relatively inert towards electrochemical oxidation and reduction. The 2PyT and 4PyT adsorbed layers are stable in UHV.

Etude de l'adsorption de la pyrazine, la pyrimidine, la pyridazine, l'acide 2-pyrazine carboxylique, l'acide 2,3-pyrazinedicarboxylique, l'acide 4-pyridazinecarboxylique et la 1,3,5-triazine sur une electrode de platine

The adsorption behavior of bipyridyls and structurally related compounds from solution at well-defined Pt(111) surfaces is examined in this study to explore the influence of adsorbate molecular structure on surface bonding, molecular orientation, vibrational spectroscopy, acid-base reactivity, and electrochemical behavior of adsorbed aromatic molecules. Molecules were selected to represent various degrees of steric hindrance at the ring nitrogens. A series of carboxylic acids was also studied in order to explore the interactions between acidic moieties and the Pt(111) surface. Packing densities (moles adsorbed per unit area) were measured by means of Auger spectroscopy. Linear potential scan voltammetry was used to determine the reactivity of the adsorbed layers toward electrochemical oxidation; electrochemical reactivity of these compounds provides important clues to their mode of bonding to the surface. Surface vibrational spectra were obtained by electron energy-loss spectroscopy (EELS) and are assigned by comparison with the IR spectra of the pure compounds. The Pt(111) surfaces used in this study were characterized by LEED. Most of the subject compounds are adsorbed with the ring plane nearly perpendicular to the platinum surface; the exceptions are those prevented from doing so by steric constraints such as bulky substituents adjacent to the aromatic nitrogen atoms.

Studies are reported of the surface packing density, vibrational spectroscopy and electrochemical oxidation of a series of straight-chain terminal alkenes adsorbed from the vapor at a Pt (111) electrode surface. Compounds studied were: ethene (ETE), propene (PPE), 1-butene (BTE), 1-pentene (PTE), 1-hexene (HXE), 1-octene (OCE) and 1-decene (DCE). Vibrational spectra of the adsorbed layers were obtained by use of electron energy-loss spectroscopy (EELS). Molecular packing densities (nmol/cm2) in the adsorbed layer were measured by use of Auger spectroscopy. Electrochemical oxidation of each adsorbed layer in aqueous inert electrolyte (KF+ HF) was investigated by means of linear potential scan voltammetry. Attachment to the surface is through the CC bond. Based upon molecular packing densities, the aliphatic chains are pendant; regardless of its chain length, each chemisorbed alkene molecule occupies an area similar to that of chemisorbed PPE. The packing densities of ETE and PPE indicate an average orientation in which the CC moiety is parallel to the Pt (111) surface. EELS spectra indicate that the CC double bond is preserved in the adsorbed state of each 1-alkene studied. Measurement of the average number of electrons, nox, required to desorb an adsorbed 1-alkene molecule electro-oxidatively reveals that the catalytic electrochemical oxidation process involves primarily the CC double bond and one adjacent saturated carbon atom.

In this study EELS spectra obtained for the adsorbed species formed from aqueous electrolytes at Pt(111) electrode surfaces are compared with the IR and Raman spectra of the unadsorbed compounds in order to reveal the changes in vibrational spectra resulting from chemisorption of various important functional groups, and to explore the differences in vibrational absorptivities between EELS spectra of adsorbed species and IR and Raman spectra of the corresponding unadsorbed compounds. Of particular interest are the variations in EELS vibrational frequency, bandwidth and absorptivity due to bonding with the surface, intermolecular interactions of adsorbed molecules and changes in adsorbate molecular orientation. The influence of surface bonding on the EELS spectrum of a functional group was explored through studies of phenol (PL), phenol-d6 (PLD6), benzyl alcohol (BZOH), catechol (CT), benzoic acid (BA), 2-picolinic acid (PA), 2,6-pyridine dicarboxylic acid (26PDCA), and propenoic acid (PPEA). The aromatic ring of adsorbed PL, PLD6, BZA, CT, BA, PA and 26PDCA is oriented parallel to the Pt(111) surface. The resulting strong interactions affect the frequencies and relative intensities of the EELS bands: weak CH stretching modes; a large CC stretching band (1600–1650 cm−1), and weak CH bending (700–800 cm−1). The carboxylic acid moieties of BA and PA interact strongly with the Pt surface, while those of 26PDCA do so only when adsorbed at relatively positive electrode potentials. OH stretching and bending are absent from the EELS spectra of adsorbed PL, BZOH and CT, perhaps due to dissociation of the hydroxyl hydrogen during adsorption of the molecule. Adsorption of alkenes at Pt(111) from solution preserves the characteristic CC stretching band near 1650 cm−1; examples are: PPEA; 1-hexene (HXE); propenol (PPEOH); 4-pentenol (PTEOH); and cis-2-butene-1,4-diol (CBED); adsorption of ethene, propene and butene from vacuum at room temperature has been reported to result in loss of double-bond character. Adsorption of propynol (PPYOH) lowers the frequency of the CC triple bond to approximately that of a double bond. EELS spectra of adsorbed pyridine (PY), 2-methylpyridine (2MPY) and 2,6-dimethylpyridine (26DMPY) were examined in order to contrast the vibrational behavior of adsorbates having the aromatic ring perpendicular to the Pt surface (PY and 2MPY), giving rise to strong perturbation of the vibrational spectra or parallel (26DMPY), leading to limited perturbation of the vibrational spectra. Compounds for which the surface interaction is limited primarily to bonding of a single sulfur atom were studied in order to observe the vibrational behavior of a comparatively unperturbed pendant ring or chain: thiophenol (TP); benzylmercaptan (BM); cysteine (CYS); and thiophene (TPE). The expected lack of perturbation was found, making TP, BM and CYS particularly suitable reference compounds for surface vibrational studies of aromatic rings and amino acids. In contrast, L-phenylalanine (PHE) interacts with the Pt(111) surface through the phenyl ring as well as the amino acid functionality. In general, chemisorption and intra-layer intermolecular interaction both lower the surface vibrational frequencies (EELS) and incidentally affect peak amplitudes. Orientation affects peak amplitudes and incidentally affects frequencies insofar as a change in orientation is accompanied by a change in mode of surface bonding. Surface roughness leads to a scrambling of adsorbed states which affects bandwidths, chemical/electrochemical reactivities, and in turn the frequencies and amplitudes of EELS peaks. Specific findings and conclusions are presented for each compound and correlated.

Background While the association between ACPA and RA has been established, the impact of citrullination at the level of the protein is not well-defined. PAD enzymes remove an imine moiety from arginine to form citrulline. This enzymatic process results in the loss of a positive charge which can lead to a change in protein structure, consequential function or susceptibility to proteolytic processing.1 In an analogous fashion to the phosphorylome (phosphoproteins), to fully elucidate the role of citrullination for applied basic and clinical research, the field requires a laboratory developed pan reactive citrullination specific antibody (Ab) that identifies members of the “citrullinome” and site-specific citrullination antibodies that are generated to each target epitope since individual citrullination sites within a protein might elicit a gain or loss in function for the protein. These types of tools have clear advantages over other identification approaches like mass spectrometry, in that they are highly reproducible, can easily be integrated into multiple assay formats and are cost effective. Objectives The objective of this study was to 1) develop a pan reactive citrullination specific antibody and 2) an assay that can detect citrullinated 14-3-3η in patient serum. Methods 5 cit peptides and their corresponding arg peptides were synthesized and conjugated to BSA. 4 of the 5 peptides corresponded to putative 14-3-3η cit sites. One of the peptides, Peptide 4, was modelled on a PAD consensus motif. Polyclonal Abs to Peptide 4 were reproducibly raised in two independent species; twice in rabbits and once in goats with 3 animals per study. Reactivity was assessed by examining titres to both the citrullinated and arginylated forms of Peptide 4. Sera selected for purification underwent a two-step purification process utilizing the arg and cit peptide. Purified Cit-Ab was tested by examining reactivity to the other 4 cit-peptides and the corresponding arg forms. The Cit-Ab was tested by immunoblot analysis using cit 14-3-3η and cit vimetin that was generated using recombinant PAD4 as well as by 14-3-3η ELISA in seven 14-3-3η positive rheumatoid arthritis patients with levels >20 ng/ml. Results Five of the 6 rabbits and 2 of the 3 goats elicited immune responses that preferentially reacted with the cit form of Peptide 4. In a serial dilution study (1:50,000 to 1:250,000) the goat sera selected for purification exhibited 20X greater reactivity for the cit versus arg form of peptide 4. Purified Ab preferentially reacted with 3 of the 5 peptides based on a 2X ratio, and detected cit 14-3-3η and vimentin over the corresponding non-modified forms of these 2 proteins. As demonstrated in the [table][1] below, the burden of citrullination varied amongst patients despite having serum 14-3-3η levels >20ng/ml. View this table: Conclusions The pan reactive cit-specific Ab can be reliably reproduced and binds to multiple cit sites within a protein and across different proteins. The ELISA data reveals that the burden of citrullination varies amongst RA patients despite having similar levels of 14-3-3η protein. Citrullination of the “14-3-3η protein” is being clinically investigated in the context of disease outcomes. References 1. International Journal of Biochemistry and Cell Biology Disclosure of Interest Y. Gui Employee of: Augurex Life Sciences Corp, M. Murphy Employee of: Augurex Life Sciences Corp, W. Maksymowych Consultant for: Augurex Life Sciences Corp, (Co-inventor of 14-3-3η), A. Marotta Employee of: Augurex Life Sciences Corp, (Co-inventor of 14-3-3η) [1]: #T1

Background 14-3-3η is a joint-derived soluble biomarker that is available as a diagnostic test in the US, Canada and Europe. As an extracellular ligand 14-3-3η potently and dose-dependently upregulates the expression of multiple factors including TNFα, IL-6 and RANKL and its clinical expression is associated with joint damage progression risk. Several disease modifying agents are available for the treatment of RA with remission efficacy rates around 30% with none that have direct companion biomarkers for patient selection and therapy response monitoring. Since RA is driven by multiple factors to varying degrees, within and between patients along the disease course, personalized medicine that enables the specific targeting and measurement of disease potentiators, such as 14-3-3η, is highly desirable. Objectives To evaluate the in vivo feasibility of targeting 14-3-3η with a monoclonal antibody drug candidate to mitigate the onset and severity of collagen-induced arthritis (CIA) in mice. Methods 27 DBA/1 mice were randomized to four study groups: non-induced mice (negative control, N=5), 0.5 mg/kg of dexamethasone group (positive control, N=6), vehicle (saline) injected mice (placebo group, N=10), and the treatment arm that was administered 10 mg/kg of 14-3-3η mAb (N=6). Treatments were initiated 2 days prior to immunization with collagen and administered daily for 6 weeks. A collagen booster was injected on day 18 of the study for all immunized mice. Arthritis scores were determined by an established and standardized chart evaluating inflammation and swelling of each paw. Each paw was scored daily from 0 to 4 based on the severity of the swelling. All animals were sacrificed 42 days after the beginning of the treatments as predetermined. No animals reached a score of 4 being the exclusion point where the animal is euthanized due to severity of the swelling. Student t-test was performed to examine differences (onset CIA score, maximum score and end score) amongst the two groups and the Kruskal Wallis test was used to compare group daily score differences over the course of disease. Results Non-induced (negative control) and Dexamethasone (positive control) mice did not develop visible signs of arthritis over the course of disease while 100% of the mice within the saline arm did. 17% of the mice in the 14-3-3η mAb group did not develop any signs of arthritis. The CIA score for the 14-3-3η mAb arm had significantly lower CIA onset scores (0.83±0.41 vs 7±1.57, p=0.0119), maximum CIA scores (2.8±1.48 vs 5.3±1.83, p=0.0052) and end CIA scores (2.2±1.79 vs 4.3±1.7, p=0.0197) than the saline treated groups. Figure 1 further demonstrates that 14-3-3η mAb treated mice have significantly lower disease over the disease course than animals in the saline group, p Conclusions 14-3-3η is a mechanistic joint damage factor involved in the pathogenesis of RA that has diagnostic and prognostic utility. It represents a novel RA personalized medicine drug target based on anti-14-3-3η mAb efficacy in delaying the onset and reducing the severity of arthritis in CIA. Disclosure of Interest A. Abulrob Employee of: National Research Council, M. Mercier Employee of: National Research Council, S. Corluka Employee of: National Research Council, R. MacKenzie Employee of: National Research Council, S. Raphael Employee of: National Research Council, S. Michienzi Employee of: Augurex Life Sciences Corp, J. Savill Employee of: Augurex Life Sciences Corp, Y. Gui Employee of: Augurex Life Sciences Corp, W. Maksymowych Consultant for: Augurex Life Sciences Corp, (Co-inventor of 14-3-3η), A. Marotta Employee of: Augurex Life Sciences Corp, (Co-inventor of 14-3-3η)

In electronic packaging, molding compounds are frequently used for encapsulation. During manufacturing processes, the combined chemical shrinkage and thermal expansion often result into undesirable product warpage. Molding temperature, molding pressure and time are three major parameters affecting the curing quality of molding materials. Investigation of the effects of molding pressure on the warpage of HVQFN (head-sink very-thin quad flat non-lead) packages is important for minimizing the warpage and residual stresses and the optimal design of the products. In previous work a cure-dependent viscoelastic constitutive model gave a good prediction of the process induced stresses and warpage in HVQFN packages with different curing temperatures and degree of cure. In this paper, the effect of molding pressure on warpage of HVQFN packages is studied with the aim of verifying and modifying the previously proposed model. The typical map-chips with 65% silica particle-filled epoxy resin are manufactured under 5 molding pressure levels from 1.8 to 12.3 MPa. The curvature measurements are performed for the packages after demolding and post curing respectively. The viscoelastic tensile relaxation modulus of molding materials is obtained by using dynamic mechanical analysis (DMA). The characterization of evolution of equilibrium moduli is analyzed for verification and future modification of the model. The experimental results show that the molding pressure has a significant effect on the warpage after molding as well as after post curing of HVQFN packages. The curvatures of HVQFN packages at both lower (1.8MPa) and higher molding pressures (12.27MPa) are about 45% less than the average max curvature at 3.6 /spl sim/ 8.66MPa. The molding pressure has influences on the glassy Young's modulus but has no effects on the rubbery modulus and relaxation time of the package materials.

The Visible Human Project is an outgrowth of the NLM's 1986 Long-Range Pian. It is creating a complete, anatomically detailed, three-dimensional representations of the male and female human body. This paper makes a brief description about VHP and it's significance, how to get VH data set and how to use it.

In this paper, a new algorithm based on Voxel Model is proposed. This algorithm combines the advantages of surface rendering and direct volume rendering. In the process of 3D reconstruction, OpenGL graphic standard and hardware accelerator can be used. By doing so, better reconstruction, result and fast speed can be achieved. Also, it is simple to turn this algorithm into programs.

To isolate and elucidate the chemical constituents in the roots of Rabdosia japonica.The constituents were extracted by ether and isolated by chromatography on silica gel and ODS. The structures were determined by IR, H NMR, 13C NMR and MS spectra respectively.Four compounds were elucidated as glaucocalgxin A, oleanolic acid, ursolic acid and daucosterol.Oleanolic acid and daucosterol were isolated from this plant for the first time.

The safety and contraceptive efficacy of Sino-implant combined with a testosterone undecanoate regimen was evaluated. A total of 16 Chinese men volunteers, aged 22-42 years, were recruited for the entire research program. The studied regimen was a subdermal insertion of a two-rod implant for 3 months. Then, after 18 weeks of implantation, the Sino-implant was removed. Findings showed that among the participants, 6 men reached azoospermia, 1 reached oligozoospermia, 5 reached sperm density declination, and 4 reached sperm density declination during the treatment period. After implantation, average duration of azoospermia was 16.7 +or- 0.5 weeks; it took 8.2 +or- 2.5 weeks to regain normal sperm density. In the first week of implantation, the levonorgestrel level in blood was the highest; it declined after 8 weeks and later became constant. Moreover, there were no significant differences in the serum triglycerides, total cholesterol, high-density lipoprotein-C and low-density lipoprotein-C levels between the baseline period and end of treatment period or end of recovery period (P 0.05). Results indicated that the regimen had little effect on the subjects' lipid and lipoprotein throughout the study. Furthermore, monthly physical examinations were normal in all subjects. Thus, this regimen was safe and effective as a male contraceptive regimen with widespread clinical use.

Background Serum 14-3-3η is a novel protein biomarker for rheumatoid arthritis (RA) and is available for clinical use in the United States, Europe, and Canada. It precedes the onset of RA and its presence is associated with the development of RA. Objectives In this study, we investigated whether serum 14-3-3η is useful as a marker for RA disease activity and a predictive factor for therapeutic efficacy of tocilizumab. Methods Serum 14-3-3η protein levels were measured in 41 patients (median age 54 yrs, range 20–78 yrs) with RA before and 12-weeks after treatment with tocilizumab (8 mg/kg iv every 4 weeks), using the Augurex 14-3-3η ELISA kit (positive ≥0.19 ng/ml). Median DAS28-ESR and CDAI of the RA cohort before treatment were 5.1 (range 2.1–7.5) and 22.7 (range 10.4–60.8), respectively. 31 of 41 patients were ACPA positive, 37 were MMP3 positive and 1 was negative for both markers. Mann-Whitney U-tests and Fisher9s exact tests were performed for comparison between treatment groups. A regression analysis was performed to determine if serum 14-3-3η levels was an independent predictor of a Good EULAR response and remission, DAS Results At pre-treatment, 28 (68%) of 41 patients were 14-3-3η positive and the 14-3-3η positive group tended to have higher baseline DAS28-ESR (4.5 vs 5.3, p =0.055) and CDAI (20.0 vs 25.4, p =0.046). The paired t-test revealed that 14-3-3η levels were significantly lower post-treatment with tocilizumab (4.7 vs 3.7, p =0.028). Patients with a post-treatment decrease in 14-3-3η had a significantly greater change in MMP3 levels compared to the group with no decrease (54.8 vs 8.0, p =0.027). The change in ACPA, DAS28-ESR and CDAI did not differ between the two 14-3-3η groups. According to the EULAR response criteria, the group of good responders ( n =17) had significantly lower pre-treatment 14-3-3η levels compared to the group of moderate and no responders ( n =24), 0.37 vs 1.76 ng/ml, p =0.0252. Similarly, the pre-treatment 14-3-3η levels were significantly lower in the group of patients that achieved remission ( n =13) by DAS28-ESR ( p =0.045) between DAS remission and 14-3-3h negativity delivering an odds ratio (OR) of 3.4 (95% CI: 0.9–13.3). No association between 14-3-3h and a good EULAR response was observed. Regression analysis controlling for baseline DAS28-ESR revealed that 14-3-3h titres were an independent predictor of remission yielding a likelihood ratio (LR) of 7.8, p =0.0052. Conclusions Serum 14-3-3η protein is a biomarker that may predict efficacy of tocilizumab treatment for RA. Further study is required to establish the usefulness of 14-3-3η in terms of treatment with other biologics and/or long-term administration of tocilizumab. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4942