In the current study we used only gene expression

In the current study, we used only gene expression data for the analysis; however, phosphoproteomics data could also be used to assign weights to the signaling interactome for the inference of niche determinants. An important limitation of the method is that it considers only DERs as the sources of niche induced signaling to regulate the expression of downstream TFs for a given phenotype. Nevertheless, even those receptors that are not differentially expressed can play a crucial role in regulating the target TFs for the stable maintenance of TRNs. Nevertheless, given only gene expression data with limited number of replicates, it is not feasible to quantitate absolute expression levels of genes without resorting to differential gene expression. However, with the advancements in single cell sequencing techniques, that can offer expression levels at single cell resolution, one can more reliably quantitate absolute gene expression levels for a given cell type. In such cases, our method does not need to rely on differential gene expression and can take advantage of absolute expression status of the receptors to infer the niche determinants. Further, this could allow considering multiple phenotypes simultaneously without the need for pair-wise comparison. Therefore, the proposed method is flexible in its application to different kinds of data including phosphoproteomics and single cell RNA sequencing.

Materials and methods
A schematic representation of our method is shown in Fig. 1 and the detailed description of the methods is provided in the Supplementary Information.


Remarkable progress has been made in the research and application of neural stem ciprofloxacin (NSCs) and progenitor cells (NPCs) demonstrating their tremendous potential for stem-cell based cell therapy or targeting endogenous NPCs to treat CNS injury and neurodegenerative diseases (Gage and Temple, 2013; Goldman et al., 2012; Gupta et al., 2012; Lu et al., 2012; Ming and Song, 2011). New opportunities have emerged to discover neural regenerative therapeutics towards significant unmet medical needs. However, many challenges still remain. For example, in injured CNS and under disease conditions, transplanted NPCs preferentially become astrocytes (Aboody et al., 2011; Reekmans et al., 2012; Robel et al., 2011). Small molecules that modulate the developmental processes of NSCs or NPCs towards desired cell fate not only offer significant opportunities for therapeutic drugs targeting endogenous NPCs for repair and regeneration, but also could enhance the efficacy of NSC transplantation for neuronal replacement (Li et al., 2013).
Once committed to a certain cell fate, NPCs undergo cell cycle arrest and terminal differentiation leading to the exhibition of cell-type-specific features. NPC differentiation including neurogenesis and gliogenesis is a highly orchestrated process that is tightly regulated via both extrinsic environmental signals and intrinsic changes in gene expression and epigenetic regulation. Several crucial signaling pathways including Wnt, Notch and the bone morphogenetic proteins (BMPs) pathway have been identified in regulating the development of ciprofloxacin NPCs (Faigle and Song, 2013; Kriegstein and Alvarez-Buylla, 2009). The interplay of transcription factors and epigenetic modifiers, including histone modifications, DNA methylation and microRNAs during development is essential for NPCs to control self-renewal, fate specification, and differentiation (Hirabayashi and Gotoh, 2010; Juliandi et al., 2010). Suppression of astrocytic lineage genes during the neurogenic phase is one of the key cell-intrinsic epigenetic mechanisms underlying fate specification (Kanski et al., 2014; Sun et al., 2001). Recent studies have identified many different types of epigenetic regulators, including polycomb group and trithorax group proteins, DNA-damage inducible protein 45b, methyl-CpG-binding protein MBD1, DNA methyltransferases, histone deacetylases (HDACs) and acetyltransferases (HATs), which are involved in the tight regulation of the proliferation and specification of NPCs or the differentiation and maturation of newborn neurons (Lim et al., 2009; Ma et al., 2010; Wu et al., 2010; Zhao et al., 2003). In the case of histone modifications, extensive studies have now illustrated the important role of the histone code in methylation and acetylation, epigenetic writers ( HATs) and erasers (HDACs) in neurogenesis (Hsieh et al., 2004; Merson et al., 2006; Montgomery et al., 2009; Prozorovski et al., 2008; Yu et al., 2009). However, little is known about epigenetic readers in the development of NPCs and neurogenesis.

br Results br Discussion The


The cognitive deficits associated with prenatal VPA exposure might not due solely to the reduced neurogenesis with the abnormal neuronal morphology in the hippocampus, and there is a possibility that the low freezing responses in fear associative tests were contributed by the deficiency in amygdala, nociception, and/or motoric functions. Nevertheless, our data suggested that the reduced neurogenesis associated with the abnormal neuronal morphology in the hippocampus were very likely to be correlated with the observed cognitive deficits for several reasons. First, voluntary running is well known for its effect on enhancing both adult neurogenesis in the DG of the hippocampus and hippocampus-dependent learning and memory (Zhao et al., 2008), and this voluntary running could recover the cognitive deficit, if not all, in VPA-treated mice with reduced neurogenesis in the DG. Second, to the best of our knowledge, there are no reports to date that show a direct contribution of voluntary running to the enhancement of amygdala function that subsequently leads to an improvement in the cued fear response. Third, based on experiments that we have conducted, we could not find any significant differences in amygdala size and in the expression levels of cortical layer-specific genes of MC- and VPA-treated mice, with or without voluntary running. Fourth, total traveled distance in the open field, elevated plus and the Y-maze tests, and the number of light/dark transitions were not significantly different between MC- and VPA-treated mice, although in our earlier experiment some of these parameters showed modest differences. Moreover, in fear associative test, VPA-treated mice move similarly to MC-treated mice before the start of the tone (pre-tone), which indicate that motor deficiency is unlikely to be the main cause of low freezing responses in VPA-treated mice. Fifth, MC- and VPA-treated mice have similar basal nociceptive response and startle response to electric footshock during the conditioning for fear-associative test, thus it seems unlikely that VPA-treated mice have abnormal nociception and cannot sense the foot shock. Taking these facts into consideration, we therefore suggested that the reduced neurogenesis associated with the abnormal neuronal morphology in the hippocampus were very likely to be a critical cause of the observed cognitive deficits. However, we still cannot completely exclude the possibility that changes in other atp gamma s areas may also contribute to the deficits, warranting further future investigation.
We and others have shown previously that VPA treatment induces neuronal differentiation but suppresses glial differentiation of cultured multipotent NPCs (Hsieh et al., 2004; Balasubramaniyan et al., 2006; Murabe et al., 2007; Abematsu et al., 2010; Juliandi et al., 2012). We have now demonstrated that VPA also increases histone acetylation in the embryonic forebrain and induces neuronal differentiation of embryonic NPCs. Previous study have shown that VPA promotes neuronal differentiation by increasing histone H4 acetylation at proneural gene promoters (Yu et al., 2009). However, several studies have suggested that the activation of GSK-3β/β-catenin and/or ERK pathway is the main cause for the increase neurogenesis of NPCs by VPA (Yuan et al., 2001; Jung et al., 2008; Hao et al., 2004; Go et al., 2012). It has been suggested that VPA might have various cellular effects that will depend on the context of VPA usage and/or cell type and experimental design used in the study, which warrant further research to reveal the connection between these effects (Kostrouchová et al., 2007; Rosenberg, 2007).
We suggest that gene expression change caused by VPA is attributable mainly to its HDAC-inhibiting activity. To date, more than a dozen HDACs have been characterized and they are classified into at least three major groups. In particular, HDAC1 and HDAC2, belonging to the class I group, have been reported to regulate NPC differentiation (Sun et al., 2011). NPCs express high levels of HDAC1 and some of them also express low levels of HDAC2 (MacDonald and Roskams, 2008). Interestingly, as NPCs are committed to the neuronal lineage, expression of HDAC2 is upregulated while that of HDAC1 is downregulated and becomes undetectable in most post-mitotic neurons (MacDonald et al., 2005; MacDonald and Roskams, 2008); on the other hand, HDAC1 expression is sustained in the majority of cells in glial lineages (astrocytes and oligodendrocytes), in which HDAC2 is not detected (Shen et al., 2005; MacDonald and Roskams, 2008). Moreover, HDAC2, but not HDAC1, was found to inhibit astrocytic differentiation (Humphrey et al., 2008). Therefore, although VPA is capable of inhibiting both HDAC1 and HDAC2 (Kazantsev and Thompson, 2008), it is tempting to speculate that the main target of VPA in HDAC inhibition-mediated neuronal differentiation of NPCs is HDAC1. It will be of interest to explore this possibility in a future study.

Previous studies suggest that approximately one

Previous studies suggest that approximately one out of ten serum-cultured ESCs contribute to embryonic development (Wang and Jaenisch, 2004). If 2i and KOSR cultures generated more single-cell chimeras by increasing the proportion of functionally potent ESCs, we would also expect to observe some chimeras from serum-cultured ESCs (n = 87 injected embryos). As a result, it is not merely that serum-cultured ESCs contain fewer “pluripotent” cells, but that their clonogenic capacity to self-renew is limited. The increased functional potential of individual 2i-cultured (Morgani et al., 2013) and KOSR-cultured ESCs to generate embryonic and extraembryonic lineages could be a feature of their increased clonogenicity. It has previously been shown that ESCs cultured in the presence of the 2i inhibitors as well as an FGF receptor inhibitor (3i) exhibit increased clonogenicity compared with serum-cultured azilsartan medoxomil in vitro (Ying et al., 2008), and single 2i-cultured cells show an increased capacity to generate multiple cell types in differentiation assays (Morgani et al., 2013). If 2i- and KOSR-cultured ESCs undergo increased numbers of self-renewing cell divisions, even in the presence of signals that promote lineage restriction, they may generate a critical mass to effectively contribute to both Epi and extraembryonic lineages. In support of this hypothesis, ESC clones exhibiting a greater rate of proliferation generate a higher number of chimeras than those with slower proliferation rates (Wang and Jaenisch, 2004).
Although individual clonogenic ESCs can appear totipotent, the fraction of these cells in different culture conditions may vary, and this could explain why aggregate gene-expression data indicate that 2i cells represent distinct developmental stages (Boroviak et al., 2014). Here we find two clear signatures in the 2i dataset, early pre-implantation development and Epi, perhaps representing this heterogeneity.
We also observed that ESC culture in KOSR enhances their functional potency. At a transcriptional and functional level, these cells are biased toward endoderm. This is distinct from cells cultured in 2i that can differentiate into both trophoblast and extraembryonic endoderm in vitro and in vivo (Morgani et al., 2013). However, ESCs grown and derived in either condition exhibit enhanced potency on a single-cell level. Thus ESC culture conditions may enhance potency by promoting competence for extraembryonic lineages. Moreover, a number of recent reports on ESC totipotency use KOSR in their culture medium (Abad et al., 2013; Macfarlan et al., 2012). As a result, it is intriguing to speculate that this media condition can enhance the reprogramming of normal ESCs to a totipotent, clonogenic state.

Experimental Procedures

Author Contributions

We thank the entire Brickman laboratory for comments and critical discussion; Gelo de la Cruz and Alexei Sharov for technical assistance; and Heiko Lickert and Minoru Ko for reagents. This work was funded by the Novo Nordisk Foundation Section for Basic Stem Cell Biology and the Faculty of Health Sciences at the University of Copenhagen. S.M.M. was supported by a University of Copenhagen Studentship.

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) are a renewable cell source for the generation of human hepatocytes that could be used for drug toxicity and metabolization studies (Baxter et al., 2010; Mann, 2015; Ulvestad et al., 2013; Zhang et al., 2013; Zhu and Huangfu, 2013). Although many groups (Baxter et al., 2015; Chen et al., 2012; Godoy et al., 2015; Hannan et al., 2013; Shan et al., 2013; Siller et al., 2015; Ulvestad et al., 2013), including ours (Helsen et al., 2016; Roelandt et al., 2012), have generated pluripotent stem cell (PSC)-derived progeny displaying hepatocyte characteristics, these cells are more akin to fetal than post-natal hepatocytes, and are therefore often termed hepatocyte-like cells (HLCs). For instance, HLCs continued to express α-fetoprotein (AFP), a typical fetal hepatocyte marker (Schmelzer et al., 2006).

El art culo est organizado como sigue En

El artículo está organizado como sigue. En la siguiente sección damos una breve revisión de la literatura referente a los estudios realizados con dea y formulamos la hipótesis que guiará esta investigación. Posteriormente, se describe la metodología del dea así como sus supuestos además de la descripción de los datos y definición de variables. Luego, realizamos la comparación de los promedios de las transferencias per cápita de los municipios eficientes con relación a los ineficientes. Finalmente, presentamos la discusión de hallazgos y su importancia para direccionar políticas públicas, limitaciones del estudio y oportunidades para futuras investigaciones sobre el tema.

Revisión de la literatura
Así pues, en el estudio de la eficiencia relativa de los gobiernos subnacionales y su asociación con las transferencias intergubenamentales, nos planteamos la interrogante sobre la relación entre las transferencias intergubernamentales y su asociación con la eficiencia relativa en los municipios de estado de Jalisco. De acuerdo a la Teoría del Federalismo Fiscal, los recursos transferidos a los gobiernos subnacionales tienen como objetivo incrementar la eficiencia en la producción y distribución de bienes y servicios así como la búsqueda de la equidad entre sus gobernados. Con Deazaneplanocin en este argumento nosotros planteamos la siguiente hipótesis:

Metodología de análisis envolvente de datos
El análisis envolvente de datos o dea (Data Envelopment Analysis) es una técnica no paramétrica que consiste en determinar “fronteras” de producción eficientes, en lugar de medidas de tendencia central. Con esta técnica se calcula las relaciones eficientes relativas (scores) a esas fronteras de la Decisión Making Units (dmus) o municipios a partir del uso de insumos (inputs) y productos (outputs). Esta técnica no paramétrica fue introducida por Charnes, Cooper, y Rhodes (1978, 1981) quienes se basaron en la idea de Farrell (1957) sobre la medida de eficiencia a través de un insumo y un producto, para generalizar el análisis a varios insumos y productos. dea asume la existencia de una frontera convexa de producción la cual es determinada a loop of Henle través de la programación lineal matemática. Esta técnica no paramétrica nos permite calcular eficiencia técnica relativa de las unidades de decisión (i.e., los municipios) a través de la asignación de valores (scores). De acuerdo con Afonso y Fernandes (2008) la relación general esperada de la eficiencia para cada municipio i es expresada por la siguiente función:
Y = Deazaneplanocin f(X), i=1,…,n
Donde Y son los indicadores que reflejan las cantidades de productos y X representa la cantidad de insumos para cada municipio i. Estas cantidades pueden ser, según los autores, per cápita o en alguna otra medida. Si Y< f(X) indica que en municipio i es ineficiente, es decir, dado una cantidad de insumos el producto es menor que el mejor nivel posible. Esta ineficiencia relativa del municipio i que está debajo de la frontera “envolvente,” la cual es calculada (no estimada) por la desviación de la frontera. Esto es, entre más alejadas estén las relaciones insumos-productos de los municipios de la frontera más ineficientes serán. Charnes, Cooper, y Rhodes (1981) señalan que hay dos maneras de construir la frontera envolvente para las Decision Making Units (dmus): a) orientación en los productos u b) orientación en los insumos. En el primero se argumenta que un municipio es eficiente si no es posible aumentar la cantidad de producto si aumentar los insumos o reducir la producción de otro producto. El segundo caso, un municipio es eficiente si no es posible reducir la cantidad de insumos para producir la cantidad de productos establecida. Los dos métodos proporcionan los mismos resultados bajo el supuesto de rendimientos constantes a escala pero dan diferentes valores cuando los rendimientos son variables (Afonso y Fernandes, 2008). Sin embargo, de acuerdo a estos autores, ambos modelos identificaran el mismo conjunto de eficientes/ineficientes dmus. Finalmente, los valores de eficiencia relativa serán uno para los eficientes (i.e., están en la frontera) y menos de uno para los ineficientes (i.e., no están en la frontera).

These open questions became the central

These open questions became the central issue in the 70s and the 80s researches. This research intensification was greatly corroborated by events occurred at that time. Events like the break of Bretton Woods system, world input price shocks, recessions, and the adoption of flexible exchange rates regime among others corroborated to intensify the economic research on international macroeconomic interdependence of the economies (Dornbusch, 1976; Helpman, 1976; Frenkel and Razin, 1985; Cooper, 1986; Frankel, 1988; Devereux and Wilson, 1989).
Besides the need for coordination of economic policies among nations engaged in world trade, the above events brought also more urgent matters to the economies. In especial the need for domestic price stability policies that required among other things choosing an exchange rate regime (Henderson, 1977; Dornbusch, 1982; Andresen and Everaert, 1987; Aoki, 1987). The emergence of different exchange regimes among the economies required also new studies on economic policies interdependence.
Hence, the theories of international economic policy interdependence and its applications evolved greatly in the 90s due to new microeconomic foundation development. The new propositions embraced wage arrangements and price NSC23766 prevailing in the market that was different from the models of 70s and 80s. Under the new microeconomic foundation the theories revealed outcomes of international macroeconomic policy interdependence not present in the previous literature (Obtsfeld and Rogoff, 1995; Wren-Lewis, 1997; Betts and Devereux, 2000; Dibooğlu, 2000).
For instance, Obtsfeld and Rogoff (1995) showed that monetary policy may not be a beggar-thy-neighbor instrument under flexible exchange rate, using a model of monopolistic competition and sticky prices. Hence, there would be no incentive to engage in a competitive depreciation. As a result, there would be little space for international coordination, and it could even reduce world welfare.
Among the proposals, the contribution of Corsetti and Pesenti (2001) stands out for improving the previous literature, especially regarding the effects of national policies on trade partners. One of the main results of the model was that an unanticipated exchange rate depreciation can be beggar-thyself rather than beggar-thy-neighbor. This result stands in contrast to the frequently practiced economic policy by nations to implement exports as way of improving national welfare. It was also in contrast to the result of Obtsfeld and Rogoff (1995) seminal paper “Exchange Rate Dynamics Redux”.
In this context, we developed an empirical analysis of the Corsetti and Pesenti (2001) model of macroeconomic interdependence as a way of learning the welfare implications for Brazil, the domestic economy, from a fiscal policy made in US, the foreign economy. The main objective is to test the effects of US fiscal policy on Brazilian consumption, real balances, terms of trade, and domestic prices.
The empirical tests are based on the solutions of the Corsetti and Pesenti (2001) model. The model solutions generate two sets of equations. The first one represents the short-term relations that highlight the effects of monetary policy on economic aggregates: output (Y), consumption (C), nominal interest rate (R), terms of trade (TT) and the nominal exchange rate (E). These effects are transitory and with no direct consequences for the formulation of economic policy in the long run for the domestic country, here Brazil. The second set of equations represents long run relations arising from fiscal policy made by foreign economy, here US. In the long run, the fiscal position of the world (domestic and foreign economies combined) is a determinant of real money balances and affects the behavior of main aggregate variables such as: long run output (), long run consumption (), long run real balances (), the terms of trade (TT), here real exchange rate, and domestic prices (P). Therefore, this paper is mainly concerned with the long run welfare effects on the Brazilian economy coming from the fiscal policy practiced by US.

br Concluding remarks and policy

Concluding remarks and policy implications

Mishkin (1982) and Kuttner (2001) empirically show the effects of anticipated monetary policy. More recently, Milani and Treadwell (2012) and Gomes et al. (2013) use a dynamic stochastic general equilibrium (DSGE) model to empirically show that anticipated monetary policy has a large persistent effect. Laséen and Svensson (2011) introduce a numerical computation of the effects of anticipated monetary policy in DSGE models. Moreover, Verona et al. (2013) use numerical simulation with a DSGE model to show that anticipated monetary easing is one of the reasons for the recent boom-bust cycles. However, theoretical studies of this purchase AZD0530 policy are rare. In this short study, we theoretically analyze the effects of anticipated monetary policy by using a simple new Keynesian model consisting of three equations (the IS curve, interest rate rule, and new Keynesian Philips curve). The model is a complete subset of that in Milani and Treadwell (2012) and therefore allows for obtaining a closed-form solution. The theoretical results of this paper are useful for considering the intuition behind complicated models.
Although we could use full-blown DSGE models such as those of Smets and Wouters (2003) or Christiano et al. (2005) and carry out numerical analysis, a theoretical analysis using a simple model would still be needed to assess how the parameters underlying the model affect the results. From our theoretical analysis, we find that the effect of anticipated monetary policy on current output critically depends on the parameter for inflationary response to a monetary policy rule. If this parameter were relatively low, an anticipated monetary easing would always have a positive effect on output. However, if the parameter were high, the policy would have a negative impact on output. This finding has not been obtained in the literature using numerical analysis. On the other hand, for the assumed parameter space, an anticipated monetary easing always has an inflationary response.
This paper is organized as follows. Section 2 presents our model and obtains a closed form of anticipated policy effects on the economy. Section 3 shows our theoretical analysis and presents our results. Section 4 performs a numerical analysis to obtain quantitative results. Finally, Section 5 concludes the paper.

A closed form of anticipated monetary policy
Consider the following simple new Keynesian model consisting of three equations,where y, π, and R denote the deviation from the steady state of output, the inflation rate, and the interest rate, respectively. Eq. (1) is the Euler equation obtained by assuming logarithmic preferences, and Eq. (2) is the new Keynesian Philips curve. Eq. (3) denotes a monetary policy rule, where e for all T≥t+1 represents an anticipated monetary policy shock. This shock purchase AZD0530 can also be identified as a news shock. In this paper, this shock can be defined aswhere v denotes the anticipation at period t for monetary policy i periods later. In this paper, we assume that E[v]=m for all t and for all , where denotes the start period of an anticipated monetary policy. This assumption is for simplicity and is not crucial for our qualitative results.
Eqs. (1)–(3) are summarized as follows:The coefficient matrix A can be diagonalized as A=QΛQ−1, where Λ is a diagonal matrix with an eigenvalue (denoted as λ1 and λ2) of A as its diagonal elements and Q is a matrix in which the column vector is an eigenvector.
Note that the Taylor principle (ϕ>1) is necessary for 1<λ1<λ2. The standard technique to solve a dynamic linear rational expectation model, like the method of Blanchard and Kahn (1980) or Klein (2000), in general, yields the following closed form of endogenous variables:where . Therefore, from QΛ−1Q−1=A−1, we haveNote thatwhere . Let , n=π,y be the first and second elements of AB. Note that when j=1, denotes the effects of the current monetary policy. In this notation, the effects of an anticipated monetary policy, which starts s periods later and ends at T, on the current economy are captured by .

The DHCR gene has been mapped to

The DHCR24 gene has been mapped to chromosome 1p32.3, a region commonly amplified in HCC and which may contribute to carcinogenesis (Yuan et al., 2003; Endo et al., 2009). Recently, two indole-3-carbinol mutations, Q88L and R311H, were identified in the DHCR24 gene in Korean HCC patients (Ahn et al., 2014). Further, overexpression of DHCR24 is a hallmark of prostate cancer, with high levels observed in low-grade prostate cancer, but diminishing as the cancer progresses (Bonaccorsi et al., 2008), and sliding filament model is also overexpressed during non-muscle-invasive urothelial carcinoma progression (Lee et al., 2014).


Conflicts of Interest

Author Contributions

This work was supported by grants from the Ministry of Health ScienceH24-B-014, H25-009 and Welfare and the Ministry of Education, Science and Culture, Japan, 23590547.


br Introduction Hepatitis C virus

Hepatitis C virus (HCV) infection has a high prevalence, incidence, and pathogenicity, and may evolve into cirrhosis and hepatocellular carcinoma (HCC) (Castello et al., 2010). HCV infection is considered a chronic liver disease, likely resulting from immune evasion by HCV quasi-species generated from high rates of replication errors (Farazi and DePinho, 2006). Since HCV does not integrate into the host genome, HCV-related HCC (HCC-C) is mainly induced through indirect pathways, including chronic inflammation, cirrhosis, cell death, and proliferation (Lorusso and Ruegg, 2008). A hallmark of HCV infection is perturbed lipid metabolism; HCV exploits host lipids for replication and further infection. The 3β-hydroxysterol Δ24-reductase (DHCR24) protein catalyzes the conversion of desmosterol to cholesterol; Bae and Paik, 1997 this reaction appears to be remarkable in HCV infection (Schaefer and Chung, 2013). Previously, we found that HCV up-regulated DHCR24 expression in human hepatoblastoma-derived RzM6-LC monensin Supplier and that DHCR24 overexpression impaired p53 activity by suppressing acetylation and increasing interactions with the MDM2 proto-oncogene. In turn, this suppressed the hydrogen peroxide-induced apoptotic response in hepatocytes (Nishimura et al., 2009; Tsukiyama-Kohara, 2012; Saito et al., 2012).
The development of novel biomarkers and surveillance strategies in high-risk populations will permit earlier discovery of HCC and improve the survival outcomes. Currently, the most commonly used biomarker for early-stage HCC is alpha-fetoprotein (AFP) (Zhang et al., 2004). However, the AFP levels remain normal in 15–20% of advanced-stage HCC patients, and only 10–20% of early-stage HCC patients show abnormal AFP values (Monsour et al., 2013). Therefore, additional HCC biomarkers, including protein induced by vitamin K absence or antagonist-II (PIVKA-II; des-gamma-carboxy-prothrombin), have been developed (Makuuchi et al., 2008). Nonetheless, the need for novel biomarkers for early detection of HCC remains an important issue. Moreover, no biomarker corresponding to the disease progression of HCV-infected diseases, such as chronic hepatitis, cirrhosis, and HCC, has been established. Accordingly, this study aimed to evaluate the levels of serum DHCR24 auto-antibody (DHCR24 Ab) in a broad spectrum of chronic hepatitis diseases.

Materials and Methods


In the serum, Abs are stable and the Ab response is enduring (Heo et al., 2012), and overexpressed, mutated, misfolded, or aberrantly degraded proteins can become immunogenic, thus resulting in auto-Ab production; consequently, the detection of these antibodies in patient sera can be exploited for prognostic and/or diagnostic purposes.
In this study, we found that serum DHCR24 Ab levels correlated with HCV-mediated chronic hepatitis, cirrhosis, and HCC, but not with HBV-related diseases, suggesting that the concentration of serum DHCR24 Abs may be useful for the diagnosis and/or prognosis in HCV-positive patients. Moreover, the sensitivity of the DHCR24 Ab in discriminating CHC from HCC-C patients was superior to serum AFP and PIVKA-II levels, and high DHCR24 Ab levels demonstrated a high positive predictive value for HCC-C. Additionally, a combination of DHCR24 Ab with AFP or PIVKA-II further increased the detection rates of HCC in HCV-positive patients. Conversely, in chronic HBV infection, the DHCR24 Ab levels did not differ between CHB, LCB, and HCC-B (P=0.1247).
Previously, we have shown that DHCR24 is overexpressed in HCV-infected cells in vitro and in vivo, and that HCV silencing by siRNA down-regulated DHCR24 expression (Nishimura et al., 2009; Saito et al., 2012; Takano et al., 2011). However, HBV infection had no significant effect on DHCR24 expression (Makuuchi et al., 2008). DHCR24 up-regulation in HCV infection may be due to increased Sp1 phosphorylation by ataxia telangiectasia mutated as a result of HCV-induced oxidative stress, which promotes transcriptional activation of DHCR24 (Tsukiyama-Kohara, 2012). Thus, chronic HCV infection could induce the augmentation of DHCR24. Also, this augmentation of DHCR24 expression by HCV suppresses p53 activity by blocking nuclear p53 acetylation and increasing the interaction between p53 and MDM2 in the cytoplasm, potentially mediated by inhibition of p53 degradation (Tsukiyama-Kohara, 2012). Consequently, impaired apoptotic signaling upon p53 activity suppression may facilitate hepatocarcinogenesis. Moreover, DHCR24 has been shown to inhibit caspase-3 activation, one of the major proteins involved in apoptosis, suggesting a role of DHCR24 in the regulation of cell survival and death (Greeve et al., 2000; Benvenuti et al., 2008). Additionally, we found that the MoAb 2-152a clone can bind DHCR24 and suppress HCV replication (Satoh et al., 2011), suggesting that the DHCR24 Ab has antiviral effects, and that high levels of DHCR24 Ab in HCC patients may lead to lower HCV RNA levels in the cancerous tissues. DHCR24 is reportedly more abundantly expressed on the surface of liver cancer cells than normal hepatocytes Satoh et al., 2011. Accordingly, Tanaka et al. observed that non-cancerous tissues of patients with HCC and HCV mono-infection displayed virus levels 10- to 1000-fold higher than cancerous tissues, and this may be one of the reasons for the higher amount of DHCR24 Ab seen in HCC patients (Tanaka et al., 2004).

According to the one dimensional

According to the one-dimensional stress wave theory, the train , stress and strain rate of the specimen can be calculated by two-wave methodwhere and are the time-resolved reflected and transmitted strains in the incident and transmission bars with cross-sectional area A; E is the Young\’s modulus of bar material; is the elastic bar wave speed in the bar material; and L are the cross-sectional area and the original length of specimen, respectively.
A pulse shaping technique is used to get the ideal waves. In other words, the purpose is to facilitate the stress equilibrium and constant strain rate deformation of specimen. As shown in Fig. 1, a pulse shaper is put between the striker and incident bar. The most ideal pulse shaping material depends on the mechanical characteristics of the specimen and the speed of the striker. In the paper, we mainly adopt asbestos tips as the pulse shaping material. The shapes of the tips are circular, and their diameters equal that Concanamycin A of bar. Fig. 3 illustrates the comparison of waveforms with and without pulse shaper. It can be seen from the above figures that the waveform with pulse Concanamycin A shaper has less high frequency oscillation than that without pulse shaper, so the influence of high frequency oscillation on the experiment data can be reduced. The increase in the rising time of incident wave is beneficial to achieve the stress equilibrium. After pulse shaping, there is a plateform on the reflected wave. According to Eq. (3), we can know that the strain rate is proportional to the reflected signal. Therefore, the reflected wave should be kept constant in order to achieve a constant strain rate during the deformation progress. In conclusion, Fig. 3 shows that the pulse shaping technique meets the requirements above mentioned.

Experimental results and discussion
Fig. 4 shows the compressive true stress–true strain curves of PTFE obtained at the strain rates ranging from 10−2 s−1 to 104 s−1. It can be seen from Fig. 4 that the mechanical characteristics of PTFE are strain rate-dependent and the initial modulus of dynamic increases markedly; After yielding, the material manifests strain hardening that can continue to a large strain range; The rising trend is roughly the same at different strain rates, which indicates the strain rate effect is unconspicuous in plastic section; The dynamic compressive true stress–true strain curves show the oscillations which may be due to the instability under impact loading during experimental measurement. The ends of dynamic compressive true stress–true strain curves decline. That is because the length of striker limits the width of loading pulse but not the material characteristics.
The yield stresses at the different strain rates are presented in Table 1. It can be seen from Table 2 that the yield stresses increase with the increase in strain rates, and the dynamic yield stresses are about two times of quasi-static yield stresses.
Walley and Field [4], Rae and Dattelbaum [5,6], Jennifer and Clive [7] got the stresses of PTFE at 15% of strain at room temperature, as shown in Fig. 5. The result in this paper is consistent with others, which further proves the reliability of the result.
A lot of scholars do some research on the relation of yield stress–strain rate of polymer materials. Hu et al. [8] used a power-law constitutive model for the description of polycarbonate (PC)where A, B and m are three undetermined coefficients.
Richeton et al. [9] and Fu S. et al. [10] proposed the modified models on the basis of Eyring theory. Mohd et al. [11] adopted the thermal activation to describe the yield stresses of polycarbonate (PC), polyethylene (PE) and polypropylene (PP). The thermal activation has the following formwhere is the internal stress, k is Boltzmann\’s constant, T is the absolute temperature, v is the activation volume, n is the material parameter, and is the characteristic strain rate. can be served as an unknown factor during numerical fitting.

br Lentigines and lentiginoses Lentigines may be exceptionally

Lentigines and lentiginoses
Lentigines may be exceptionally present at birth. The typical lentigine (lentigo simplex) is a discrete, small, tan/brown/black, oval or circular macule that may occur on any cutaneous surface or on mucous membranes. Exposure to sunlight does not darken it, and it does not disappear spontaneously. Histologic changes in lentigines are limited to an increased activity of basal epidermal melanocytes, without nesting of melanocytes, but the number of TGF-beta Smad Compound Library can be increased. The multiple lentigines syndrome or LEOPARD syndrome is rarely diagnosed at birth. The acronym LEOPARD describes the following features: lentigines, lesions noted most prominently on the face and trunk that increase in number with age; electrocardiographic abnormalities; ocular hypertelorism; pulmonary stenosis; abnormal genitalia, particularly undescended testicles; retarded growth; and deafness (sensory). Another multisystemic disease associated with lentigines is Peutz–Jeghers syndrome TGF-beta Smad Compound Library (Figure 6), an autosomal-dominant disorder that consists of multiple lentigines clustered in the perioral area and elsewhere and gastrointestinal hamartomas situated most densely in the jejunum. Lesions may occur in infancy. Unlike other lentiginoses, lesions may remit completely during adolescence. Germline mutations in STK11, a serine/threonine kinase with a wide tissue distribution, probably in conjunction with acquired genetic defects of the second allele in somatic cells, cause the manifestations of Peutz–Jeghers syndrome.STK11 is a tumor suppressor gene that acts as an early gatekeeper and regulates the development of hamartomas in Peutz–Jeghers syndrome, which may be pathogenetic precursors of adenocarcinoma. Additional somatic mutation events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in most colorectal carcinomas.
The complex of myxomas, spotty pigmentation, and endocrine overactivity is a condition currently known as Carney complex and is caused by mutation in the protein kinase A regulatory subunit-1-alpha gene (PRKAR1A) on chromosome 17q; however, genetic heterogeneity occurs within this phenotype. A typical patient with this syndrome has at least two of the following findings: cardiac myxomas; hyperpigmentation of the skin, including lentigines, ephelides, and nevi (although histologically almost all these lesions are lentigines); cutaneous myxomas; myxoid mammary fibroadenomas; testicular tumors; pigmented nodular adrenocortical disease; and pituitary adenomas with gigantism or acromegaly. Multiple pigmented macules are distributed diffusely but are concentrated most heavily on the central face, including the lips, neck, and upper trunk. Skin lesions are present at birth and frequently increase in number at puberty. Multiple subcutaneous myxomas occur in approximately 50% of cases and usually appear in the periorbital and postauricular areas. Early recognition of this syndrome is important because surgical correction of cardiac myxomas may prevent the potentially fatal complication of embolism of tumor fragments.

Ephelides (freckles)
Freckles are common in light-skinned, red-haired people and seem to be inherited as an autosomal-dominant trait. On histologic examination, ephelides show increased melanin in the epidermis without the melanocytic proliferation or epidermal elongation noted in lentigines. They are not present at birth but arise in infancy or early childhood, mainly on sun-exposed skin. They darken in summer and tend to fade during the winter months, which indicates that sunlight exposure is necessary for their induction. These lesions become less noticeable in adult life. Typically, freckles are well-circumscribed, red–tan macules that occur most commonly on the face, back, and upper shoulders, and spare the mucous membranes. Xeroderma pigmentosum (Figure 7) may be diagnosed as a benign freckling condition in sun-exposed areas. Severe forms, such as xeroderma pigmentosum-C, manifest early in life. The diagnosis is usually made in the first 2 years of life, with a diagnostic delay because of the rarity of the disease in western countries. Photosensitivity with a prolonged erythema helps make a diagnosis, which needs a confirmation using fibroblast cultures to perform an in vitro study of unscheduled DNA synthesis.