Sample records for cellular restriction factors

  1. Vif proteins of human and simian immunodeficiency viruses require cellular CBFβ to degrade APOBEC3 restriction factors. (United States)

    Hultquist, Judd F; Binka, Mawuena; LaRue, Rebecca S; Simon, Viviana; Harris, Reuben S


    HIV-1 requires the cellular transcription factor CBFβ to stabilize its accessory protein Vif and promote APOBEC3G degradation. Here, we demonstrate that both isoforms of CBFβ allow for increased steady-state levels of Vif, enhanced APOBEC3G degradation, and increased viral infectivity. This conserved functional interaction enhances the steady-state levels of Vif proteins from multiple HIV-1 subtypes and is required for the degradation of all human and rhesus Vif-sensitive APOBEC3 proteins by their respective lentiviral Vif proteins.

  2. Cellular restriction of retrovirus particle-mediated mRNA transfer. (United States)

    Galla, Melanie; Schambach, Axel; Towers, Greg J; Baum, Christopher


    Analyzing cellular restriction mechanisms provides insight into viral replication strategies, identifies targets for antiviral drug design, and is crucial for the development of novel tools for experimental or therapeutic delivery of genetic information. We have previously shown that retroviral vector mutants that are unable to initiate reverse transcription mediate a transient expression of any sequence which replaces the gag-pol transcription unit, a process we call retrovirus particle-mediated mRNA transfer (RMT). Here, we further examined the mechanism of RMT by testing its sensitivity to cellular restriction factors and short hairpin RNAs (shRNAs). We found that both human TRIM5alpha and, to a lesser extent, Fv1 effectively restrict RMT if the RNA is delivered by a restriction-sensitive capsid. While TRIM5alpha restriction of RMT led to reduced levels of retroviral mRNA in target cells, restriction by Fv1 did not. Treatment with the proteasome inhibitor MG132 partially relieved TRIM5alpha-mediated restriction of RMT. Finally, cells expressing shRNAs specifically targeting the retroviral mRNA inhibited RMT particles, but not reverse-transcribing particles. Retroviral mRNA may thus serve as a translation template if not used as a template for reverse transcription. Our data imply that retroviral nucleic acids become accessible to host factors, including ribosomes, as a result of particle remodeling during cytoplasmic trafficking.

  3. Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection. (United States)

    Maudet, Claire; Mano, Miguel; Sunkavalli, Ushasree; Sharan, Malvika; Giacca, Mauro; Förstner, Konrad U; Eulalio, Ana


    Increasing evidence suggests an important role for miRNAs in the molecular interplay between bacterial pathogens and host cells. Here we perform a fluorescence microscopy-based screen using a library of miRNA mimics and demonstrate that miRNAs modulate Salmonella infection. Several members of the miR-15 miRNA family were among the 17 miRNAs that more efficiently inhibit Salmonella infection. We discovered that these miRNAs are downregulated during Salmonella infection, through the inhibition of the transcription factor E2F1. Analysis of miR-15 family targets revealed that derepression of cyclin D1 and the consequent promotion of G1/S transition are crucial for Salmonella intracellular proliferation. In addition, Salmonella induces G2/M cell cycle arrest in infected cells, further promoting its replication. Overall, these findings uncover a mechanism whereby Salmonella renders host cells more susceptible to infection by controlling cell cycle progression through the active modulation of host cell miRNAs.

  4. A whole genome screen for HIV restriction factors

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    Liu Li


    Full Text Available Abstract Background Upon cellular entry retroviruses must avoid innate restriction factors produced by the host cell. For human immunodeficiency virus (HIV human restriction factors, APOBEC3 (apolipoprotein-B-mRNA-editing-enzyme, p21 and tetherin are well characterised. Results To identify intrinsic resistance factors to HIV-1 replication we screened 19,121 human genes and identified 114 factors with significant inhibition of infection. Those with a known function are involved in a broad spectrum of cellular processes including receptor signalling, vesicle trafficking, transcription, apoptosis, cross-nuclear membrane transport, meiosis, DNA damage repair, ubiquitination and RNA processing. We focused on the PAF1 complex which has been previously implicated in gene transcription, cell cycle control and mRNA surveillance. Knockdown of all members of the PAF1 family of proteins enhanced HIV-1 reverse transcription and integration of provirus. Over-expression of PAF1 in host cells renders them refractory to HIV-1. Simian Immunodeficiency Viruses and HIV-2 are also restricted in PAF1 expressing cells. PAF1 is expressed in primary monocytes, macrophages and T-lymphocytes and we demonstrate strong activity in MonoMac1, a monocyte cell line. Conclusions We propose that the PAF1c establishes an anti-viral state to prevent infection by incoming retroviruses. This previously unrecognised mechanism of restriction could have implications for invasion of cells by any pathogen.

  5. Real Moments of the Restrictive Factor

    Indian Academy of Sciences (India)

    Andrew Ledoan; Alexandru Zaharescu


    Let be a real number such that 0 < < 1. We establish asymptotic formulas for the weighted real moments $\\sum_{n≤ x}R^(n)(1-n/x)$, where $R(n)=\\prod^k_{v=1}p^{ v-1}_v$ is the Atanassov strong restrictive factor function and $n=\\prod^k_{v=1}p^{ v}_v$ is the prime factorization of .

  6. Cellular Factors Required for Lassa Virus Budding


    Urata, Shuzo; Noda, Takeshi; Kawaoka, Yoshihiro; Yokosawa, Hideyoshi; Yasuda, Jiro


    It is known that Lassa virus Z protein is sufficient for the release of virus-like particles (VLPs) and that it has two L domains, PTAP and PPPY, in its C terminus. However, little is known about the cellular factor for Lassa virus budding. We examined which cellular factors are used in Lassa virus Z budding. We demonstrated that Lassa Z protein efficiently produces VLPs and uses cellular factors, Vps4A, Vps4B, and Tsg101, in budding, suggesting that Lassa virus budding uses the multivesicula...

  7. 77 FR 1889 - Drivers of CMVs: Restricting the Use of Cellular Phones; Technical Amendment (United States)


    .... See 76 FR 75472-75474, December 2, 2011. Background The December 3, 2011, Drivers of CMVs: Restricting the Use of Cellular Phones final rule (76 FR 75470) had a clerical error in Sec. 391.15(f)(1) that... Use of Cellular Phones; Technical Amendment AGENCY: Federal Motor Carrier Safety Administration...

  8. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. (United States)

    Lee, C; Longo, V D


    The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting--no calorie intake--induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels. Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells. Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks-months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans. In this study, we review the basic as well as clinical studies on fasting, cellular protection and chemotherapy resistance, and compare them to those on DR and cancer treatment. Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.

  9. Parental factors associated with intrauterine growth restriction

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    Hăşmăşanu Monica G.


    Full Text Available Introduction. Linear growth failure is caused by multiple factors including parental factors. Objective. The aim of this study was to evaluate parental risk factors for intrauterine growth restriction (IUGR on a population of Romanian newborn infants in a tertiary level maternity facility for a period of 2.5 years. Methods. A retrospective matched case-control study was conducted in the Emergency County Hospital of Cluj-Napoca, a university hospital in North-Western Romania. The sample was selected from 4,790 infants admitted to the Neonatal Ward at 1st Gynecology Clinic between January 2012 and June 2014. Results. The age of mothers was significantly lower in the IUGR group compared to controls (p=0.041. A significantly higher percentage of mothers had hypertension in the IUGR group compared to those in the control group (p0.13. The age of fathers of infants with IUGR proved significantly lower compared to controls (p=0.0278. The analysis of infants’ comorbidities revealed no significant difference between groups for respiratory distress, hyperbilirubinemia, hypocalcaemia, and heart failure (p>0.27. Intracranial hemorrhage, necrotizing enterocolitis and hypoglycemia were significantly higher in the IUGR group compared to controls. The logistic regression identified hypertension as a significant risk factor for IUGR (OR=2.4, 95% CI [1.3-4.5]. Conclusion. Although the age of the mothers and fathers proved significantly lower in the IUGR group compared to controls, only hypertension in the mothers proved significant risk factors for IUGR.

  10. Cellular signaling by fibroblast growth factor receptors. (United States)

    Eswarakumar, V P; Lax, I; Schlessinger, J


    The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. A variety of human skeletal dysplasias have been linked to specific point mutations in FGFR1, FGFR2 and FGFR3 leading to severe impairment in cranial, digital and skeletal development. Gain of function mutations in FGFRs were also identified in a variety of human cancers such as myeloproliferative syndromes, lymphomas, prostate and breast cancers as well as other malignant diseases. The binding of FGF and HSPG to the extracellular ligand domain of FGFR induces receptor dimerization, activation and autophosphorylation of multiple tyrosine residues in the cytoplasmic domain of the receptor molecule. A variety of signaling proteins are phosphorylated in response to FGF stimulation including Shc, phospholipase-Cgamma, STAT1, Gab1 and FRS2alpha leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. The docking proteins FRS2alpha and FRS2beta are major mediators of the Ras/MAPK and PI-3 kinase/Akt signaling pathways as well as negative feedback mechanisms that fine-tune the signal that is initiated at the cell surface following FGFR stimulation.

  11. Long-Term Calorie Restriction Enhances Cellular Quality-Control Processes in Human Skeletal Muscle

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    Ling Yang


    Full Text Available Calorie restriction (CR retards aging, acts as a hormetic intervention, and increases serum corticosterone and HSP70 expression in rodents. However, less is known regarding the effects of CR on these factors in humans. Serum cortisol and molecular chaperones and autophagic proteins were measured in the skeletal muscle of subjects on CR diets for 3–15 years and in control volunteers. Serum cortisol was higher in the CR group than in age-matched sedentary and endurance athlete groups (15.6 ± 4.6 ng/dl versus 12.3 ± 3.9 ng/dl and 11.2 ± 2.7 ng/dl, respectively; p ≤ 0.001. HSP70, Grp78, beclin-1, and LC3 mRNA and/or protein levels were higher in the skeletal muscle of the CR group compared to controls. Our data indicate that CR in humans is associated with sustained rises in serum cortisol, reduced inflammation, and increases in key molecular chaperones and autophagic mediators involved in cellular protein quality control and removal of dysfunctional proteins and organelles.

  12. Risk Factors for Restricting Back Pain in Older Persons (United States)

    Makris, Una E.; Fraenkel, Liana; Han, Ling; Leo-Summers, Linda; Gill, Thomas M.


    Objectives To identify risk factors for back pain leading to restricted activity (restricting back pain) in older persons. Design Prospective cohort study. Setting Greater New Haven, Connecticut. Participants 731 men and women aged 70 years or older, who were community-living and non-disabled in essential activities of daily living at baseline. Measurements Candidate risk factors were ascertained every 18 months for 108 months during comprehensive home-based assessments. Restricting back pain was assessed during monthly telephone interviews for up to 126 months. Incident episodes of: (1) short-term (one episode lasting one month) restricting back pain; and (2) persistent (one episode lasting two or more months) or recurrent (two or more episodes of any duration) restricting back pain were determined during each 18-month interval. The associations between the candidate risk factors and short-term and persistent/recurrent restricting back pain, respectively, were evaluated using a multivariable Cox model. Results The cumulative incidence was 21.3% (95% confidence interval (CI) 19.6%, 23.1%) for short-term restricting back pain and 20.6% (CI 18.6%, 22.9%) for persistent/recurrent restricting back pain over a median follow-up of 109 months. In a recurrent event multivariable analysis, female sex (HR 1.30; 1.07, 1.58), weak grip strength (HR 1.24; 1.01,1.52), and hip weakness (HR 1.19; 1.07,1.32) were independently associated with an increased likelihood of having short-term restricting back pain, while female sex (HR 1.48; CI 1.13,1.94), depressive symptoms (HR 1.57; 1.23, 2.00), 2 or more chronic conditions (HR 1.38; 1.08, 1.77), and arthritis (HR1.66; 1.31, 2.09) were independently associated with persistent/recurrent restricting back pain. Conclusion In this prospective study, several factors were independently associated with restricting back pain, including some that may be modifiable and therefore potential targets for interventions to reduce this common and

  13. Restricting factors of the development of SEA in China

    Institute of Scientific and Technical Information of China (English)

    Wang Xianghua; Zhu Xiaodong; LiYangfan; Chen Shanshan


    "Environmental Impact Assessment Law of P. R. China" was promulgated on Oct. 28th, 2002 and has been put into effect on Sep 1st, 2003. This paper puts forward some important factors which restrict the development of Strategic Environmental Assessment according to the preliminary practices of SEA in China. These restricting factors are: (1) potential resistance from some departments; (2) poor cooperation between different departments; (3) limited availability of information resources; (4) lack of well-developed SEA methods; (5) difficulties in public participation. The primary thought to solve these problems were proposed at policy and technique level.

  14. Maintenance of cellular ATP level by caloric restriction correlates chronological survival of budding yeast

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    Choi, Joon-Seok; Lee, Cheol-Koo, E-mail:


    Highlights: •CR decreases total ROS and mitochondrial superoxide during the chronological aging. •CR does not affect the levels of oxidative damage on protein and DNA. •CR contributes extension of chronological lifespan by maintenance of ATP level -- Abstract: The free radical theory of aging emphasizes cumulative oxidative damage in the genome and intracellular proteins due to reactive oxygen species (ROS), which is a major cause for aging. Caloric restriction (CR) has been known as a representative treatment that prevents aging; however, its mechanism of action remains elusive. Here, we show that CR extends the chronological lifespan (CLS) of budding yeast by maintaining cellular energy levels. CR reduced the generation of total ROS and mitochondrial superoxide; however, CR did not reduce the oxidative damage in proteins and DNA. Subsequently, calorie-restricted yeast had higher mitochondrial membrane potential (MMP), and it sustained consistent ATP levels during the process of chronological aging. Our results suggest that CR extends the survival of the chronologically aged cells by improving the efficiency of energy metabolism for the maintenance of the ATP level rather than reducing the global oxidative damage of proteins and DNA.

  15. Translation Factors Specify Cellular Metabolic State

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    Juan Mata


    Full Text Available In this issue of Cell Reports, Shah et al. present evidence that a subcomplex of the eIF3 translation initiation factor regulates translation of mRNAs encoding components of the mitochondrial electron transport chain and glycolytic enzymes, thus linking translational control with energy metabolism.

  16. p16(INK4a suppression by glucose restriction contributes to human cellular lifespan extension through SIRT1-mediated epigenetic and genetic mechanisms.

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    Yuanyuan Li

    Full Text Available Although caloric restriction (CR has been shown to increase lifespan in various animal models, the mechanisms underlying this phenomenon have not yet been revealed. We developed an in vitro system to mimic CR by reducing glucose concentration in cell growth medium which excludes metabolic factors and allows assessment of the effects of CR at the cellular and molecular level. We monitored cellular proliferation of normal WI-38, IMR-90 and MRC-5 human lung fibroblasts and found that glucose restriction (GR can inhibit cellular senescence and significantly extend cellular lifespan compared with cells receiving normal glucose (NG in the culture medium. Moreover, GR decreased expression of p16(INK4a (p16, a well-known senescence-related gene, in all of the tested cell lines. Over-expressed p16 resulted in early replicative senescence in glucose-restricted cells suggesting a crucial role of p16 regulation in GR-induced cellular lifespan extension. The decreased expression of p16 was partly due to GR-induced chromatin remodeling through effects on histone acetylation and methylation of the p16 promoter. GR resulted in an increased expression of SIRT1, a NAD-dependent histone deacetylase, which has positive correlation with CR-induced longevity. The elevated SIRT1 was accompanied by enhanced activation of the Akt/p70S6K1 signaling pathway in response to GR. Furthermore, knockdown of SIRT1 abolished GR-induced p16 repression as well as Akt/p70S6K1 activation implying that SIRT1 may affect p16 repression through direct deacetylation effects and indirect regulation of Akt/p70S6K1 signaling. Collectively, these results provide new insights into interactions between epigenetic and genetic mechanisms on CR-induced longevity that may contribute to anti-aging approaches and also provide a general molecular model for studying CR in vitro in mammalian systems.

  17. Tombusvirus-yeast interactions identify conserved cell-intrinsic viral restriction factors

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    Zsuzsanna eSasvari


    Full Text Available To combat viral infections, plants possess innate and adaptive immune pathways, such as RNA silencing, R gene and recessive gene-mediated resistance mechanisms. However, it is likely that additional cell-intrinsic restriction factors (CIRF are also involved in limiting plant virus replication. This review discusses novel CIRFs with antiviral functions, many of them RNA-binding proteins or affecting the RNA binding activities of viral replication proteins. The CIRFs against tombusviruses have been identified in yeast (Saccharomyces cerevisiae, which is developed as an advanced model organism. Grouping of the identified CIRFs based on their known cellular functions and subcellular localization in yeast reveals that TBSV replication is limited by a wide variety of host gene functions. Yeast proteins with the highest connectivity in the network map include the well-characterized Xrn1p 5’-3’ exoribonuclease, Act1p actin protein and Cse4p centromere protein. The protein network map also reveals an important interplay between the pro-viral Hsp70 cellular chaperone and the antiviral co-chaperones, and possibly key roles for the ribosomal or ribosome-associated factors. We discuss the antiviral functions of selected CIRFs, such as the RNA binding nucleolin, ribonucleases, WW-domain proteins, single- and multi-domain cyclophilins, TPR-domain co-chaperones and cellular ion pumps. These restriction factors frequently target the RNA-binding region in the viral replication proteins, thus interfering with the recruitment of the viral RNA for replication and the assembly of the membrane-bound viral replicase. Although many of the characterized CIRFs act directly against TBSV, we propose that the TPR-domain co-chaperones function as guardians of the cellular Hsp70 chaperone system, which is subverted efficiently by TBSV for viral replicase assembly in the absence of the TPR-domain co-chaperones.

  18. 77 FR 15665 - Cellular Service, Including Changes in Licensing of Unserved Area; Interim Restrictions and... (United States)


    ... for every Cellular Market Area (CMA) and corresponding channel block (Block A or Block B), in two... this document. FOR FURTHER INFORMATION CONTACT: Nina Shafran, Wireless Telecommunications Bureau... Proposed Rulemaking I. Introduction 1. Since its inception roughly 30 years ago, the Cellular Service...

  19. Cellular Reprogramming Using Defined Factors and MicroRNAs. (United States)

    Eguchi, Takanori; Kuboki, Takuo


    Development of human bodies, organs, and tissues contains numerous steps of cellular differentiation including an initial zygote, embryonic stem (ES) cells, three germ layers, and multiple expertized lineages of cells. Induced pluripotent stem (iPS) cells have been recently developed using defined reprogramming factors such as Nanog, Klf5, Oct3/4 (Pou5f1), Sox2, and Myc. This outstanding innovation is largely changing life science and medicine. Methods of direct reprogramming of cells into myocytes, neurons, chondrocytes, and osteoblasts have been further developed using modified combination of factors such as N-myc, L-myc, Sox9, and microRNAs in defined cell/tissue culture conditions. Mesenchymal stem cells (MSCs) and dental pulp stem cells (DPSCs) are also emerging multipotent stem cells with particular microRNA expression signatures. It was shown that miRNA-720 had a role in cellular reprogramming through targeting the pluripotency factor Nanog and induction of DNA methyltransferases (DNMTs). This review reports histories, topics, and idea of cellular reprogramming.

  20. Robust Template Decomposition without Weight Restriction for Cellular Neural Networks Implementing Arbitrary Boolean Functions Using Support Vector Classifiers

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    Yih-Lon Lin


    Full Text Available If the given Boolean function is linearly separable, a robust uncoupled cellular neural network can be designed as a maximal margin classifier. On the other hand, if the given Boolean function is linearly separable but has a small geometric margin or it is not linearly separable, a popular approach is to find a sequence of robust uncoupled cellular neural networks implementing the given Boolean function. In the past research works using this approach, the control template parameters and thresholds are restricted to assume only a given finite set of integers, and this is certainly unnecessary for the template design. In this study, we try to remove this restriction. Minterm- and maxterm-based decomposition algorithms utilizing the soft margin and maximal margin support vector classifiers are proposed to design a sequence of robust templates implementing an arbitrary Boolean function. Several illustrative examples are simulated to demonstrate the efficiency of the proposed method by comparing our results with those produced by other decomposition methods with restricted weights.

  1. 76 FR 23923 - Hazardous Materials: Restricting the Use of Cellular Phones by Drivers of Commercial Motor... (United States)

    2011-04-29 . B. PHMSA Distracted Driving Safety Advisory Notice and Texting Restriction In support of... for talking on mobile telephones and 200 more for texting while driving. II. Applicability of this... the use of hand-held mobile telephones while driving. This rulemaking would improve health and...

  2. Cacao in México: Restrictive factors and productivity levels

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    Julio Díaz-José


    Full Text Available Cacao (Theobroma cacao L. represents one of the most important agricultural crops of the humid Mexican tropics. In the last 10 yr, approximately 23.000 t of this grain were no longer produced per cycle. The objective of this study was to identify characteristics and factors that restrict production in the states of Tabasco and Chiapas. A survey was applied to obtain information about 184 producers and their plantations by two-stage sampling. Descriptive statistics were calculated and multilevel models were adjusted to analyze the information. Results show that there are differences (P < 0.05 in cacao yield between municipalities (380 kg ha-1 + u,o j is the estimated residual for each municipality. Crop productivity levels are higher in the state of Tabasco than in Chiapas (644 and 344 kg ha-1, respectively. Incidence of frosty pod rot of cacoa, also known as moniliasis, induced by Moniliophthora roreri [(Cif H.C. Evans, Stalpers, Samson & Benny 1978] is significantly greater (P < 0.05 in the state of Chiapas (60% than in Tabasco (48%.Producers who carry out more crop management practices increase yields and decrease the pathogen's impact on their plantations. Results suggest the need to apply differentiated public policies to promote production within each region or municipality.

  3. Effect of dietary restriction, pregnancy, and fetal type on intestinal cellularity and vascularity in Columbia and Romanov ewes. (United States)

    Scheaffer, A N; Caton, J S; Redmer, D A; Arnold, D R; Reynolds, L P


    The objectives of this study were to evaluate intestinal cellularity and vascularity in mature ewes in response to dietary restriction and pregnancy status and to quantify the response of these variables to increased nutrient demand of fetal growth. In Exp. 1, 28 mature Dorset x crossbred white-faced ewes (61.6+/-1.8 kg initial BW) were fed a pelleted, forage-based diet. Treatments were arranged in a 2 x 3 factorial, with dietary restriction (60% restriction vs. 100% maintenance for respective states of pregnancy) and pregnancy status (nonpregnant, NP; d 90 and 130) as main effects. Dietary treatments were initiated on d 50 of gestation and remained at 60 or 100% maintenance throughout the experiment. Nonpregnant ewes were fed dietary treatments for 40 d. In Exp. 2, four Romanov ewes were naturally serviced (Romanov fetus and Romanov dam; R/R); two Romanov embryos per recipient were transferred to four Columbia recipients (Romanov fetus and Columbia recipient; R/C), and three Columbia ewes were naturally serviced (Columbia fetus and Columbia dam; C/C). In Exp. 1, dietary restriction and pregnancy status interacted with regard to maternal jejunal DNA concentration (P < 0.01), with restricted ewes having a greater DNA concentration (mg/g; fresh basis) at d 130. Vascularity (percentage of total tissue area) in the jejunum was increased (P < 0.06) as a result of dietary restriction and pregnancy status. Total microvascular volume ofjejunal tissue was not altered by dietary restriction and increased (P < 0.01) at d 130 of pregnancy. In Exp. 2, R/R ewes had less (P < 0.09) DNA (g) in the jejunum compared with R/C and C/C ewes. Jejunal vascularity (%) was increased (P < 0.05) in R/R ewes compared with R/C or C/C ewes, whereas total jejunal microvascular volume remained unchanged. These data demonstrate intestinal vascular density responds to changes in diet and physiological state. In addition, pregnancy increased total jejunal microvascular volume.

  4. Effect of dietary restriction on carcass composition and adipocyte cellularity of swine with different propensities for obesity. (United States)

    Etherton, T D; Wangsness, P J; Hammers, V M; Ziegler, J H


    Experiments were conducted to determine whether dietary restriction altered body composition and adipocyte cellularity similarly in growing lean (Yorkshire) and obese (Ossabaw) swine. Yorkshire (YR) and Ossabaw (OR) swine were fed 65% of the weekly intake of ad libitum-fed Yorkshire (YA) and Ossabaw (OA) swine for 20 weeks. At 200 days of age, adipose tissue mass was 7-fold lower and muscle mass was 50% lower in YR than YA. However, adipose tissue mass of OR was only 2.6-fold less than OA. Furthermore, muscle mass did not differ between OR and OA. Adipocyte number per carcass was 6-fold higher in YA than YR. No differences in carcass adipocyte number were observed between OA and OR. Dietary restriction resulted in a reduced adipocyte size in both breeds of swine. However, adipocyte size for both dietary treatments was greater for obese than lean swine. When carcass adipocyte number was expressed per Kilogram of muscle, there were no differences among YA, OA, and OR; however, this ratio was lower in YR. These results demonstrate: 1) that alterations in nutrient partitioning as measured by accretion of these tissues are different in lean and obese swine when intake is restricted, 2) that differences in adipose tissue mass of YA and OA are due to differences in cell size, and 3) that muscle growth and adipocyte hyperplasia in swine may have a physiological relationship.

  5. Cellular & Molecular Immunology receives its first Impact Factor

    Institute of Scientific and Technical Information of China (English)

    Zhigang Tian


    @@ The 2009 edition of the JCR, in which Cellular (c) Molecular Immunology (CMI) is listed for the first time, reveals an Impact Factor of 2.765, placing CMI 63rd out of 128 in the Immunology subject category. According to ISI's ranking this also places the journal 5th out of 114 journals published in China and 23rd out of 587 journals published in the Asia-Pacific region. This is an excellent first Impact Factor for a young journal like CMI and,together with our publishing partner Nature Publishing Group and the continued support of our readers and authors, we hope to further build on this into the future. We are delighted that CMI can be internationally recognized as important in the field of immunology.

  6. Restricting Factors at Modification of Parameters of Associative Engineering Objects (United States)

    Horváth, László

    Advancements in product development have reached full integration of engineering activities and processes in product lifecycle management (PLM) systems. PLM systems are based on high-level modeling, simulation and data management. Despite significant development of modeling in PLM systems, a strong demand was recognized for improved decision assistance in product development. Decision assistance can be improved by application of methods from the area of computer intelligence. In order for a product development company to stay competitive, it is important for its modeling system to be relied on local even personal knowledge. The authors analyzed current PLM systems for shortcomings and possibilities for extended intelligence at decision-making during product development. They propose methods in order to increase suitability of current modeling systems to accommodate knowledge based IT at definition of sets of parameters of modeled objects and in the management of frequent changes of modeled objects. In the center of the proposed methodology, constrained parameters act as restricting factors at definition and modification of parameters of associative engineering objects. Paper starts with an outlook to modeling in current engineering systems and preliminary results by the authors. Following this, groups of essential information as handled by he proposed modeling are summarized and procedures for processing of that groups of information are detailed. Next, management of chains of changes along chains of associa-tive product objects and a new style of decision assistance in modeling systems are explained. Changes are created or verified by behavior analysis. Finally, behavior analysis, human intent combination, product data view creation, and change management are discussed as the proposed integrated and coordinated methodology for enhanced support of decision-making in product development.

  7. Cortical factor feedback model for cellular locomotion and cytofission.

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    Shin I Nishimura


    Full Text Available Eukaryotic cells can move spontaneously without being guided by external cues. For such spontaneous movements, a variety of different modes have been observed, including the amoeboid-like locomotion with protrusion of multiple pseudopods, the keratocyte-like locomotion with a widely spread lamellipodium, cell division with two daughter cells crawling in opposite directions, and fragmentations of a cell to multiple pieces. Mutagenesis studies have revealed that cells exhibit these modes depending on which genes are deficient, suggesting that seemingly different modes are the manifestation of a common mechanism to regulate cell motion. In this paper, we propose a hypothesis that the positive feedback mechanism working through the inhomogeneous distribution of regulatory proteins underlies this variety of cell locomotion and cytofission. In this hypothesis, a set of regulatory proteins, which we call cortical factors, suppress actin polymerization. These suppressing factors are diluted at the extending front and accumulated at the retracting rear of cell, which establishes a cellular polarity and enhances the cell motility, leading to the further accumulation of cortical factors at the rear. Stochastic simulation of cell movement shows that the positive feedback mechanism of cortical factors stabilizes or destabilizes modes of movement and determines the cell migration pattern. The model predicts that the pattern is selected by changing the rate of formation of the actin-filament network or the threshold to initiate the network formation.

  8. Handheld cellular phones restrict head movements and range of visual regard. (United States)

    Thumser, Zachary C; Stahl, John S


    Numerous studies have reported the ability of mobile phones to distract users and thereby degrade performance of concurrent tasks. Less is known about whether the phone-holding posture can itself influence concurrent motor activities. Horizontal eye movements are often coordinated with head movements, particularly when the amplitude of the gaze shift is large. Holding a phone to one ear has been shown to restrict the range of spontaneously generated head movements. In order to determine whether the phone-holding posture also influences gaze, we recorded eye and head movements as volunteers looked about themselves spontaneously. Holding the phone to the ear narrowed the range of gaze, principally in subjects who exhibit a strong propensity to move the head with the eyes. We argue that visual exploration may be influenced by the balance between costs and benefits of turning the head, with the phone-holding posture increasing the costs. The effects on gaze would be seen most clearly in subjects who have a higher predilection for coupling eye and head movements. Conversely, this effect would be minimal if tested in tasks that rarely elicit head movements in the specific subjects being tested. The results emphasize the close coordination between eye and head movements, and have implications for the design of ergonomic studies comparing the effects of handheld vs. hands-free mobile phones on performance of specific tasks, such as driving.

  9. Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

    Energy Technology Data Exchange (ETDEWEB)

    Salaita, Khalid; Nair, Pradeep M; Petit, Rebecca S; Neve, Richard M; Das, Debopriya; Gray, Joe W; Groves, Jay T


    Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.

  10. A Study of Evaluation System of Restricting Factors in Training Students' Qualities

    Institute of Scientific and Technical Information of China (English)

    MA Xiao-yan


    This paper studies evaluation system of restricting factors in training students' qualities by modern mathematical method of analysis hierarchy process and principal factor analysis, and to build up a mathematical model of evaluation system.

  11. Transcription of human respiratory syncytial virus genome RNA in vitro: requirement of cellular factor(s).


    Barik, S


    Extracts made from human respiratory syncytial virus (RSV)-infected Hep-2 cells synthesized mRNAs encoded by all known viral genes. In contrast, RSV ribonucleoproteins purified from infected cells failed to transcribe in vitro; transcription was restored by addition of a cytoplasmic extract of uninfected Hep-2 cells, demonstrating that a cellular factor(s) has a role in RSV gene expression. Quantitation of the individual gene mRNAs transcribed in vitro revealed polarity of transcription of th...

  12. Factors underlying restricted crossover localization in barley meiosis. (United States)

    Higgins, James D; Osman, Kim; Jones, Gareth H; Franklin, F Chris H


    Meiotic recombination results in the formation of cytological structures known as chiasmata at the sites of genetic crossovers (COs). The formation of at least one chiasma/CO between homologous chromosome pairs is essential for accurate chromosome segregation at the first meiotic division as well as for generating genetic variation. Although DNA double-strand breaks, which initiate recombination, are widely distributed along the chromosomes, this is not necessarily reflected in the chiasma distribution. In many species there is a tendency for chiasmata to be distributed in favored regions along the chromosomes, whereas in others, such as barley and some other grasses, chiasma localization is extremely pronounced. Localization of chiasma to the distal regions of barley chromosomes restricts the genetic variation available to breeders. Studies reviewed herein are beginning to provide an explanation for chiasma localization in barley. Moreover, they suggest a potential route to manipulating chiasma distribution that could be of value to plant breeders.

  13. Computation of the pseudoskin factor for a restricted-entry well

    Energy Technology Data Exchange (ETDEWEB)

    Ding, W. (Joshi Technologies International Inc., Tulsa, OK (United States)); Reynolds, A.C. Jr. (Univ. of Tulsa, OK (United States))


    Wells frequently are completed over a fraction of the oil zone to delay water and gas coning. This type of completion is called a restricted-entry or partially penetrating well. When analyzing well-test data from a restricted-entry well, semilog analysis of pseudoradial flow data yields an estimate of the total skin factor, which is a linear combination of the mechanical skin factor and the pseudoskin factor caused by restricted entry. This work presented two new equations for computing the pseudoskin factor from a restricted-entry well completed in a multilayer reservoir. These equations represent generalization of formulas presented by Papatzacos and Vrbik for single-layer homogeneous reservoirs. For ranges of reservoir and well parameters ordinarily encountered, the new equations provide results approximately equal to those obtained from the Yeh-Reynolds calculation procedure, but are easier to use than this equation.

  14. Modeling mechanical restriction differences between car and heavy truck in two-lane cellular automata traffic flow model (United States)

    Li, Xin; Li, Xingang; Xiao, Yao; Jia, Bin


    Real traffic is heterogeneous with car and truck. Due to mechanical restrictions, the car and the truck have different limited deceleration capabilities, which are important factors in safety driving. This paper extends the single lane safety driving (SD) model with limited deceleration capability to two-lane SD model, in which car-truck heterogeneous traffic is considered. A car has a larger limited deceleration capability while a heavy truck has a smaller limited deceleration capability as a result of loaded goods. Then the safety driving conditions are different as the types of the following and the leading vehicles vary. In order to eliminate the well-known plug in heterogeneous two-lane traffic, it is assumed that heavy truck has active deceleration behavior when the heavy truck perceives the forming plug. The lane-changing decisions are also determined by the safety driving conditions. The fundamental diagram, spatiotemporal diagram, and lane-changing frequency were investigated to show the effect of mechanical restriction on heterogeneous traffic flow. It was shown that there would be still three traffic phases in heterogeneous traffic condition; the active deceleration of the heavy truck could well eliminate the plug; the lane-changing frequency was low in synchronized flow; the flow and velocity would decrease as the proportion of heavy truck grows or the limited deceleration capability of heavy truck drops; and the flow could be improved with lane control measures.

  15. some notes on discount factor restrictions for dynamic optimization problems


    Gerhard Sorger


    We consider dynamic optimization problems on one-dimensional state spaces. Un- der standard smoothness and convexity assumptions, the optimal solutions are characterized by an optimal policy function h mapping the state space into itself. There exists an extensive literature on the relation between the size of the discount factor of the dynamic optimization problem on the one hand and the properties of the dynamical system xt+1 = h(xt) on the other hand. The purpose of this paper is to survey...

  16. Removing phase-space restrictions in factorized cross sections

    CERN Document Server

    Feige, Ilya; Yan, Kai


    Factorization in gauge theories holds at the amplitude or amplitude-squared level for states of given soft or collinear momenta. When performing phase-space integrals over such states, one would generally like to avoid putting in explicit cuts to separate soft from collinear momenta. Removing these cuts induces an overcounting of the soft-collinear region and adds new infrared-ultraviolet divergences in the collinear region. In this paper, we first present a regulator-independent subtraction algorithm for removing soft-collinear overlap at the amplitude level which may be useful in pertubative QCD. We then discuss how both the soft-collinear and infrared-ultraviolet overlap can be undone for certain observables in a way which respects factorization. Our discussion clarifies some of the subtleties in phase-space subtractions and includes a proof of the infrared finiteness of a suitably subtracted jet function. These results complete the connection between factorized QCD and Soft-Collinear Effective Theory.

  17. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

    DEFF Research Database (Denmark)

    Heintz, Caroline; Doktor, Thomas K; Lanjuin, Anne;


    via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also...... homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction...

  18. Cellular origin and procoagulant activity of tissue factor-exposing microparticles in cancer patients

    NARCIS (Netherlands)

    Kleinjan, A.; Berckmans, R.J.; Böing, A.N.; Sturk, A.; Büller, H.R.; Kamphuisen, P.W.; Nieuwland, R.


    Background: In patients with cancer, tissue factor-exposing microparticles (TF-exposing MP) have been associated with disease progression and thrombosis. The cellular origin and coagulant activity of TF-exposing MP, however, remain disputed. Therefore, we investigated the cellular origin of the TF-e

  19. Restrictive Factors of Vocational Education Development in Cultivation of Rural Practical Skilled Personnel and Countermeasures



    Kunming City is accelerating the process of agricultural modernization, industrialization, informationization and ecological development. In this process, it needs speeding up building new high level and advanced rural practical skilled personnel team suitable for development demand. By empirical analysis method, this paper discussed the factors restricting vocational education in cultivation of rural practical skilled personnel. Then, it came up with countermeasures in cultivation objective ...

  20. Inter-organizational relationships: promoters and restrictive factors in the formation of cooperation network

    Directory of Open Access Journals (Sweden)

    Marcos Antonio Gaspar


    Full Text Available The present paper had as aim to identify factors of inter-organizational relationships which promotes and restricts the formation of companies’ cooperation network, from two levels of analysis (organizational and inter-organizational. To achieve this goal, it was developed a descriptive-qualitative study, with prospecting for primary and secondary data on a cooperation network. The universe was composed by 41 participating companies associated to the analyzed network. The sampling procedure was for researcher’s accessibility and convenience. As a result, it was identified that the network is guided by goals of cooperation among the participating companies, in addition to representing the sector and provide services in the interests of the associates. The main factors influencing the formation of the network were: business center, marketing and training; but only training has been achieved satisfactorily. The business center and marketing factors have not yet been fully developed, being both identified as restrictive factors.

  1. Mechanisms of cellular adaptation to quantum dots--the role of glutathione and transcription factor EB. (United States)

    Neibert, Kevin D; Maysinger, Dusica


    Cellular adaptation is the dynamic response of a cell to adverse changes in its intra/extra cellular environment. The aims of this study were to investigate the role of: (i) the glutathione antioxidant system, and (ii) the transcription factor EB (TFEB), a newly revealed master regulator of lysosome biogenesis, in cellular adaptation to nanoparticle-induced oxidative stress. Intracellular concentrations of glutathione species and activation of TFEB were assessed in rat pheochromocytoma (PC12) cells following treatment with uncapped CdTe quantum dots (QDs), using biochemical, live cell fluorescence and immunocytochemical techniques. Exposure to toxic concentrations of QDs resulted in a significant enhancement of intracellular glutathione concentrations, redistribution of glutathione species and a progressive translocation and activation of TFEB. These changes were associated with an enlargement of the cellular lysosomal compartment. Together, these processes appear to have an adaptive character, and thereby participate in the adaptive cellular response to toxic nanoparticles.

  2. The function and evolution of the restriction factor viperin in primates was not driven by lentiviruses

    Directory of Open Access Journals (Sweden)

    Lim Efrem S


    Full Text Available Abstract Background Viperin, also known as RSAD2, is an interferon-inducible protein that potently restricts a broad range of different viruses such as influenza, hepatitis C virus, human cytomegalovirus and West Nile virus. Viperin is thought to affect virus budding by modification of the lipid environment within the cell. Since HIV-1 and other retroviruses depend on lipid domains of the host cell for budding and infectivity, we investigated the possibility that Viperin also restricts human immunodeficiency virus and other retroviruses. Results Like other host restriction factors that have a broad antiviral range, we find that viperin has also been evolving under positive selection in primates. The pattern of positive selection is indicative of Viperin's escape from multiple viral antagonists over the course of primate evolution. Furthermore, we find that Viperin is interferon-induced in HIV primary target cells. We show that exogenous expression of Viperin restricts the LAI strain of HIV-1 at the stage of virus release from the cell. Nonetheless, the effect of Viperin restriction is highly strain-specific and does not affect most HIV-1 strains or other retroviruses tested. Moreover, knockdown of endogenous Viperin in a lymphocytic cell line did not significantly affect the spreading infection of HIV-1. Conclusion Despite positive selection having acted on Viperin throughout primate evolution, our findings indicate that Viperin is not a major restriction factor against HIV-1 and other retroviruses. Therefore, other viral lineages are likely responsible for the evolutionary signatures of positive selection in viperin among primates.

  3. Overexpression of factor VIII after AAV delivery is transiently associated with cellular stress in hemophilia A mice (United States)

    Lange, Amy M; Altynova, Ekaterina S; Nguyen, Giang N; Sabatino, Denise E


    Factor VIII (FVIII) is a large glycoprotein that is challenging to express both in vitro and in vivo. Several studies suggest that high levels of FVIII expression can lead to cellular stress. After gene transfer, transgene expression is restricted to a subset of cells and the increased FVIII load per cell may impact activation of the unfolded protein response. We sought to determine whether increased FVIII expression in mice after adeno-associated viral liver gene transfer would affect the unfolded protein response and/or immune response to the transgene. The FVIII gene was delivered as B-domain deleted single chain or two chain (light and heavy chains) at a range of doses in hemophilia A mice. A correlation between FVIII expression and anti-FVIII antibody titers was observed. Analysis of key components of the unfolded protein response, binding immunoglobulin protein (BiP), and C/EBP homologous protein (CHOP), showed transient unfolded protein response activation in the single chain treated group expressing >200% of FVIII but not after two chain delivery. These studies suggest that supraphysiological single chain FVIII expression may increase the likelihood of a cellular stress response but does not alter liver function. These data are in agreement with the observed long-term expression of FVIII at therapeutic levels after adeno-associated viral delivery in hemophilia A dogs without evidence of cellular toxicity. PMID:27738645

  4. MRI-derived Restriction Spectrum Imaging Cellularity Index is Associated with High Grade Prostate Cancer on Radical Prostatectomy Specimens


    Michael Andre Liss; White, Nathan S.; J. Kellogg Parsons; Schenker-Ahmed, Natalie M.; Rebecca eRakow-Penner; Kuperman, Joshua M.; Hauke eBartsch; Choi, Hyung W.; Mattrey, Robert F.; Bradley, William G.; Ahmed eShabaik; Jiaoti eHuang; Daniel J. A. Margolis; Raman, Steven S.; Marks, Leonard S.


    Objectives: We evaluate a novel magnetic resonance imaging (MRI) technique to improve detection of aggressive prostate cancer. Methods: We performed a retrospective analysis of presurgical prostate MRI scans using an advanced diffusion weighted imaging technique called Restriction Spectrum Imaging (RSI), which can be presented as a normalized z-score statistic (RSI z-score). Scans were acquired prior to radical prostatectomy. Prostatectomy specimens were processed using whole mount sectioning...

  5. MRI-Derived Restriction Spectrum Imaging Cellularity Index is Associated with High Grade Prostate Cancer on Radical Prostatectomy Specimens


    Liss, Michael A.; White, Nathan S.; Parsons, J. Kellogg; Schenker-Ahmed, Natalie M.; Rakow-Penner, Rebecca; Kuperman, Joshua M.; Bartsch, Hauke; Choi, Hyung W.; Mattrey, Robert F.; Bradley, William G.; Shabaik, Ahmed; Huang, Jiaoti; Daniel J. A. Margolis; Raman, Steven S.; Marks, Leonard S.


    Purpose: We evaluate a novel magnetic resonance imaging (MRI) technique to improve detection of aggressive prostate cancer (PCa). Materials and Methods: We performed a retrospective analysis of pre-surgical prostate MRI scans using an advanced diffusion-weighted imaging technique called restriction spectrum imaging (RSI), which can be presented as a normalized z-score statistic. Scans were acquired prior to radical prostatectomy. Prostatectomy specimens were processed using whole-mount sec...

  6. DNA methylation restricts lineage-specific functions of transcription factor Gata4 during embryonic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Masaaki Oda


    Full Text Available DNA methylation changes dynamically during development and is essential for embryogenesis in mammals. However, how DNA methylation affects developmental gene expression and cell differentiation remains elusive. During embryogenesis, many key transcription factors are used repeatedly, triggering different outcomes depending on the cell type and developmental stage. Here, we report that DNA methylation modulates transcription-factor output in the context of cell differentiation. Using a drug-inducible Gata4 system and a mouse embryonic stem (ES cell model of mesoderm differentiation, we examined the cellular response to Gata4 in ES and mesoderm cells. The activation of Gata4 in ES cells is known to drive their differentiation to endoderm. We show that the differentiation of wild-type ES cells into mesoderm blocks their Gata4-induced endoderm differentiation, while mesoderm cells derived from ES cells that are deficient in the DNA methyltransferases Dnmt3a and Dnmt3b can retain their response to Gata4, allowing lineage conversion from mesoderm cells to endoderm. Transcriptome analysis of the cells' response to Gata4 over time revealed groups of endoderm and mesoderm developmental genes whose expression was induced by Gata4 only when DNA methylation was lost, suggesting that DNA methylation restricts the ability of these genes to respond to Gata4, rather than controlling their transcription per se. Gata4-binding-site profiles and DNA methylation analyses suggested that DNA methylation modulates the Gata4 response through diverse mechanisms. Our data indicate that epigenetic regulation by DNA methylation functions as a heritable safeguard to prevent transcription factors from activating inappropriate downstream genes, thereby contributing to the restriction of the differentiation potential of somatic cells.

  7. Inhibition of microtubules and dynein rescues human immunodeficiency virus type 1 from owl monkey TRIMCyp-mediated restriction in a cellular context-specific fashion. (United States)

    Pawlica, Paulina; Dufour, Caroline; Berthoux, Lionel


    IFN-induced restriction factors can significantly affect the replicative capacity of retroviruses in mammals. TRIM5α (tripartite motif protein 5, isoform α) is a restriction factor that acts at early stages of the virus life cycle by intercepting and destabilizing incoming retroviral cores. Sensitivity to TRIM5α maps to the N-terminal domain of the retroviral capsid proteins. In several New World and Old World monkey species, independent events of retrotransposon-mediated insertion of the cyclophilin A (CypA)-coding sequence in the trim5 gene have given rise to TRIMCyp (also called TRIM5-CypA), a hybrid protein that is active against some lentiviruses in a species-specific fashion. In particular, TRIMCyp from the owl monkey (omkTRIMCyp) very efficiently inhibits human immunodeficiency virus type 1 (HIV-1). Previously, we showed that disrupting the integrity of microtubules (MTs) and of cytoplasmic dynein complexes partially rescued replication of retroviruses, including HIV-1, from restriction mediated by TRIM5α. Here, we showed that efficient restriction of HIV-1 by omkTRIMCyp was similarly dependent on the MT network and on dynein complexes, but in a context-dependent fashion. When omkTRIMCyp was expressed in human HeLa cells, restriction was partially counteracted by pharmacological agents targeting MTs or by small interfering RNA-mediated inhibition of dynein. The same drugs (nocodazole and paclitaxel) also rescued HIV-1 from restriction in cat CRFK cells, although to a lesser extent. Strikingly, neither nocodazole, paclitaxel nor depletion of the dynein heavy chain had a significant effect on the restriction of HIV-1 in an owl monkey cell line. These results suggested the existence of cell-specific functional interactions between MTs/dynein and TRIMCyp.

  8. The ubiquitin ligase TRIM27 functions as a host restriction factor antagonized by Mycobacterium tuberculosis PtpA during mycobacterial infection (United States)

    Wang, Jing; Teng, Jade L. L.; Zhao, Dongdong; Ge, Pupu; Li, Bingxi; Woo, Patrick C. Y.; Liu, Cui Hua


    Macrophage-mediated innate immune responses play crucial roles in host defense against pathogens. Recent years have seen an explosion of host proteins that act as restriction factors blocking viral replication in infected cells. However, the essential factors restricting Mycobacterium tuberculosis (Mtb) and their regulatory roles during mycobacterial infection remain largely unknown. We previously reported that Mtb tyrosine phosphatase PtpA, a secreted effector protein required for intracellular survival of Mtb, inhibits innate immunity by co-opting the host ubiquitin system. Here, we identified a new PtpA-interacting host protein TRIM27, which is reported to possess a conserved RING domain and usually acts as an E3 ubiquitin ligase that interferes with various cellular processes. We further demonstrated that TRIM27 restricts survival of mycobacteria in macrophages by promoting innate immune responses and cell apoptosis. Interestingly, Mtb PtpA could antagonize TRIM27-promoted JNK/p38 MAPK pathway activation and cell apoptosis through competitively binding to the RING domain of TRIM27. TRIM27 probably works as a potential restriction factor for Mtb and its function is counteracted by Mtb effector proteins such as PtpA. Our study suggests a potential tuberculosis treatment via targeting of the TRIM27-PtpA interfaces. PMID:27698396

  9. Demand Forecasting at Low Aggregation Levels using Factored Conditional Restricted Boltzmann Machine

    DEFF Research Database (Denmark)

    Mocanu, Elena; Nguyen, Phuong H.; Gibescu, Madeleine


    The electrical demand forecasting problem can be regarded as a nonlinear time series prediction problem depending on many complex factors since it is required at various aggregation levels and at high temporal resolution. To solve this challenging problem, various time series and machine learning...... developed deep learning model for time series prediction, namely Factored Conditional Restricted Boltzmann Machine (FCRBM), and extend it for electrical demand forecasting. The assessment is made on the EcoGrid dataset, originating from the Bornholm island experiment in Denmark, consisting of aggregated...

  10. Dual roles of lineage restricted transcription factors: the case of MITF in melanocytes. (United States)

    Levy, Carmit; Fisher, David E


    Microphthalmia-associated Transcription Factor, MITF, is a master regulator of melanocyte development, differentiation, migration, and survival.(1) A broad collection of studies have indicated that MITF directly regulates the transcription of genes involved in pigmentation, which are selective to the melanocyte lineage. In addition, MITF controls expression of genes which are expressed in multiple cell lineages, and may also play differential roles in activating vs. maintaining gene expression patterns. In this Point of View article, we discuss lineage restricted transcription factor activation of both tissue-specific and ubiquitously expressed genes using melanocytes and MITF as a model system that may eventually provide insights into such processes in multiple cell lineages.

  11. KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

    DEFF Research Database (Denmark)

    Bürck, Carolin; Mund, Andreas; Berscheminski, Julia


    and cellular SWI/SNF chromatin remodeling play a key role in HAdV transcriptional regulation (1-4). We observed that the cellular chromatin-associated factor, and epigenetic reader SPOC1 represses HAdV infection and gene expression. Here, we illustrate the role of the SPOC1 interacting factor KAP1 during...

  12. Reverse Transcriptase and Cellular Factors: Regulators of HIV-1 Reverse Transcription

    Directory of Open Access Journals (Sweden)

    David Harrich


    Full Text Available There is ample evidence that synthesis of HIV-1 proviral DNA from the viral RNA genome during reverse transcription requires host factors. However, only a few cellular proteins have been described in detail that affect reverse transcription and interact with reverse transcriptase (RT. HIV-1 integrase is an RT binding protein and a number of IN-binding proteins including INI1, components of the Sin3a complex, and Gemin2 affect reverse transcription. In addition, recent studies implicate the cellular proteins HuR, AKAP149, and DNA topoisomerase I in reverse transcription through an interaction with RT. In this review we will consider interactions of reverse transcription complex with viral and cellular factors and how they affect the reverse transcription process.

  13. Quantification and control of restrictive ecological factors in acidogenic de-sulfate bioreactor

    Institute of Scientific and Technical Information of China (English)

    王爱杰; 任南琪


    As an artificial microbial ecosystem, acidogenic de-sulfate bioreactor has high efficiency of sulfate removal. The restrictive ecological factors, including causing ecological factors, such as COD/SO42- ratio and sulfate loading rate (Ns), and following ecological factors, such as pH value, oxidation reduction potential (ORP) and alkalinity (ALK) have significant effect on the ability and stability of acidogenic de-sulfate bio-reactor. Continuous flow and batch test were carried out to investigate the quantification and control of COD/SO42- ratio, Ns, pH value, ORP and ALK in acidogenic de-sulfate bioreactor supplied with molasses wastewater as sole organic carbon source and sodium sulfate as electron donor. It was demonstrated that In order to maintain high sulfate removal rate (SRR) of 80% to 90%, the restrictive factors should meet all the requirement as follows: kCOD/ SO42- ratio≥2.0, Ns≤7.5 kg (m3·d)-1,pH=5.7~6.2,ORP=-320~-420 mV and ALK=1 500~2 000 mg/L.

  14. A general strategy for cellular reprogramming: the importance of transcription factor cross-repression. (United States)

    Crespo, Isaac; Del Sol, Antonio


    Transcription factor cross-repression is an important concept in cellular differentiation. A bistable toggle switch constitutes a molecular mechanism that determines cellular commitment and provides stability to transcriptional programs of binary cell fate choices. Experiments support that perturbations of these toggle switches can interconvert these binary cell fate choices, suggesting potential reprogramming strategies. However, more complex types of cellular transitions could involve perturbations of combinations of different types of multistable motifs. Here, we introduce a method that generalizes the concept of transcription factor cross-repression to systematically predict sets of genes, whose perturbations induce cellular transitions between any given pair of cell types. Furthermore, to our knowledge, this is the first method that systematically makes these predictions without prior knowledge of potential candidate genes and pathways involved, providing guidance on systems where little is known. Given the increasing interest of cellular reprogramming in medicine and basic research, our method represents a useful computational methodology to assist researchers in the field in designing experimental strategies.

  15. Food restriction beginning at lactation interferes with the cellular dynamics of the mucosa and colonic myenteric innervation in adult rats

    Directory of Open Access Journals (Sweden)



    Full Text Available The effects of food restriction (FR on the morphoquantitative aspects of the wall and myenteric neurons of the proximal colon in adult rats were analysed. FR was imposed by duplication of the experimental brood size in relation to the control brood during lactation. The FR group received a 50% reduction of food from weaning until 90 days of age. Samples of the colon underwent histological processing to morphometrically analyze the crypts, muscularis mucosae, tunica mucosa, and muscularis externa. We determined the number of goblet cells and serotoninergic enteroendocrine cells, and morphoquantitatively studied the myenteric neuronal population. FR caused hypertrophy in the tunica mucosa, increase in crypt depth and in the muscular layer of the mucosa, a decrease in the thickness of the tunica muscularis and in the number of goblet cells and an increase in serotoninergic cells. A higher neuronal density in the ganglia and a reduction of the cell profile area were observed in the FR group. FR imposed since lactation led to hypertrophy of the tunica mucosa, a reduction of neutral mucin production, atrophy of the tunica muscularis, and an increase in the survival neuronal in adult rats, attributable to an increase in the number of serotoninergic enteroendocrine cells in mucosa.

  16. Factors that restrict the intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE)

    DEFF Research Database (Denmark)

    Ouyang, Hui; Chen, Weiqing; Andersen, Thomas E;


    inactive or substantially less active than PSC-833 in increasing the P(B) values of these prodrugs. These data suggest that, while P-gp plays a role, other factors (e.g., substrate activity for other efflux transporters and/or for metabolic enzymes) may contribute to restricting the permeation of AOA......The objective of this study was to elucidate the role of P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, and OMCA-DADLE) of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). In the Caco-2 cell model, the high P......(app,BL-to-AP)/P(app,AP-to-BL) ratios of AOA-DADLE, CA-DADLE, and OMCA-DADLE (71-117) were significantly decreased by including known P-gp inhibitors, GF-12098, cyclosporine (CyA), or PSC-833, in the incubation media, suggesting that P-gp is restricting the AP-to-BL permeation of these cyclic prodrugs. In the in situ perfused rat...

  17. Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor.

    Directory of Open Access Journals (Sweden)

    Debrah A Fine

    Full Text Available The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

  18. [Study on restriction factors and countermeasures of influence of China medical devices competitiveness]. (United States)

    Zhang, Zhijun


    Recent years, China medical devices industry has been a sunrise industry with widely-ranged products, high-tech innovation, and booming market demands. But with the globalization of market economy, China industry is still in the inferior position of competition. How to promote the industrial structure transition, increase scientific and technological level, speed up the updating of products, enhance the international competitiveness is one of the major tasks to maintain the healthy development of industry. This article makes a study on current situation of China medical devices industry, analyses the new opportunities, challenges and restriction factors, provides the countermeasures of strengthening industry competitiveness as well.

  19. Restrictive Factors of Vocational Education Development in Cultivation of Rural Practical Skilled Personnel and Countermeasures

    Institute of Scientific and Technical Information of China (English)

    Ning; WANG; Fang; LIU


    Kunming City is accelerating the process of agricultural modernization,industrialization,informationization and ecological development. In this process,it needs speeding up building new high level and advanced rural practical skilled personnel team suitable for development demand. By empirical analysis method,this paper discussed the factors restricting vocational education in cultivation of rural practical skilled personnel. Then,it came up with countermeasures in cultivation objective of rural vocational education,arrangement of specialized disciplines,key development tasks,and establishment of diversified investment system.

  20. Model identification with BPNN on restrictive ecological factors of SRB for sulfate-reduction

    Institute of Scientific and Technical Information of China (English)


    The model of back-propagation neural network(BPNN)was presented to demonstrate the effect of restrictive ecological factors,COD/SO42-ratio,pH value,alkalinity(ALK)and SO42-loading rate(Ns),on sulfate-reduction of Sulfate Reducing Bacteria(SRB)in an acidogenic sulfate-reducing reactor supplied with molasses as sole organic carbon source and sodium sulfate as electron acceptor.The compare of experimental results and computer simulation was also discussed.It was shown that the method of BPNN had a powerful ability to analyze the ecological characteristic of acidogenic sulfate-reducing ecosystem quantitatively.

  1. Stress testing at the cellular and molecular level to unravel cellular dysfunction and growth factor signal transduction defects: what Molecular Cell Biology can learn from Cardiology. (United States)

    Waltenberger, Johannes


    Clinical medicine has been revolutionized by the impact of cellular and molecular biology in the past 30 years. This article focuses on a novel approach, whereby the clinically proven and important concept of patient or organ stress testing is being applied to cellular models, thereby developing and validating novel quantitative molecular and cellular stress tests. One example is monocyte chemotaxis analysis, whereby circulating monocytes freshly isolated from peripheral blood are being tested for their migratory responsiveness towards relevant biological stimuli such as growth factors or chemokines. These stimuli are relevant for recruiting monocytes to sites of local inflammation such as during wound healing or arteriogenesis, i.e. growth of collateral arteries. Initial clinical studies to validate "ligand-induced monocyte chemotaxis" indicate that this parameter is impaired in the presence of various cardiovascular risk factors including diabetes mellitus, hypercholesterolemia or smoking. In addition, there is proof of concept that impaired monocyte chemotaxis is reversible as shown for anti-oxidants in smokers. Moreover, the parameter "ligand-induced monocyte chemotaxis" is of great relevance for basic science (including Molecular Cell Biology) as unravelling the underlying molecular mechanisms of cellular dysfunction will certainly stimulate our understanding of the molecular basis of cellular function. This article highlights the concept of stress testing in modern medicine. Cellular stress testing is introduced as a novel and intriguing approach, which was developed as bedside-to-bench. Future prospective clinical trials will have to validate the predictive value of cellular stress testing.

  2. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

    NARCIS (Netherlands)

    Humalda, J.K.; Lambers Heerspink, H.J.; Kwakernaak, A.J.; Slagman, M.C.; Waanders, F.; Vervloet, M.G.; Wee, P.M. Ter; Navis, G.; Borst, M.H. de; Wee, P.M. ter; Vervloet, M.; Bindels, R.J.; Hoenderop, J.G.J.; Hillebrands, J.L.


    BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  3. Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

    NARCIS (Netherlands)

    Humalda, Jelmer K; Lambers Heerspink, Hiddo J; Kwakernaak, Arjan J; Slagman, Maartje C J; Waanders, Femke; Vervloet, Marc G; Ter Wee, Pieter M; Navis, Gerarda; de Borst, Martin H


    Background: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  4. Analysis of the restricting factors of laser countermeasure active detection technology (United States)

    Zhang, Yufa; Sun, Xiaoquan


    The detection effect of laser active detection system is affected by various kinds of factors. In view of the application requirement of laser active detection, the influence factors for laser active detection are analyzed. The mathematical model of cat eye target detection distance has been built, influence of the parameters of laser detection system and the environment on detection range and the detection efficiency are analyzed. Various parameters constraint detection performance is simulated. The results show that the discovery distance of laser active detection is affected by the laser divergence angle, the incident angle and the visibility of the atmosphere. For a given detection range, the laser divergence angle and the detection efficiency are mutually restricted. Therefore, in view of specific application environment, it is necessary to select appropriate laser detection parameters to achieve optimal detection effect.

  5. Early Life Stress and Sleep Restriction as Risk Factors in PTSD: An Integrative Pre-Clinical Approach (United States)


    M., He, H., Arora, J., Lu, N., Tu, X. M. and Katz, I. R. (2014). Posttraumatic stress disorder and suicide in 5.9 million individuals receiving...Award Number: W81XWH-11-2-0111 TITLE: Early Life Stress and Sleep Restriction as Risk Factors in PTSD: An Integrative Pre-Clinical Approach...2015 4. TITLE AND SUBTITLE “Early Life Stress and Sleep Restriction as Risk Factors in PTSD: An Integrative Pre- Clinical Approach” 5a. CONTRACT NUMBER

  6. Computation of the pseudoskin factor caused by a restricted-entry well completed in a multilayer reservoir

    Energy Technology Data Exchange (ETDEWEB)

    Yeh, N.; Reynolds, A.C.


    This work considers flow to a restricted-entry well in a single- or multilayer reservoir where crossflow occurs between reservoir layers. A simple algebraic expression for approximating the pseudoskin factor caused by restricted entry is presented. It is shown that, for practical purposes, this equation yields sufficiently accurate estimates of the pseudoskin factor regardless of the location of the open interval.This work also extends single-layer results of interest in well testing to the multilayer case and shows that if sufficient data are available, the results of this work can be used to prepare a complete analysis of well testing pressure data obtained at a restricted-entry well.

  7. Insulin-like growth factor and fibroblast growth factor expression profiles in growth-restricted fetal sheep pancreas. (United States)

    Chen, Xiaochuan; Rozance, Paul J; Hay, William W; Limesand, Sean W


    Placental insufficiency results in intrauterine growth restriction (IUGR), impaired fetal insulin secretion and less fetal pancreatic β-cell mass, partly due to lower β-cell proliferation rates. Insulin-like growth factors (IGFs) and fibroblast growth factors (FGFs) regulate fetal β-cell proliferation and pancreas development, along with transcription factors, such as pancreatic and duodenal homeobox 1 (PDX-1). We determined expression levels for these growth factors, their receptors and IGF binding proteins in ovine fetal pancreas and isolated islets. In the IUGR pancreas, relative mRNA expression levels of IGF-I, PDX-1, FGF7 and FGFR2IIIb were 64% (P pancreas compared with controls. In isolated islets from IUGR fetuses, IGF-II and IGFBP-2 mRNA concentrations were 1.5- and 3.7-fold greater (P < 0.05), and insulin mRNA was 56% less (P < 0.05) than control islets. The growth factor expression profiles for IGF and FGF signaling pathways indicate that declines in β-cell mass are due to decreased growth factor signals for both pancreatic progenitor epithelial cell and mature β-cell replication.

  8. Pineal gland expression of the transcription factor Egr-1 is restricted to a population of glia that are distinct from nestin-immunoreactive cells. (United States)

    Man, Pui-Sin; Carter, David A


    Egr-1 is a plasticity-related transcription factor that has been implicated in circadian regulation of the pineal gland. In the present study we have investigated the cellular expression pattern of Egr-1 in the adult rat pineal. Egr-1 protein is restricted to the nucleus of a sub-population of cells. These cells were characterised using a new transgenic rat model (egr-1-d2EGFP) in which green fluorescent protein is driven by the egr-1 promoter. Cellular filling by GFP revealed that Egr-1-positive cells exhibited processes, indicating a glial cell-type morphology. This was confirmed by co-localizing the GFP-filled processes with vimentin and S-100beta. However, GFP/Egr-1 is expressed in only a tiny minority of the previously identified Id-1/vimentin-positive glial cells and therefore represents a novel sub-set of this (GFAP-negative) glial population. We have also demonstrated for the first time an extensive network of nestin-positive cells throughout the adult pineal gland, however these cells do not co-express Egr-1. Our studies have therefore broadened our understanding of the cell populations that constitute the adult pineal. Cellular localization of Egr-1 has revealed that this factor does not appear to be directly involved in pinealocyte production of melatonin but is required in a sub-set of pineal glia.

  9. Antagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartment.

    Directory of Open Access Journals (Sweden)

    Mathieu Dubé


    Full Text Available The Vpu accessory protein promotes HIV-1 release by counteracting Tetherin/BST-2, an interferon-regulated restriction factor, which retains virions at the cell-surface. Recent reports proposed beta-TrCP-dependent proteasomal and/or endo-lysosomal degradation of Tetherin as potential mechanisms by which Vpu could down-regulate Tetherin cell-surface expression and antagonize this restriction. In all of these studies, Tetherin degradation did not, however, entirely account for Vpu anti-Tetherin activity. Here, we show that Vpu can promote HIV-1 release without detectably affecting Tetherin steady-state levels or turnover, suggesting that Tetherin degradation may not be necessary and/or sufficient for Vpu anti-Tetherin activity. Even though Vpu did not enhance Tetherin internalization from the plasma membrane (PM, it did significantly slow-down the overall transport of the protein towards the cell-surface. Accordingly, Vpu expression caused a specific removal of cell-surface Tetherin and a re-localization of the residual pool of Tetherin in a perinuclear compartment that co-stained with the TGN marker TGN46 and Vpu itself. This re-localization of Tetherin was also observed with a Vpu mutant unable to recruit beta-TrCP, suggesting that this activity is taking place independently from beta-TrCP-mediated trafficking and/or degradation processes. We also show that Vpu co-immunoprecipitates with Tetherin and that this interaction involves the transmembrane domains of the two proteins. Importantly, this association was found to be critical for reducing cell-surface Tetherin expression, re-localizing the restriction factor in the TGN and promoting HIV-1 release. Overall, our results suggest that association of Vpu to Tetherin affects the outward trafficking and/or recycling of the restriction factor from the TGN and as a result promotes its sequestration away from the PM where productive HIV-1 assembly takes place. This mechanism of antagonism that results

  10. Dynamic Monitoring of Cellular Remodeling Induced by the Transforming Growth Factor-β1

    Directory of Open Access Journals (Sweden)

    Kubala Lukáš


    Full Text Available Abstract The plasticity of differentiated adult cells could have a great therapeutic potential, but at the same time, it is characteristic of progression of serious pathological states such as cancer and fibrosis. In this study, we report on the application of a real-time noninvasive system for dynamic monitoring of cellular plasticity. Analysis of the cell impedance profile recorded as cell index using a real-time cell analyzer revealed its significant increase after the treatment of prostate epithelial cells with the transforming growth factor-β1. Changes in the cell index profile were paralleled with cytoskeleton rebuilding and induction of epithelial–mesenchymal transition and negatively correlated with cell proliferation. This novel application of such approach demonstrated a great potential of the impedance-based system for noninvasive and real-time monitoring of cellular fate.

  11. Modest dietary K+ restriction provokes insulin resistance of cellular K+ uptake and phosphorylation of renal outer medulla K+ channel without fall in plasma K+ concentration. (United States)

    Chen, Pei; Guzman, John P; Leong, Patrick K K; Yang, Li E; Perianayagam, Anjana; Babilonia, Elisa; Ho, Jennifer S; Youn, Jang H; Wang, Wen Hui; McDonough, Alicia A


    Extracellular K(+) concentration ([K(+)]) is closely regulated by the concerted regulatory responses of kidney and muscle. In this study, we aimed to define the responses activated when dietary K(+) was moderately reduced from a control diet (1.0% K(+)) to a 0.33% K(+) diet for 15 days. Although body weight and baseline plasma [K(+)] (4.0 mM) were not reduced in the 0.33% K(+) group, regulatory responses to conserve plasma [K(+)] were evident in both muscle and kidney. Insulin-stimulated clearance of K(+) from the plasma was estimated in vivo in conscious rats with the use of tail venous and arterial cannulas. During infusion of insulin.(50, plasma [K(+)] level fell to 3.2 +/- 0.1 mM in the 1.0% K(+) diet group and to only 3.47 +/- 0.07 mM in the 0.33% K(+) diet group (P < 0.01) with no reduction in urinary K(+) excretion, which is evidence of insulin resistance to cellular K(+) uptake. Insulin-stimulated cellular K(+) uptake was quantitated by measuring the K(+) infusion rate necessary to clamp plasma K(+) at baseline (in during 5 mU of infusion: 9.7 +/- 1.5 in 1% K(+) diet was blunted to 5.2 +/- 1.7 in the 0.33% K(+) diet group (P < 0.001). Muscle [K(+)] and Na(+)-K(+)-ATPase activity and abundance were unchanged during the 0.33% K(+) diet. Renal excretion, which was measured overnight in metabolic cages, was reduced by 80%, from 117.6 +/- 10.5 micromol/h/animal (1% K(+) diet) to 24.2 +/- 1.7 micromol/h/animal (0.33% K(+) diet) (P < 0.001). There was no significant change in total abundance of key renal K(+) transporters, but 50% increases in both renal PTK cSrc abundance and ROMK phosphorylation in the 0.33% K(+) vs. 1% K(+) diet group, previously established to be associated with internalization of ROMK. These results indicate that plasma [K(+)] can be maintained during modest K(+) restriction due to a decrease in insulin-stimulated cellular K(+) uptake as well as renal K(+) conservation

  12. Interacting factors and cellular localization of SR protein-specific kinase Dsk1

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Zhaohua, E-mail: [W.M. Keck Science Center, The Claremont Colleges, Claremont, CA 91711 (United States); Luca, Maria; Taggart-Murphy, Laura; Portillio, Jessica; Chang, Cathey; Guven, Ayse [W.M. Keck Science Center, The Claremont Colleges, Claremont, CA 91711 (United States); Lin, Ren-Jang [Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010 (United States); Murray, Johanne; Carr, Antony [Genome Damage and Stability Center, University of Sussex, Falmer, BN1 9RQ (United Kingdom)


    Schizosaccharomyces pombe Dsk1 is an SR protein-specific kinase (SRPK), whose homologs have been identified in every eukaryotic organism examined. Although discovered as a mitotic regulator with protein kinase activity toward SR splicing factors, it remains largely unknown about what and how Dsk1 contributes to cell cycle and pre-mRNA splicing. In this study, we investigated the Dsk1 function by determining interacting factors and cellular localization of the kinase. Consistent with its reported functions, we found that pre-mRNA processing and cell cycle factors are prominent among the proteins co-purified with Dsk1. The identification of these factors led us to find Rsd1 as a novel Dsk1 substrate, as well as the involvement of Dsk1 in cellular distribution of poly(A){sup +} RNA. In agreement with its role in nuclear events, we also found that Dsk1 is mainly localized in the nucleus during G{sub 2} phase and at mitosis. Furthermore, we revealed the oscillation of Dsk1 protein in a cell cycle-dependent manner. This paper marks the first comprehensive analysis of in vivo Dsk1-associated proteins in fission yeast. Our results reflect the conserved role of SRPK family in eukaryotic organisms, and provide information about how Dsk1 functions in pre-mRNA processing and cell-division cycle.

  13. Effect of age on the gene expression of neural-restrictive silencing factor NRSF/REST. (United States)

    Mori, Nozomu; Mizuno, Takafumi; Murai, Kiyohito; Nakano, Itsuko; Yamashita, Hitoshi


    Aging affects a wide range of gene expression changes in the nervous system. Such effects could be attributed to random changes in the environment with age around each gene, but also could be caused by selective changes in a limited set of key regulatory transcription factors and/or chromatin remodeling components. To approach the question of whether neural-restrictive silencer factor NRSF, a key determinant of the neuron-specific gene expression, is involved in these changes, we examined the levels of NRSF in the rat brain and dosal root ganglia during aging by semi-quantitative reverse transcriptase-mediated polymerase chain reaction (PCR) (RT-PCR). Complementary expression profiles of transcripts of NRSF and SCG10 in the mature brain were shown by in situ hybridization. Neither the mRNA levels of NRSF nor a splicing variant NRnV were changed, at least in rats up to 26 months old. The gene expression level of SCG10, one of the NRSF targets, was also unaffected by age. The stable expression of SCG10 transcripts in aging was confirmed by in situ hybridization. The NRS-binding ability of NRSF was also unchanged significantly in the nuclear extracts of aged rat brain. These results suggest that the genetic machinery associated with the NRS-NRSF system is well maintained during aging.

  14. Hypoxia-inducible factor-1a restricts the anabolic actions of parathyroid hormone

    Institute of Scientific and Technical Information of China (English)

    Julie L Frey; David P Stonko; Marie-Claude Faugere; Ryan C Riddle


    The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1a in osteoanabolic signaling, we assessed the effect of Hif-1a loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1a in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1a protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1a-mediated suppression of b-catenin transcriptional activity. Together, these data indicate that Hif-1a functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1a function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.

  15. Suture restriction of the temporal bone as a risk factor for acute otitis media in children: cohort study

    Directory of Open Access Journals (Sweden)

    Morin Chantal


    Full Text Available Abstract Background Eustachian tube (ET dysfunction plays an important role in the pathogenesis of acute otitis media (AOM. Unfortunately, there is a lack of knowledge about the exact role of the ET’s bony support, the temporal bone, on occurrence of AOM. This study investigates whether severe suture restriction of the temporal bone is a risk factor for development of AOM in young children. Methods Using a prospective cohort design, 64 children aged 6 to 18 months without prior history of AOM were followed during the cold season (September 2009 to April 2010. Temporal bone status (categorized as with or without severe suture restriction was evaluated using palpation and a cranial bone mobility test. Information about potential baseline confounders and risk factors for AOM (gender, age, birth weight, gestational age, use of pacifier, daycare attendance, presence of siblings, low socioeconomic status, breastfeeding ≥ 6 months, parental smoking and history of upper respiratory tract infection were also collected. Occurrence of AOM diagnosed by physicians blinded to temporal bone status was the main outcome. Data were analyzed using hierarchical linear and nonlinear (multilevel models. Results Severe suture restriction of the temporal bone was identified in 23 children (35.9%. At least one AOM episode was diagnosed in 14 (48.3% of the ears associated with temporal bones previously identified as having severe suture restriction and in 28 (28.3% of those without severe suture restriction. Higher risk for AOM was explained by severe suture restriction of the temporal bone (adjusted relative risk (RR, 2.26, 95% CI 1.43 to 2.91, p Conclusions The study results indicate that severe suture restriction of the temporal bone is a risk factor for AOM in young children. Subsequent intervention studies are needed to determine if this mechanical risk factor can be modified in young children.

  16. Brain-derived neurotrophic factor deficiency restricts proliferation of oligodendrocyte progenitors following cuprizone-induced demyelination. (United States)

    Tsiperson, Vladislav; Huang, Yangyang; Bagayogo, Issa; Song, Yeri; VonDran, Melissa W; DiCicco-Bloom, Emanuel; Dreyfus, Cheryl F


    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that through its neurotrophic tyrosine kinase, receptor, type 2 (TrkB) receptor, increases 5-bromo-2-deoxyuridine incorporation in oligodendrocyte progenitor cells (OPCs) in culture. Roles in vivo are less well understood; however, increases in numbers of OPCs are restricted in BDNF+/- mice following cuprizone-elicited demyelination. Here, we investigate whether these blunted increases in OPCs are associated with changes in proliferation. BDNF+/+ and BDNF+/- mice were fed cuprizone-containing or control feed. To assess effects on OPC numbers, platelet-derived growth factor receptor alpha (PDGFRα)+ or NG2+ cells were counted. To monitor DNA synthesis, 5-ethynyl-2'-deoxyuridine (EdU) was injected intraperitoneally and colocalized with PDGFRα+ cells. Alternatively, proliferating cell nuclear antigen (PCNA) was colocalized with PDGFRα or NG2. Labeling indices were determined in the BDNF+/+ and BDNF+/- animals. After 4 or 5 weeks of control feed, BDNF+/- mice exhibit similar numbers of OPCs compared with BDNF+/+ animals. The labeling indices for EdU and PCNA also were not significantly different, suggesting that neither the DNA synthesis phase (S phase) nor the proliferative pool size was different between genotypes. In contrast, when mice were challenged by cuprizone for 4 or 5 weeks, increases in OPCs observed in BDNF+/+ mice were reduced in the BDNF+/- mice. This difference in elevations in cell number was accompanied by decreases in EdU labeling and PCNA labeling without changes in cell death, indicating a reduction in the DNA synthesis and the proliferative pool. Therefore, levels of BDNF influence the proliferation of OPCs resulting from a demyelinating lesion.

  17. Severe Calorie Restriction Reduces Cardiometabolic Risk Factors and Protects Rat Hearts from Ischemia/Reperfusion Injury (United States)

    Melo, Dirceu S.; Costa-Pereira, Liliane V.; Santos, Carina S.; Mendes, Bruno F.; Costa, Karine B.; Santos, Cynthia Fernandes F.; Rocha-Vieira, Etel; Magalhães, Flávio C.; Esteves, Elizabethe A.; Ferreira, Anderson J.; Guatimosim, Sílvia; Dias-Peixoto, Marco F.


    Background and Aims: Recent studies have proposed that if a severe caloric restriction (SCR) is initiated at the earliest period of postnatal life, it can lead to beneficial cardiac adaptations later on. We investigated the effects of SCR in Wistar rats from birth to adult age on risk factors for cardiac diseases (CD), as well as cardiac function, redox status, and HSP72 content in response to ischemia/reperfusion (I/R) injury. Methods and Results: From birth to the age of 3 months, CR50 rats were fed 50% of the food that the ad libitum group (AL) was fed. Food intake was assessed daily and body weight were assessed weekly. In the last week of the SCR protocol, systolic blood pressure and heart rate were measured and the double product index was calculated. Also, oral glucose and intraperitoneal insulin tolerance tests were performed. Thereafter, rats were decapitated, visceral fat was weighed, and blood and hearts were harvested for biochemical, functional, tissue redox status, and western blot analyzes. Compared to AL, CR50 rats had reduced the main risk factors for CD. Moreover, the FR50 rats showed increased cardiac function both at baseline conditions (45% > AL rats) and during the post-ischemic period (60% > AL rats) which may be explained by a decreased cardiac oxidative stress and increased HSP72 content. Conclusion: SCR from birth to adult age reduced risk factors for CD, increased basal cardiac function and protected hearts from the I/R, possibly by a mechanism involving ROS. PMID:27092082

  18. Cellular factors controlling neuronal vulnerability in the brain: a lesson from the striatum. (United States)

    Calabresi, P; Centonze, D; Bernardi, G


    In many acute and chronic neurologic disorders, both deficits in energy metabolism and defects in glutamate-mediated excitatory synaptic transmission have been proposed as important pathogenic factors. Brain cells, however, express variable vulnerability to these insults, as indicated by the fact that certain brain areas and even different cell types in the same area are preferentially spared until the very late stages of various diseases. This can be clearly seen in the striatum, where GABAergic projection cells but not cholinergic interneurons are precociously damaged in the course of both acute metabolic insults (such as hypoxia, hypoglycemia, and ischemia) and chronic neurodegenerative disorders (such as Huntington's disease). A well-mapped pattern of cell loss, in fact, is a common finding in the striatum of patients suffering from these pathologic conditions. Physiologic and molecular studies have been directed in recent years to the identification of the cellular mechanisms underlying the cell-type specific vulnerability of striatal cells. These studied recognized that, in striatal spiny and aspiny cells, specific membrane ion channels, glutamate receptor subtypes and subunits, and intracellular enzymatic activities are involved in the cascade of events responsible for opposite responses and vulnerabilities to oxygen or glucose deprivation and to glutamate receptor-mediated toxicity. Specific molecules able to target these cellular factors might be employed as therapeutic agents during acute and chronic neurologic disorders affecting this brain area.

  19. Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming.

    Directory of Open Access Journals (Sweden)

    Masamitsu Konno

    Full Text Available Noncoding microRNAs inhibit translation and lower the transcript stability of coding mRNA, however miR-369 s, in aberrant silencing genomic regions, stabilizes target proteins under cellular stress. We found that in vitro differentiation of embryonic stem cells led to chromatin methylation of histone H3K4 at the miR-369 region on chromosome 12qF in mice, which is expressed in embryonic cells and is critical for pluripotency. Proteomic analyses revealed that miR-369 stabilized translation of pyruvate kinase (Pkm2 splicing factors such as HNRNPA2B1. Overexpression of miR-369 stimulated Pkm2 splicing and enhanced induction of cellular reprogramming by induced pluripotent stem cell factors, whereas miR-369 knockdown resulted in suppression. Furthermore, immunoprecipitation analysis showed that the Argonaute complex contained the fragile X mental retardation-related protein 1 and HNRNPA2B1 in a miR-369-depedent manner. Our findings demonstrate a unique role of the embryonic miR-369-HNRNPA2B1 axis in controlling metabolic enzyme function, and suggest a novel pathway linking epigenetic, transcriptional, and metabolic control in cell reprogramming.

  20. Is abnormal vaginal microflora a risk factor for intrauterine fetal growth restriction?

    Institute of Scientific and Technical Information of China (English)

    NatalijaVedmedovska; Dace Rezeberga; GilbertG G Donders


    Objective:To conduct a literature review in search of possible preventable causes for fetal growth restriction.Methods:We performed a systematic literature search regarding abnormal vaginal microflora and fetal growth encompassing the last 27-year (starting from 1986) in PubMed, Embase, and Cochrane Central to study the evidence that abnormal vaginal microflora is may be related to diminished fetal growth or small for date birth.Results:Most of the 14 studies suggested a significant role of vaginal organisms in impaired fetal growth, unrelated to preterm birth. The neonatal outcome has shown to be largely linked to the preventable or foreseeable fetal factors, such as genetic abnormalities, but also ascending intrauterine infections. Our previous work suggested a role of vaginal organisms in adverse pregnancy outcome, not only preterm birth, but also impaired fetal growth.Conclusions:There is a need for cohort studies designed to unravel this link between abnormal microflora and FGR, in order to enable preventive actions to protect these small babies from severe damage and death by early screening and treatment.

  1. Intrauterine growth restriction: distribution, risk factors, management of labour and outcome

    Directory of Open Access Journals (Sweden)

    Diana Andzane


    Full Text Available Background: The development of Intrauterine growth restriction (IUGR determines maternal, fetal and placental factors. Many of these factors are preventable. There is still no enough developed effective pregnancy and labour management tactics that could protect both mother and child from the unintended consequences. Methods: The research was made in Riga Maternity Hospital. In the research there were included pregnant women who gave birth neonates with weight under 10th percentile (IUGR group as well there was compiled the control group. The weight of neonates was evaluated using the percentile scales - Intrauterine Growth Curves based on US data. Results: According to the criteria, in the IUGR group were included 209 pregnant women and in the control group was the same number of patients. In the IUGR group mothers discharged from the hospital one day later than it was in the control group both after vaginal delivery (4.0 +/- 1.5 vs. 3.3 +/- 1.0, p and #706;0.0001 and after caesarean (5.6 +/- 1.5 vs. 4.5 +/- 1.0, p=0.0001. Comparing the evaluations after Apgar scale after spontaneous birth, induced labour and caesarean it was discovered that there is no statistically significant difference. Conclusions: IUGR negatively affect not just the fetus but also the mother and this is the reason why she should stay in the hospital for a longer period due to the child or experience the caesarean. [Int J Reprod Contracept Obstet Gynecol 2015; 4(4.000: 1117-1121

  2. Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2)

    Energy Technology Data Exchange (ETDEWEB)

    McDonough,M.; Li, V.; Flashman, E.; Chowdhury, R.; Mohr, C.; Lienard, B.; Zondlo, J.; Oldham, N.; Clifton, I.; et al.


    Cellular and physiological responses to changes in dioxygen levels in metazoans are mediated via the posttranslational oxidation of hypoxia-inducible transcription factor (HIF). Hydroxylation of conserved prolyl residues in the HIF-{alpha} subunit, catalyzed by HIF prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The requirement of the PHDs for dioxygen links changes in dioxygen levels with the transcriptional regulation of the gene array that enables the cellular response to chronic hypoxia; the PHDs thus act as an oxygen-sensing component of the HIF system, and their inhibition mimics the hypoxic response. We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an inhibitor to 1.7 Angstroms resolution. PHD2 crystallizes as a homotrimer and contains a double-stranded {beta}-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1-3). The structure provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease.

  3. Factors that restrict intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE)

    DEFF Research Database (Denmark)

    Ouyang, Hui; Chen, Weiqing; Andersen, Thomas E;


    The objective of this study was to determine the relative importance of metabolism by cytochrome P450 (CYP) enzymes versus efflux by P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, OMCA-DADLE) of the opioid peptide DADLE (H......-gp), not metabolic enzymes (e.g., CYP 3A, esterases), restrict the permeation of peptide prodrugs across the rat intestinal mucosa....

  4. Restricted maternal nutrition alters myogenic regulatory factor expression in satellite cells of ovine offspring. (United States)

    Raja, J S; Hoffman, M L; Govoni, K E; Zinn, S A; Reed, S A


    Poor maternal nutrition inhibits muscle development and postnatal muscle growth. Satellite cells are myogenic precursor cells that contribute to postnatal muscle growth, and their activity can be evaluated by the expression of several transcription factors. Paired-box (Pax)7 is expressed in quiescent and active satellite cells. MyoD is expressed in activated and proliferating satellite cells and myogenin is expressed in terminally differentiating cells. Disruption in the expression pattern or timing of expression of myogenic regulatory factors negatively affects muscle development and growth. We hypothesized that poor maternal nutrition during gestation would alter the in vitro temporal expression of MyoD and myogenin in satellite cells from offspring at birth and 3 months of age. Ewes were fed 100% or 60% of NRC requirements from day 31±1.3 of gestation. Lambs from control-fed (CON) or restricted-fed (RES) ewes were euthanized within 24 h of birth (birth; n=5) or were fed a control diet until 3 months of age (n=5). Satellite cells isolated from the semitendinosus muscle were used for gene expression analysis or cultured for 24, 48 or 72 h and immunostained for Pax7, MyoD or myogenin. Fusion index was calculated from a subset of cells allowed to differentiate. Compared with CON, temporal expression of MyoD and myogenin was altered in cultured satellite cells isolated from RES lambs at birth. The percent of cells expressing MyoD was greater in RES than CON (P=0.03) after 24 h in culture. After 48 h of culture, there was a greater percent of cells expressing myogenin in RES compared with CON (P0.05). In satellite cells from RES lambs at 3 months of age, the percent of cells expressing MyoD and myogenin were greater than CON after 72 h in culture (Psatellite cells of the offspring, which may reduce the pool of myoblasts, decrease myoblast fusion and contribute to the poor postnatal muscle growth previously observed in these animals.

  5. Characterization and restriction analysis of the P sex factor and the cryptic plasmid of Vibrio cholerae strain V58. (United States)

    Bartowsky, E J; Morelli, G; Kamke, M; Manning, P A


    The P plasmid of Vibrio cholerae is a derepressed sex factor restricted to V. cholerae and has been shown to express surface exclusion. We have isolated the plasmids of strain V58 and have found that in addition to P, two further cryptic plasmids are also present. P has a size of 68 kb as determined by both electron microscopy and restriction endonuclease analysis. These other plasmids are 34 and 4.7 kb in size. Restriction maps of P and the larger cryptic plasmid have been determined. It has been demonstrated that P differs from the standard Inc group test plasmids and also expresses a surface exclusion system. The ability of the type Inc plasmids to be transferred to V. cholerae by either liquid or filter matings and the stability of these plasmids in V. cholerae have also been examined.

  6. Graphene Enhances Cellular Proliferation through Activating the Epidermal Growth Factor Receptor. (United States)

    Liu, Wei; Sun, Cheng; Liao, Chunyang; Cui, Lin; Li, Haishan; Qu, Guangbo; Yu, Wenlian; Song, Naining; Cui, Yuan; Wang, Zheng; Xie, Wenping; Chen, Huiming; Zhou, Qunfang


    Graphene has promising applications in food packaging, water purification, and detective sensors for contamination monitoring. However, the biological effects of graphene are not fully understood. It is necessary to clarify the potential risks of graphene exposure to humans through diverse routes, such as foods. In the present study, graphene, as the model nanomaterial, was used to test its potential effects on the cell proliferation based on multiple representative cell lines, including HepG2, A549, MCF-7, and HeLa cells. Graphene was characterized by Raman spectroscopy, particle size analysis, atomic force microscopy, and transmission electron microscopy. The cellular responses to graphene exposure were evaluated using flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and alamarBlue assays. Rat cerebral astrocyte cultures, as the non-cancer cells, were used to assess the potential cytotoxicity of graphene as well. The results showed that graphene stimulation enhanced cell proliferation in all tested cell cultures and the highest elevation in cell growth was up to 60%. A western blot assay showed that the expression of epidermal growth factor (EGF) was upregulated upon graphene treatment. The phosphorylation of EGF receptor (EGFR) and the downstream proteins, ShC and extracellular regulating kinase (ERK), were remarkably induced, indicating that the activation of the mitogen-activated protein kinase (MAPK)/ERK signaling pathway was triggered. The activation of PI3 kinase p85 and AKT showed that the PI3K/AKT signaling pathway was also involved in graphene-induced cell proliferation, causing the increase of cell ratios in the G2/M phase. No influences on cell apoptosis were observed in graphene-treated cells when compared to the negative controls, proving the low cytotoxicity of this emerging nanomaterial. The findings in this study revealed the potential cellular biological effect of graphene, which may give useful hints on its biosafety

  7. Downregulation of cellular protective factors of rumen epithelium in goats fed high energy diet.

    Directory of Open Access Journals (Sweden)

    Manfred Hollmann

    Full Text Available Energy-rich diets can challenge metabolic and protective functions of the rumen epithelial cells, but the underlying factors are unclear. This study sought to evaluate proteomic changes of the rumen epithelium in goats fed a low, medium, or high energy diet. Expression of protein changes were compared by two-dimensional differential gel electrophoresis followed by protein identification with matrix assisted laser desorption ionisation tandem time-of-flight mass spectrometry. Of about 2,000 spots commonly detected in all gels, 64 spots were significantly regulated, which were traced back to 24 unique proteins. Interestingly, the expression profiles of several chaperone proteins with important cellular protective functions such as heat shock cognate 71 kDa protein, peroxiredoxin-6, serpin H1, protein disulfide-isomerase, and selenium-binding protein were collectively downregulated in response to high dietary energy supply. Similar regulation patterns were obtained for some other proteins involved in transport or metabolic functions. In contrast, metabolic enzymes like retinal dehydrogenase 1 and ATP synthase subunit beta, mitochondrial precursor were upregulated in response to high energy diet. Lower expressions of chaperone proteins in the rumen epithelial cells in response to high energy supply may suggest that these cells were less protected against the potentially harmful rumen toxic compounds, which might have consequences for rumen and systemic health. Our findings also suggest that energy-rich diets and the resulting acidotic insult may render rumen epithelial cells more vulnerable to cellular damage by attenuating their cell defense system, hence facilitating the impairment of rumen barrier function, typically observed in energy-rich fed ruminants.

  8. Identification of elongation factor G as the conserved cellular target of argyrin B. (United States)

    Nyfeler, Beat; Hoepfner, Dominic; Palestrant, Deborah; Kirby, Christina A; Whitehead, Lewis; Yu, Robert; Deng, Gejing; Caughlan, Ruth E; Woods, Angela L; Jones, Adriana K; Barnes, S Whitney; Walker, John R; Gaulis, Swann; Hauy, Ervan; Brachmann, Saskia M; Krastel, Philipp; Studer, Christian; Riedl, Ralph; Estoppey, David; Aust, Thomas; Movva, N Rao; Wang, Zuncai; Salcius, Michael; Michaud, Gregory A; McAllister, Gregory; Murphy, Leon O; Tallarico, John A; Wilson, Christopher J; Dean, Charles R


    Argyrins, produced by myxobacteria and actinomycetes, are cyclic octapeptides with antibacterial and antitumor activity. Here, we identify elongation factor G (EF-G) as the cellular target of argyrin B in bacteria, via resistant mutant selection and whole genome sequencing, biophysical binding studies and crystallography. Argyrin B binds a novel allosteric pocket in EF-G, distinct from the known EF-G inhibitor antibiotic fusidic acid, revealing a new mode of protein synthesis inhibition. In eukaryotic cells, argyrin B was found to target mitochondrial elongation factor G1 (EF-G1), the closest homologue of bacterial EF-G. By blocking mitochondrial translation, argyrin B depletes electron transport components and inhibits the growth of yeast and tumor cells. Further supporting direct inhibition of EF-G1, expression of an argyrin B-binding deficient EF-G1 L693Q variant partially rescued argyrin B-sensitivity in tumor cells. In summary, we show that argyrin B is an antibacterial and cytotoxic agent that inhibits the evolutionarily conserved target EF-G, blocking protein synthesis in bacteria and mitochondrial translation in yeast and mammalian cells.

  9. Identification of elongation factor G as the conserved cellular target of argyrin B.

    Directory of Open Access Journals (Sweden)

    Beat Nyfeler

    Full Text Available Argyrins, produced by myxobacteria and actinomycetes, are cyclic octapeptides with antibacterial and antitumor activity. Here, we identify elongation factor G (EF-G as the cellular target of argyrin B in bacteria, via resistant mutant selection and whole genome sequencing, biophysical binding studies and crystallography. Argyrin B binds a novel allosteric pocket in EF-G, distinct from the known EF-G inhibitor antibiotic fusidic acid, revealing a new mode of protein synthesis inhibition. In eukaryotic cells, argyrin B was found to target mitochondrial elongation factor G1 (EF-G1, the closest homologue of bacterial EF-G. By blocking mitochondrial translation, argyrin B depletes electron transport components and inhibits the growth of yeast and tumor cells. Further supporting direct inhibition of EF-G1, expression of an argyrin B-binding deficient EF-G1 L693Q variant partially rescued argyrin B-sensitivity in tumor cells. In summary, we show that argyrin B is an antibacterial and cytotoxic agent that inhibits the evolutionarily conserved target EF-G, blocking protein synthesis in bacteria and mitochondrial translation in yeast and mammalian cells.

  10. DDX5 facilitates HIV-1 replication as a cellular co-factor of Rev.

    Directory of Open Access Journals (Sweden)

    Xiuxia Zhou

    Full Text Available HIV-1 Rev plays an important role in the late phase of HIV-1 replication, which facilitates export of unspliced viral mRNAs from the nucleus to cytoplasm in infected cells. Recent studies have shown that DDX1 and DDX3 are co-factors of Rev for the export of HIV-1 transcripts. In this report, we have demonstrated that DDX5 (p68, which is a multifunctional DEAD-box RNA helicase, functions as a new cellular co-factor of HIV-1 Rev. We found that DDX5 affects Rev function through the Rev-RRE axis and subsequently enhances HIV-1 replication. Confocal microscopy and co-immunoprecipitation analysis indicated that DDX5 binds to Rev and this interaction is largely dependent on RNA. If the DEAD-box motif of DDX5 is mutated, DDX5 loses almost all of its ability to bind to Rev, indicating that the DEAD-box motif of DDX5 is required for the interaction between DDX5 and Rev. Our data indicate that interference of DDX5-Rev interaction could reduce HIV-1 replication and potentially provide a new molecular target for anti-HIV-1 therapeutics.

  11. Identification of small peptides inhibiting the integrase-LEDGF/p75 interaction through targeting the cellular co-factor. (United States)

    Cavalluzzo, Claudia; Christ, Frauke; Voet, Arnout; Sharma, Ajendra; Singh, Brajendra Kumar; Zhang, Kam Y J; Lescrinier, Eveline; De Maeyer, Marc; Debyser, Zeger; Van der Eycken, Erik


    The integration of the viral DNA into the host genome is one of the essential steps in the HIV replication cycle. This process is mediated by the viral enzyme integrase (IN) and lens epithelium-derived growth factor (LEDGF/p75). LEDGF/p75 has been identified as a crucial cellular co-factor of integration that acts by tethering IN to the cellular chromatin. Recently, circular peptides were identified that bind to the C-terminal domain of IN and disrupt the interaction with LEDGF/p75. Starting from the circular peptides, we identified a short peptidic sequence able to inhibit the LEDGF/p75-IN interaction at low μM concentration through its binding to the IN binding site of LEDGF/p75. This discovery can lead to the synthesis of peptidomimetics with high anti-HIV activity targeting the cellular co-factor LEDGF/p75 and not the viral protein IN.

  12. Knowledge-based matrix factorization temporally resolves the cellular responses to IL-6 stimulation

    Directory of Open Access Journals (Sweden)

    Gretz Norbert


    Full Text Available Abstract Background External stimulations of cells by hormones, cytokines or growth factors activate signal transduction pathways that subsequently induce a re-arrangement of cellular gene expression. The analysis of such changes is complicated, as they consist of multi-layered temporal responses. While classical analyses based on clustering or gene set enrichment only partly reveal this information, matrix factorization techniques are well suited for a detailed temporal analysis. In signal processing, factorization techniques incorporating data properties like spatial and temporal correlation structure have shown to be robust and computationally efficient. However, such correlation-based methods have so far not be applied in bioinformatics, because large scale biological data rarely imply a natural order that allows the definition of a delayed correlation function. Results We therefore develop the concept of graph-decorrelation. We encode prior knowledge like transcriptional regulation, protein interactions or metabolic pathways in a weighted directed graph. By linking features along this underlying graph, we introduce a partial ordering of the features (e.g. genes and are thus able to define a graph-delayed correlation function. Using this framework as constraint to the matrix factorization task allows us to set up the fast and robust graph-decorrelation algorithm (GraDe. To analyze alterations in the gene response in IL-6 stimulated primary mouse hepatocytes, we performed a time-course microarray experiment and applied GraDe. In contrast to standard techniques, the extracted time-resolved gene expression profiles showed that IL-6 activates genes involved in cell cycle progression and cell division. Genes linked to metabolic and apoptotic processes are down-regulated indicating that IL-6 mediated priming renders hepatocytes more responsive towards cell proliferation and reduces expenditures for the energy metabolism. Conclusions GraDe provides

  13. Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. (United States)

    Nakase, Ikuhiko; Kobayashi, Nahoko Bailey; Takatani-Nakase, Tomoka; Yoshida, Tetsuhiko


    Exosomes are approximately 100-nm vesicles that consist of a lipid bilayer of cellular membranes secreted in large quantities from various types of normal and disease-related cells. Endocytosis has been reported as a major pathway for the cellular uptake of exosomes; however, the detailed mechanisms of their cellular uptake are still unknown. Here, we demonstrate the active induction of macropinocytosis (accompanied by actin reorganisation, ruffling of plasma membrane, and engulfment of large volumes of extracellular fluid) by stimulation of cancer-related receptors and show that the epidermal growth factor (EGF) receptor significantly enhances the cellular uptake of exosomes. We also demonstrate that oncogenic K-Ras-expressing MIA PaCa-2 cells exhibit intensive macropinocytosis that actively transports extracellular exosomes into the cells compared with wild-type K-Ras-expressing BxPC-3 cells. Furthermore, encapsulation of the ribosome-inactivating protein saporin with EGF in exosomes using our simple electroporation method produces superior cytotoxicity via the enhanced cellular uptake of exosomes. Our findings contribute to the biological, pharmaceutical, and medical research fields in terms of understanding the macropinocytosis-mediated cellular uptake of exosomes with applications for exosomal delivery systems.

  14. Cellular Levels of Signaling Factors Are Sensed by β-actin Alleles to Modulate Transcriptional Pulse Intensity

    Directory of Open Access Journals (Sweden)

    Alon Kalo


    Full Text Available The transcriptional response of β-actin to extra-cellular stimuli is a paradigm for transcription factor complex assembly and regulation. Serum induction leads to a precisely timed pulse of β-actin transcription in the cell population. Actin protein is proposed to be involved in this response, but it is not known whether cellular actin levels affect nuclear β-actin transcription. We perturbed the levels of key signaling factors and examined the effect on the induced transcriptional pulse by following endogenous β-actin alleles in single living cells. Lowering serum response factor (SRF protein levels leads to loss of pulse integrity, whereas reducing actin protein levels reveals positive feedback regulation, resulting in elevated gene activation and a prolonged transcriptional response. Thus, transcriptional pulse fidelity requires regulated amounts of signaling proteins, and perturbations in factor levels eliminate the physiological response, resulting in either tuning down or exaggeration of the transcriptional pulse.

  15. Endogenous Murine BST-2/Tetherin Is Not a Major Restriction Factor of Influenza A Virus Infection.

    Directory of Open Access Journals (Sweden)

    Sarah L Londrigan

    Full Text Available BST-2 (tetherin, CD317, HM1.24 restricts virus growth by tethering enveloped viruses to the cell surface. The role of BST-2 during influenza A virus infection (IAV is controversial. Here, we assessed the capacity of endogenous BST-2 to restrict IAV in primary murine cells. IAV infection increased BST-2 surface expression by primary macrophages, but not alveolar epithelial cells (AEC. BST-2-deficient AEC and macrophages displayed no difference in susceptibility to IAV infection relative to wild type cells. Furthermore, BST-2 played little role in infectious IAV release from either AEC or macrophages. To examine BST-2 during IAV infection in vivo, we infected BST-2-deficient mice. No difference in weight loss or in viral loads in the lungs and/or nasal tissues were detected between BST-2-deficient and wild type animals. This study rules out a major role for endogenous BST-2 in modulating IAV in the mouse model of infection.

  16. Pancreatic cellular injury after cardiac surgery with cardiopulmonary bypass: frequency, time course and risk factors. (United States)

    Nys, Monique; Venneman, Ingrid; Deby-Dupont, Ginette; Preiser, Jean-Charles; Vanbelle, Sophie; Albert, Adelin; Camus, Gérard; Damas, Pierre; Larbuisson, Robert; Lamy, Maurice


    Although often clinically silent, pancreatic cellular injury (PCI) is relatively frequent after cardiac surgery with cardiopulmonary bypass; and its etiology and time course are largely unknown. We defined PCI as the simultaneous presence of abnormal values of pancreatic isoamylase and immunoreactive trypsin (IRT). The frequency and time evolution of PCI were assessed in this condition using assays for specific exocrine pancreatic enzymes. Correlations with inflammatory markers were searched for preoperative risk factors. One hundred ninety-three patients submitted to cardiac surgery were enrolled prospectively. Blood IRT, amylase, pancreatic isoamylase, lipase, and markers of inflammation (alpha1-protease inhibitor, alpha2-macroglobulin, myeloperoxidase) were measured preoperatively and postoperatively until day 8. The postoperative increase in plasma levels of pancreatic enzymes and urinary IRT was biphasic in all patients: early after surgery and later (from day 4 to 8 after surgery). One hundred thirty-three patients (69%) experienced PCI, with mean IRT, isoamylase, and alpha1-protease inhibitor values higher for each sample than that in patients without PCI. By multiple regression analysis, we found preoperative values of plasma IRT >or=40 ng/mL, amylase >or=42 IU/mL, and pancreatic isoamylase >or=20 IU/L associated with a higher incidence of postsurgery PCI (P < 0.005). In the PCI patients, a significant correlation was found between the 4 pancreatic enzymes and urinary IRT, total calcium, myeloperoxidase, alpha1-protease inhibitor, and alpha2-macroglobulin. These data support a high prevalence of postoperative PCI after cardiac surgery with cardiopulmonary bypass, typically biphasic and clinically silent, especially when pancreatic enzymes were elevated preoperatively.

  17. A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse. (United States)

    Bloch, Nicolin; Gläsker, Sabine; Sitaram, Poojitha; Hofmann, Henning; Shepard, Caitlin N; Schultz, Megan L; Kim, Baek; Landau, Nathaniel R


    The triphosphohydrolase SAMHD1 (sterile α motif and histidine-aspartate domain-containing protein 1) restricts HIV-1 replication in nondividing myeloid cells by depleting the dNTP pool, preventing reverse transcription. SAMHD1 is also reported to have ribonuclease activity that degrades the virus genomic RNA. Human SAMHD1 is regulated by phosphorylation of its carboxyl terminus at Thr-592, which abrogates its antiviral function yet has only a small effect on its phosphohydrolase activity. In the mouse, SAMHD1 is expressed as two isoforms (ISF1 and ISF2) that differ at the carboxyl terminus due to alternative splicing of the last coding exon. In this study we characterized the biochemical and antiviral properties of the two mouse isoforms of SAMHD1. Both are antiviral in nondividing cells. Mass spectrometry analysis showed that SAMHD1 is phosphorylated at several amino acid residues, one of which (Thr-634) is homologous to Thr-592. Phosphomimetic mutation at Thr-634 of ISF1 ablates its antiviral activity yet has little effect on phosphohydrolase activity in vitro dGTP caused ISF1 to tetramerize, activating its catalytic activity. In contrast, ISF2, which lacks the phosphorylation site, was significantly more active, tetramerized, and was active without added dGTP. Neither isoform nor human SAMHD1 had detectable RNase activity in vitro or affected HIV-1 genomic RNA stability in newly infected cells. These data support a model in which SAMHD1 catalytic activity is regulated through tetramer stabilization by the carboxyl-terminal tail, phosphorylation destabilizing the complexes and inactivating the enzyme. ISF2 may serve to reduce the dNTP pool to very low levels as a means of restricting virus replication.

  18. NcoI restriction fragment length polymorphism (RFLP) of the tumour necrosis factor (TNF alpha) region in primary biliary cirrhosis and in healthy Danes

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Ryder, L P;


    The restriction fragment length polymorphism of the human tumour necrosis factor (TNF alpha) region was investigated by means of 20 different restriction enzymes and a human TNF alpha cDNA probe. Only one of the enzymes, NcoI, revealed a polymorphic pattern consisting of fragments of 10.5 and 5...

  19. Vif of feline immunodeficiency virus from domestic cats protects against APOBEC3 restriction factors from many felids. (United States)

    Zielonka, Jörg; Marino, Daniela; Hofmann, Henning; Yuhki, Naoya; Löchelt, Martin; Münk, Carsten


    To get more insight into the role of APOBEC3 (A3) cytidine deaminases in the species-specific restriction of feline immunodeficiency virus (FIV) of the domestic cat, we tested the A3 proteins present in big cats (puma, lion, tiger, and lynx). These A3 proteins were analyzed for expression and sensitivity to the Vif protein of FIV. While A3Z3s and A3Z2-Z3s inhibited Deltavif FIV, felid A3Z2s did not show any antiviral activity against Deltavif FIV or wild-type (wt) FIV. All felid A3Z3s and A3Z2-Z3s were sensitive to Vif of the domestic cat FIV. Vif also induced depletion of felid A3Z2s. Tiger A3s showed a moderate degree of resistance against the Vif-mediated counter defense. These findings may imply that the A3 restriction system does not play a major role to prevent domestic cat FIV transmission to other Felidae. In contrast to the sensitive felid A3s, many nonfelid A3s actively restricted wt FIV replication. To test whether Vif(FIV) can protect also the distantly related human immunodeficiency virus type 1 (HIV-1), a chimeric HIV-1.Vif(FIV) was constructed. This HIV-1.Vif(FIV) was replication competent in nonpermissive feline cells expressing human CD4/CCR5 that did not support the replication of wt HIV-1. We conclude that the replication of HIV-1 in some feline cells is inhibited only by feline A3 restriction factors and the absence of the appropriate receptor or coreceptor.

  20. Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins. (United States)

    Meng, Xiangzhi; Krumm, Brian; Li, Yongchao; Deng, Junpeng; Xiang, Yan


    Human sterile alpha motif domain-containing 9 (SAMD9) protein is a host restriction factor for poxviruses, but it can be overcome by some poxvirus host-range proteins that share homology with vaccinia virus C7 protein. To understand the mechanism of action for this important family of host-range factors, we determined the crystal structures of C7 and myxoma virus M64, a C7 family member that is unable to antagonize SAMD9. Despite their different functions and only 23% sequence identity, the two proteins have very similar overall structures, displaying a previously unidentified fold comprised of a compact 12-stranded antiparallel β-sandwich wrapped in two short α helices. Extensive structure-guided mutagenesis of C7 identified three loops clustered on one edge of the β sandwich as critical for viral replication and binding with SAMD9. The loops are characterized with functionally important negatively charged, positively charged, and hydrophobic residues, respectively, together forming a unique "three-fingered molecular claw." The key residues of the claw are not conserved in two C7 family members that do not antagonize SAMD9 but are conserved in distantly related C7 family members from four poxvirus genera that infect diverse mammalian species. Indeed, we found that all in the latter group of proteins bind SAMD9. Taken together, our data indicate that diverse mammalian poxviruses use a conserved molecular claw in a C7-like protein to target SAMD9 and overcome host restriction.

  1. Serratia marcescens suppresses host cellular immunity via the production of an adhesion-inhibitory factor against immunosurveillance cells. (United States)

    Ishii, Kenichi; Adachi, Tatsuo; Hamamoto, Hiroshi; Sekimizu, Kazuhisa


    Injection of a culture supernatant of Serratia marcescens into the bloodstream of the silkworm Bombyx mori increased the number of freely circulating immunosurveillance cells (hemocytes). Using a bioassay with live silkworms, serralysin metalloprotease was purified from the culture supernatant and identified as the factor responsible for this activity. Serralysin inhibited the in vitro attachment of both silkworm hemocytes and murine peritoneal macrophages. Incubation of silkworm hemocytes or murine macrophages with serralysin resulted in degradation of the cellular immune factor BmSPH-1 or calreticulin, respectively. Furthermore, serralysin suppressed in vitro phagocytosis of bacteria by hemocytes and in vivo bacterial clearance in silkworms. Disruption of the ser gene in S. marcescens attenuated its host killing ability in silkworms and mice. These findings suggest that serralysin metalloprotease secreted by S. marcescens suppresses cellular immunity by decreasing the adhesive properties of immunosurveillance cells, thereby contributing to bacterial pathogenesis.

  2. On the Restricting Factors & System Arrangements of Chinese Land Tenure Marketization

    Institute of Scientific and Technical Information of China (English)

    YU Peng-yi; ZHANG Wei-dong


    As a general rule of Economics of Development,economic growth and development require rational institution guarantee.Land Tenure.As a main institution factor in agricultural development,closely relates to the reform of Chinese agriculture.Based on the relevant theories of Economics of Institution and Economics of Development,and combined with the marketization process of Chinese Land Tenure of Property Rights,the article studied the effects of institutional factors and put forward some choices in the development of agriculture,which is of both significant and practical importance.

  3. The Complexity of DRw6 DR5 Haplotypes in American Blacks Demonstrated by Serology, Cellular Typing, and Restriction Fragment Length Polymorphism Analysis (United States)


    A second, less polymorphic 8 gene, DRB3 , controls the expression of DRw52a, 52b, and 52c molecules [7]. The third is a pseudogene, DRB2. The DQ...well as nonexpressed genes (DQA2 and DQB2) [6]. The DRB 1, DRB3 and DQ alleles are often nonrandomly associated with each other forming haplotypes, a...Haplotypes expressing DRw52b carry a 12-kb Taql/DR133 DNA restriction fragment while haplotypes expressing DRw52a or DRw52c carry a 9.6-kb Taql/ DRB3 fragment

  4. ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression. (United States)

    Fallone, F; Britton, S; Nieto, L; Salles, B; Muller, C


    Tumor cells adaptation to severe oxygen deprivation (hypoxia) plays a major role in tumor progression. The transcription factor HIF-1 (hypoxia-inducible factor 1), whose α-subunit is stabilized under hypoxic conditions is a key component of this process. Recent studies showed that two members of the phosphoinositide 3-kinase-related kinases (PIKKs) family, ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), regulate the hypoxic-dependent accumulation of HIF-1. These proteins initiate cellular stress responses when DNA damage occurs. In addition, it has been demonstrated that extreme hypoxia induces a replicative stress resulting in regions of single-stranded DNA at stalled replication forks and the activation of ATR (ataxia telangiectasia and Rad3 related protein), another member of the PIKKs family. Here, we show that even less severe hypoxia (0.1% O2) also induces activation of ATR through replicative stress. Importantly, in using either transiently silenced ATR cells, cells expressing an inactive form of ATR or cells exposed to an ATR inhibitor (CGK733), we demonstrate that hypoxic ATR activation positively regulates the key transcription factor HIF-1 independently of the checkpoint kinase Chk1. We show that ATR kinase activity regulates HIF-1α at the translational level and we find that the elements necessary for the regulation of HIF-1α translation are located within the coding region of HIF-1α mRNA. Finally, by using three independent cellular models, we clearly show that the loss of ATR expression and/or kinase activity results in the decrease of HIF-1 DNA binding under hypoxia and consequently affects protein expression levels of two HIF-1 target genes, GLUT-1 and CAIX. Taken together, our data show a new function for ATR in cellular adaptation to hypoxia through regulation of HIF-1α translation. Our work offers new prospect for cancer therapy using ATR inhibitors with the potential to decrease cellular adaptation in hypoxic

  5. Identification of repressor element 1 in cytochrome P450 genes and their negative regulation by RE1 silencing transcription factor/neuron-restrictive silencer factor. (United States)

    García-Sánchez, Rubén; Ayala-Luján, Jorge; Hernández-Peréz, Ascensión; Mendoza-Figueroa, Tomás; Tapia-Ramírez, José


    RE1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) mediates transcriptional repression in many neuron-specific genes by interaction with the repressor element 1/neuron-restrictive silencing element (RE1/NRSE). This element has been identified at least in 20 neuron specific genes. REST/NRSF is highly expressed in non-neuronal tissues, where it is thought to repress gene transcription. We performed a BLAST search to look for the presence of RE1/NRSE elements in the rat cytochrome P450 genes. We identified the presence of RE1/NRSE element in the cytochrome P450 genes CYP1A1, 2A2, 2E1 and 3A2. Electrophoretic mobility shift assay and supershift assays were carried out to prove functionality of these sites and detect the interaction of REST/NRSF with this sequence. Cotransfection studies in PC12 cells with a plasmid containing the RE1 element of the CYP genes, cloned upstream of the minimal type II sodium channel promoter, in the presence of REST/NRSF, showed a marked expression inhibition of the CAT reporter gene. These data suggest that the RE1 elements that exist in these four CYP genes might be a target for the REST/NRSF transcription factor and such an interaction might play a role in the negative regulation of these genes.

  6. Cognitive effects of cellular phones: a possible role of non-radiofrequency radiation factors. (United States)

    Hareuveny, Ronen; Eliyahu, Ilan; Luria, Roy; Meiran, Nachshon; Margaliot, Menachem


    Some studies found that cognitive functions of human beings may be altered while exposed to radiofrequency radiation (RFR) emitted by cellular phones. In two recent studies, we have found that experiment duration and exposure side (i.e., phone's location--right or left) may have a major influence on the detection of such effects. In this brief follow-up experiment, 29 right-handed male subjects were divided into two groups. Each subject had two standard cellular phones attached to both sides of his head. The subjects performed a spatial working memory task that required either a left-hand or a right-hand response under one of the two exposure conditions: left side of the head or right side. Contrary to our previous studies, in this work external antennas located far away from the subjects were connected to the cellular phones. This setup prevents any emission of RFR from the internal antenna, thus drastically reducing RFR exposure. Despite that, the results remain similar to those obtained in our previous work. These results indicate that some of the effects previously attributed to RFR can be the result of some confounders.

  7. Familial partial lipodystrophy, mandibuloacral dysplasia and restrictive dermopathy feature barrier-to-autointegration factor (BAF) nuclear redistribution. (United States)

    Capanni, Cristina; Squarzoni, Stefano; Cenni, Vittoria; D'Apice, Maria Rosaria; Gambineri, Alessandra; Novelli, Giuseppe; Wehnert, Manfred; Pasquali, Renato; Maraldi, Nadir M; Lattanzi, Giovanna


    Prelamin A processing impairment is a common feature of a restricted group of rare genetic alterations/disorders associated with a wide range of clinical phenotypes. Changes in histone posttranslational modifications, alterations in non-histone chromatin proteins and chromatin disorganization have been specifically linked to impairment of specific, distinct prelamin A processing steps, but the molecular mechanism involved in these processes is not yet understood . In this study, we show that the accumulation of wild-type prelamin A detected in restrictive dermopathy (RD), as well as the accumulation of mutated forms of prelamin A identified in familial partial lipodystrophy (FPLD) and mandibuloacral dysplasia (MADA), affect the nuclear localization of barrier-to-autointegration factor (BAF), a protein able to link lamin A precursor to chromatin remodeling functions. Our findings, in accordance with previously described results, support the hypothesis of a prelamin A involvement in BAF nuclear recruitment and suggest BAF-prelamin A complex as a protein platform usually activated in prelamin A-accumulating diseases. Finally, we demonstrate the involvement of the inner nuclear membrane protein emerin in the proper localization of BAF-prelamin A complex.

  8. Coordinated destruction of cellular messages in translation complexes by the gammaherpesvirus host shutoff factor and the mammalian exonuclease Xrn1. (United States)

    Covarrubias, Sergio; Gaglia, Marta M; Kumar, G Renuka; Wong, Wesley; Jackson, Andrew O; Glaunsinger, Britt A


    Several viruses encode factors that promote host mRNA degradation to silence gene expression. It is unclear, however, whether cellular mRNA turnover pathways are engaged to assist in this process. In Kaposi's sarcoma-associated herpesvirus this phenotype is enacted by the host shutoff factor SOX. Here we show that SOX-induced mRNA turnover is a two-step process, in which mRNAs are first cleaved internally by SOX itself then degraded by the cellular exonuclease Xrn1. SOX therefore bypasses the regulatory steps of deadenylation and decapping normally required for Xrn1 activation. SOX is likely recruited to translating mRNAs, as it cosediments with translation initiation complexes and depletes polysomes. Cleaved mRNA intermediates accumulate in the 40S fraction, indicating that recognition occurs at an early stage of translation. This is the first example of a viral protein commandeering cellular mRNA turnover pathways to destroy host mRNAs, and suggests that Xrn1 is poised to deplete messages undergoing translation in mammalian cells.

  9. Coordinated destruction of cellular messages in translation complexes by the gammaherpesvirus host shutoff factor and the mammalian exonuclease Xrn1.

    Directory of Open Access Journals (Sweden)

    Sergio Covarrubias


    Full Text Available Several viruses encode factors that promote host mRNA degradation to silence gene expression. It is unclear, however, whether cellular mRNA turnover pathways are engaged to assist in this process. In Kaposi's sarcoma-associated herpesvirus this phenotype is enacted by the host shutoff factor SOX. Here we show that SOX-induced mRNA turnover is a two-step process, in which mRNAs are first cleaved internally by SOX itself then degraded by the cellular exonuclease Xrn1. SOX therefore bypasses the regulatory steps of deadenylation and decapping normally required for Xrn1 activation. SOX is likely recruited to translating mRNAs, as it cosediments with translation initiation complexes and depletes polysomes. Cleaved mRNA intermediates accumulate in the 40S fraction, indicating that recognition occurs at an early stage of translation. This is the first example of a viral protein commandeering cellular mRNA turnover pathways to destroy host mRNAs, and suggests that Xrn1 is poised to deplete messages undergoing translation in mammalian cells.

  10. Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease. (United States)

    McGinley, Lisa M; Sims, Erika; Lunn, J Simon; Kashlan, Osama N; Chen, Kevin S; Bruno, Elizabeth S; Pacut, Crystal M; Hazel, Tom; Johe, Karl; Sakowski, Stacey A; Feldman, Eva L


    Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD.

  11. Cytosolic iron-sulfur cluster assembly (CIA) system: factors, mechanism, and relevance to cellular iron regulation. (United States)

    Sharma, Anil K; Pallesen, Leif J; Spang, Robert J; Walden, William E


    FeS cluster biogenesis is an essential process in virtually all forms of life. Complex protein machineries that are conserved from bacteria through higher eukaryotes facilitate assembly of the FeS cofactor in proteins. In the last several years, significant strides have been made in our understanding of FeS cluster assembly and the functional overlap of this process with cellular iron homeostasis. This minireview summarizes the present understanding of the cytosolic iron-sulfur cluster assembly (CIA) system in eukaryotes, with a focus on information gained from studies in budding yeast and mammalian systems.

  12. In vitro cellular adaptations of indicators of longevity in response to treatment with serum collected from humans on calorie restricted diets.

    Directory of Open Access Journals (Sweden)

    Joanne S Allard

    Full Text Available Calorie restriction (CR produces several health benefits and increases lifespan in many species. Studies suggest that alternate-day fasting (ADF and exercise can also provide these benefits. Whether CR results in lifespan extension in humans is not known and a direct investigation is not feasible. However, phenotypes observed in CR animals when compared to ad libitum fed (AL animals, including increased stress resistance and changes in protein expression, can be simulated in cells cultured with media supplemented with blood serum from CR and AL animals. Two pilot studies were undertaken to examine the effects of ADF and CR on indicators of health and longevity in humans. In this study, we used sera collected from those studies to culture human hepatoma cells and assessed the effects on growth, stress resistance and gene expression. Cells cultured in serum collected at the end of the dieting period were compared to cells cultured in serum collected at baseline (before the dieting period. Cells cultured in serum from ADF participants, showed a 20% increase in Sirt1 protein which correlated with reduced triglyceride levels. ADF serum also induced a 9% decrease in proliferation and a 25% increase in heat resistance. Cells cultured in serum from CR participants induced an increase in Sirt1 protein levels by 17% and a 30% increase in PGC-1alpha mRNA levels. This first in vitro study utilizing human serum to examine effects on markers of health and longevity in cultured cells resulted in increased stress resistance and an up-regulation of genes proposed to be indicators of increased longevity. The use of this in vitro technique may be helpful for predicting the potential of CR, ADF and other dietary manipulations to affect markers of longevity in humans.

  13. Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis

    Directory of Open Access Journals (Sweden)

    Eckard Jonathan


    Full Text Available Abstract Background Young women diagnosed with breast cancer are known to have a higher mortality rate from the disease than older patients. Specific risk factors leading to this poorer outcome have not been identified. In the present study, we hypothesized that iron deficiency, a common ailment in young women, contributes to the poor outcome by promoting the hypoxia inducible factor-1α (HIF-1α and vascular endothelial growth factor (VEGF formation. This hypothesis was tested in an in vitro cell culture model system. Results Human breast cancer MDA-MB-231 cells were transfected with transferrin receptor-1 (TfR1 shRNA to constitutively impair iron uptake. Cellular iron status was determined by a set of iron proteins and angiogenesis was evaluated by levels of VEGF in cells as well as by a mouse xenograft model. Significant decreases in ferritin with concomitant increases in VEGF were observed in TfR1 knockdown MDA-MB-231 cells when compared to the parental cells. TfR1 shRNA transfectants also evoked a stronger angiogenic response after the cells were injected subcutaneously into nude mice. The molecular mechanism appears that cellular iron deficiency elevates VEGF formation by stabilizing HIF-1α. This mechanism is also true in human breast cancer MCF-7 and liver cancer HepG2 cells. Conclusions Cellular iron deficiency increased HIF-1α, VEGF, and angiogenesis, suggesting that systemic iron deficiency might play an important part in the tumor angiogenesis and recurrence in this young age group of breast cancer patients.

  14. [Molecular-cellular and hormonal mechanisms of induced brain tolerance of extreme factors]. (United States)

    Samoĭlov, M O; Rybnikova, E A


    This review includes results of own studies and literature data on the topical problem of neurobiology and medicine: discovery of the mechanisms of increased brain resistance to extreme exposures. The emphasis is made on the molecular-cellular and hormonal mechanisms of hypoxic preconditioning-induced brain tolerance to injurious hypoxia, psychoemotional and traumatic stress. A role of basic hormonal and intracellular cascade pro-adaptive processes mediating the neuroprotective action of hypoxic preconditioning is reviewed. A dynamics of the mechanisms of development of induced susceptible brain areas (hippocampus, neocortex) tolerance which includes phases of induction, transformation and expression, is presented. New data on preconditioning-induced cross-tolerance providing increased brain resistance not only to hypoxia but also to other stresses are reported. For the first time neuroprotective effects of hypoxic postconditioning are described.

  15. Immunochemical determination of cellular content of translation release factor RF4 in Escherichia coli

    DEFF Research Database (Denmark)

    Andersen, Lars Dyrskjøt; Manuel Palacios Moreno, Juan; Clark, Brian F. C.;


    The biosynthesis of proteins in prokaryotes is terminated when a stop codon is present in the A-site of the 70S ribosomal complex. Four different translation termination factors are known to participate in the termination process. Release factor RF1 and RF2 are responsible for the recognition of ...

  16. Identification of human leukemia antigen A*0201-restricted epitopes derived from epidermal growth factor pathway substrate number 8. (United States)

    Tang, Baishan; Zhou, Weijun; Du, Jingwen; He, Yanjie; Li, Yuhua


    T-cell-mediated immunotherapy of hematological malignancies requires selection of targeted tumor-associated antigens and T-cell epitopes contained in these tumor proteins. Epidermal growth factor receptor pathway substrate 8 (EPS8), whose function is pivotal for tumor proliferation, progression and metastasis, has been found to be overexpressed in most human tumor types, while its expression in normal tissue is low. The aim of the present study was to identify human leukemia antigen (HLA)-A*0201-restricted epitopes of EPS8 by using a reverse immunology approach. To achieve this, computer algorithms were used to predict HLA-A*0201 molecular binding, proteasome cleavage patterns as well as translocation of transporters associated with antigen processing. Candidate peptides were experimentally validated by T2 binding affinity assay and brefeldin-A decay assay. The functional avidity of peptide-specific cytotoxic T lymphocytes (CTLs) induced from peripheral blood mononuclear cells of healthy volunteers were evaluated by using an enzyme-linked immunosorbent spot assay and a cytotoxicity assay. Four peptides, designated as P455, P92, P276 and P360, had high affinity and stability of binding towards the HLA-A*0201 molecule, and specific CTLs induced by them significantly responded to the corresponding peptides and secreted IFN-γ. At the same time, the CTLs were able to specifically lyse EPS8-expressing cell lines in an HLA-A*0201-restricted manner. The present study demonstrated that P455, P92, P276 and P360 were CTL epitopes of EPS8, and were able to be used for epitope-defined adoptive T-cell transfer and multi-epitope-based vaccine design.

  17. Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF can regulate HSV-1 immediate-early transcription via histone modification

    Directory of Open Access Journals (Sweden)

    Hill James M


    Full Text Available Abstract Background During primary infection of its human host, Herpes Simplex Virus Type-1 (HSV-1 establishes latency in neurons where the viral genome is maintained in a circular form associated with nucleosomes in a chromatin configration. During latency, most viral genes are silenced, although the molecular mechanisms responsible for this are unclear. We hypothesized that neuronal factors repress HSV-1 gene expression during latency. A search of the HSV-1 DNA sequence for potential regulatory elements identified a Repressor Element-1/Neuronal Restrictive Silencer Element (RE-1/NRSE located between HSV-1 genes ICP22 and ICP4. We predicted that the Repressor Element Silencing Transcription Factor/Neuronal Restrictive Silencer Factor (REST/NRSF regulates expression of ICP22 and ICP4. Results Transient cotransfection indicated that REST/NRSF inhibited the activity of both promoters. In contrast, cotransfection of a mutant form of REST/NRSF encoding only the DNA-binding domain of the protein resulted in less inhibition. Stably transformed cell lines containing episomal reporter plasmids with a chromatin structure showed that REST/NRSF specifically inhibited the ICP4 promoter, but not the ICP22 promoter. REST/NRSF inhibition of the ICP4 promoter was reversed by histone deacetylase (HDAC inhibitor Trichostatin A (TSA. Additionally, chromatin immuno-precipitation (ChIP assays indicated that the corepressor CoREST was recruited to the proximity of ICP4 promoter and that acetylation of histone H4 was reduced in the presence of REST/NRSF. Conclusion Since the ICP4 protein is a key transactivator of HSV-1 lytic cycle genes, these results suggest that REST/NRSF may have an important role in the establishment and/or maintenance of HSV-1 gene silencing during latency by targeting ICP4 expression.

  18. Gene Transfer and Expression of Platelet-derived Growth Factors Modulate Periodontal Cellular Activity


    Zhu, Z.; Lee, C. S.; Tejeda, K.M.; Giannobile, W.V.


    Platelet-derived growth factor (PDGF) is a potent stimulator of wound healing. PDGF gene therapy may promote greater periodontal regeneration than local protein application, due to sustained growth factor delivery to the target tissue. This investigation tested the ability of recombinant adenoviruses (rAds) encoding PDGF-A or PDGF-1308 (a PDGF-A dominant-negative mutant that disrupts endogenous PDGF bioactivity) to affect cells derived from the periodontium. Osteoblasts, periodontal ligament ...

  19. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information



    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFα) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFα- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFα and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune...

  20. Role of vascular endothelial growth factor in the stimulation of cellular invasion and signaling of breast cancer cells. (United States)

    Price, D J; Miralem, T; Jiang, S; Steinberg, R; Avraham, H


    The expression of vascular endothelial growth factor (VEGF) by breast tumors has been previously correlated with a poor prognosis in the pathogenesis of breast cancer. Furthermore, VEGF secretion is a prerequisite for tumor development. Although most of the effects of VEGF have been shown to be attributable to the stimulation of endothelial cells, we present evidence here that breast tumor cells are capable of responding to VEGF. We show that VEGF stimulation of T-47D breast cancer cells leads to changes in cellular signaling and invasion. VEGF increases the cellular invasion of T-47D breast cancer cells on Matrigel/ fibronectin-coated transwell membranes by a factor of two. Northern analysis for the expression of the known VEGF receptors shows the presence of moderate levels of Flt-1 and low levels of Flk-1/KDR mRNAs in a variety of breast cancer cell lines. T-47D breast cancer cells bind 125I-labeled VEGF with a Kd of 13 x 10(-9) M. VEGF induces the activation of the extracellular regulated kinases 1,2 as well as activation of phosphatidylinositol 3'-kinase, Akt, and Forkhead receptor L1. These findings in T-47D breast cancer cells strongly suggest an autocrine role for VEGF contributing to the tumorigenic phenotype.

  1. Study Design for a Case Control Investigation of Cellular Telephones and Other Risk Factors for Brain Tumors in Adults

    Energy Technology Data Exchange (ETDEWEB)

    Inskip, P.D.; Hatch, E.E.; Stewart, P.A.; Heineman, E.F.; Ziegler, R.G.; Dosemeci, M.; Parry, D.; Rothman, N.; Boice, J.D. Jr.; Wilcosky, T.C.; Watson, D.J.; Shapiro, W.R.; Selker, R.G.; Fine, H.A.; Black, P. McL.; Loeffler, J.S.; Linet, M.S


    The aetiology of brain tumours is poorly understood. Due, in part, to public concern about a postulated relationship between the use of cellular telephones or other increasingly prevalent environmental exposures and the incidence of brain cancer in adults, the National Cancer Institute is collaborating with three US hospitals in a comprehensive case control study of malignant and benign brain tumours. Factors under consideration include use of cellular phones and other wireless communication devices, workplace exposures to chemical agents and electromagnetic fields, dietary factors, family history of tumours, genetic determinants of susceptibility, home appliance use, reproductive history and hormonal exposures, viruses, medical and dental exposure to ionising radiation, and other aspects of medical history. Approximately 800 newly diagnosed brain tumour cases and 800 controls were enrolled at hospitals in Boston, Phoenix and Pittsburgh from 1994 to 1998. Cases include all adults (age {>=} 18 y) newly diagnosed with a histologically confirmed intracranial glioma, histologically confirmed intracranial meningioma or acoustic neuroma. Controls are patients admitted to the same hospitals as the cases, and treated for any of a variety of non-malignant conditions. Key features of the study include its large size, the emphasis on rapid ascertainment of incident cases and interview of study subjects rather than surrogate respondents, the use of detailed, job-specific questions developed by industrial hygienists to ascertain occupational exposures, and the storage of blood samples for future evaluation of inherited susceptibility, biomarkers of exposure and gene environment interactions. (author)

  2. Reactive species, cellular repair and risk factors in the onset of type 2 diabetes mellitus: review and hypothesis. (United States)

    Fridlyand, Leonid E; Philipson, Louis H


    Insulin resistance (IRe) and a failure of insulin secretion are the major features of the early pathophysiology of type-2 diabetes mellitus (T2D) but the etiology is still not well understood. We suggest that: 1. The cellular mechanisms that protect against oxidative stress per se are capable of creating a reactive species-dependent IRe. 2. Reactive species-induced mitochondrial dysfunction can lead to disruption of lipid metabolism, increased intracellular lipid content, and can also contribute to lipid-dependent IRe in myocytes and adipocytes. 3. Metabolic secretagogues that stimulate insulin secretion by the activation of initial steps in the glucose-stimulated insulin secretion pathway can also lead to increased reactive species production and cellular destruction contributing to beta-cell damage and apoptosis. These events that underlie the repair mechanisms in beta-cells, muscle and adipocytes, are important factors in the early etiology of T2D, leading to both IRe and decreased insulin secretion. This hypothesis is supported by data from multiple disciplines and includes aging, obesity and genetic factors in promoting multiple failures in this system leading to the onset of T2D. On the basis of this hypothesis therapeutic strategies should be directed towards increasing insulin secretion and reducing IRe without increasing reactive species production or concentration. Pharmacological or other approaches that result in the activation of mitochondrial biogenesis could be beneficial for both IRe and T2D.

  3. Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus. (United States)

    Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing; Reilly, Karlyne M; McFadden, Grant; Yong, V Wee; Forsyth, Peter A


    Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation.

  4. Deconvolution and chromatic aberration corrections in quantifying colocalization of a transcription factor in three-dimensional cellular space. (United States)

    Abraham, Thomas; Allan, Sarah E; Levings, Megan K


    In the realm of multi-dimensional confocal microscopy, colocalization analysis of fluorescent emission signals has proven to be an invaluable tool for detecting molecular interactions between biological macromolecules at the subcellular level. We show here that image processing operations such as the deconvolution and chromatic corrections play a crucial role in the accurate determination of colocalization between biological macromolecules particularly when the fluorescent signals are faint, and when the fluorescent signals are in the blue and red emission regions. The cellular system presented here describes quantification of an activated forkhead box P3 (FOXP3) transcription factor in three-dimensional (3D) cellular space. 293T cells transfected with a conditionally active form of FOXP3 were stained for anti-FOXP3 conjugated to a fluorescent red dye (Phycoerythrin), and counterstained for DNA (nucleus) with fluorescent blue dye (Hoechst). Due to the broad emission spectra of these dyes, the fluorescent signals were collected only from peak regions and were acquired sequentially. Since the PE signal was weak, a confocal pinhole size of two Airy size was used to collect the 3D image data sets. The raw images supplemented with the spectral data show the preferential association of activated FOXP3 molecules with the nucleus. However, the PE signals were found to be highly diffusive and colocalization quantification from these raw images was not possible. In order to deconvolve the 3D raw image data set, point spread functions (PSFs) of these emissions were measured. From the measured PSF, we found that chromatic shifts between the blue and red colors were quite considerable. Followed by the applications of both the axial and lateral chromatic corrections, colocalization analysis performed on the deconvolved-chromatic corrected-3D image data set showed that 98% of DNA molecules were associated with FOXP3 molecules, whereas only 66% of FOXP3 molecules were colocalized

  5. RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro. (United States)

    Soldati, Chiara; Caramanica, Pasquale; Burney, Matthew J; Toselli, Camilla; Bithell, Angela; Augusti-Tocco, Gabriella; Stanton, Lawrence W; Biagioni, Stefano; Buckley, Noel J; Cacci, Emanuele


    Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate.

  6. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information (United States)

    Ott, Lee W.; Resing, Katheryn A.; Sizemore, Alecia W.; Heyen, Joshua W.; Cocklin, Ross R.; Pedrick, Nathan M.; Woods, H. Cary; Chen, Jake Y.; Goebl, Mark G.; Witzmann, Frank A.; Harrington, Maureen A.


    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFα) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFα- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFα and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFα and IL-1 regulate different processes. A large-scale proteomic analysis of TNFα- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFα and IL-1. When combined with genomic studies, our results indicate that TNFα, but not IL-1, mediates cell cycle arrest. PMID:17503796

  7. Tumor Necrosis Factor-alpha- and interleukin-1-induced cellular responses: coupling proteomic and genomic information. (United States)

    Ott, Lee W; Resing, Katheryn A; Sizemore, Alecia W; Heyen, Joshua W; Cocklin, Ross R; Pedrick, Nathan M; Woods, H Cary; Chen, Jake Y; Goebl, Mark G; Witzmann, Frank A; Harrington, Maureen A


    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFalpha) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFalpha- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFalpha and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFalpha and IL-1 regulate different processes. A large-scale proteomic analysis of TNFalpha- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFalpha and IL-1. When combined with genomic studies, our results indicate that TNFalpha, but not IL-1, mediates cell cycle arrest.

  8. Molecular and Cellular Interactions between Mother and Fetus. Pregnancy as a Rejuvenating Factor. (United States)

    Popkov, V A; Silachev, D N; Jankauskas, S S; Zorova, L D; Pevzner, I B; Babenko, V A; Plotnikov, E Y; Zorov, D B


    Aging is associated with a decline of various body functions, including ability to regenerate. Over recent decades, it has been demonstrated that some of these changes could be reversed in response to factors originating from a young organism, for example, fetal stem cells or "young blood" in models of heterochronic parabiosis. Pregnancy might be considered as parabiotic model of the interaction between two organisms of different age. In this work, we analyzed and summarized data on the effects of pregnancy on the maternal organism that confirm the hypothesis that pregnancy rejuvenates the mother's organism or slows its aging.

  9. Antioxidant factors, nitric oxide levels, and cellular damage in leprosy patients

    Directory of Open Access Journals (Sweden)

    Taysa Ribeiro Schalcher


    Full Text Available Introduction The immune response caused by Mycobacterium leprae is a risk factor for the development of oxidative stress (OS in leprosy patients. This study aimed to assess OS in leprosy patients before the use of a multidrug therapy. Methods We evaluated the nitric oxide (NO concentration; antioxidant capacity; levels of malondialdehyde, methemoglobin and reduced glutathione; and the activity of catalase and superoxide dismutase (SOD in leprosy patients. Results We observed lower SOD activity in these leprosy patients; however, the NO levels and antioxidant capacity were increased. Conclusions The infectious process in response to M. leprae could primarily be responsible for the OS observed in these patients.

  10. Potential for cellular stress response to hepatic factor VIII expression from AAV vector (United States)

    Zolotukhin, Irene; Markusic, David M; Palaschak, Brett; Hoffman, Brad E; Srikanthan, Meera A; Herzog, Roland W


    Hemophilia A and B are coagulation disorders resulting from the loss of functional coagulation factor VIII (FVIII) or factor IX proteins, respectively. Gene therapy for hemophilia with adeno-associated virus vectors has shown efficacy in hemophilia B patients. Although hemophilia A patients are more prevalent, the development of therapeutic adeno-associated virus vectors has been impeded by the size of the F8 cDNA and impaired secretion of FVIII protein. Further, it has been reported that over-expression of the FVIII protein induces endoplasmic reticulum stress and activates the unfolded protein response pathway both in vitro and in hepatocytes in vivo, presumably due to retention of misfolded FVIII protein within the endoplasmic reticulum. Engineering of the F8 transgene, including removal of the B domain (BDD-FVIII) and codon optimization, now allows for the generation of adeno-associated virus vectors capable of expressing therapeutic levels of FVIII. Here we sought to determine if the risks of inducing the unfolded protein response in murine hepatocytes extend to adeno-associated virus gene transfer. Although our data show a mild activation of unfolded protein response markers following F8 gene delivery at a certain vector dose in C57BL/6 mice, it was not augmented upon further elevated dosing, did not induce liver pathology or apoptosis, and did not impact FVIII immunogenicity. PMID:27738644

  11. Cellular Effects of Pyocyanin, a Secreted Virulence Factor of Pseudomonas aeruginosa (United States)

    Hall, Susan; McDermott, Catherine; Anoopkumar-Dukie, Shailendra; McFarland, Amelia J.; Forbes, Amanda; Perkins, Anthony V.; Davey, Andrew K.; Chess-Williams, Russ; Kiefel, Milton J.; Arora, Devinder; Grant, Gary D.


    Pyocyanin has recently emerged as an important virulence factor produced by Pseudomonas aeruginosa. The redox-active tricyclic zwitterion has been shown to have a number of potential effects on various organ systems in vitro, including the respiratory, cardiovascular, urological, and central nervous systems. It has been shown that a large number of the effects to these systems are via the formation of reactive oxygen species. The limitations of studies are, to date, focused on the localized effect of the release of pyocyanin (PCN). It has been postulated that, given its chemical properties, PCN is able to readily cross biological membranes, however studies have yet to be undertaken to evaluate this effect. This review highlights the possible manifestations of PCN exposure; however, most studies to date are in vitro. Further high quality in vivo studies are needed to fully assess the physiological manifestations of PCN exposure on the various body systems. PMID:27517959

  12. A novel HIV-1 restriction factor that is biologically distinct from APOBEC3 cytidine deaminases in a human T cell line CEM.NKR

    Directory of Open Access Journals (Sweden)

    Zhou Tao


    Full Text Available Abstract Background Isolation of novel retroviral restriction factors will open new avenues for anti-HIV/AIDS treatment. Although HIV-1 replication is restricted by APOBEC3G/APOBEC3F, TRIM5α, and CD317, none defend HIV-1 infection under natural conditions. Previously, we demonstrated a host factor from the human T cell line CEM.NKR that potently restricted wild-type HIV-1 replication. Interestingly, this restriction resembled the APOBEC3G/APOBEC3F pattern in that viral replication was inhibited from the second round of replication cycle at a post-entry step. Results Here, we further characterized this factor and found it distinguishable from the known anti-HIV APOBEC3 proteins. Although CEM.NKR cells expressed both APOBEC3G and APOBEC3F, their levels were at least 10 or 4-fold lower than those in H9 cells, and importantly, Vif effectively neutralized their activity. Among eight subclones isolated from CEM.NKR cells, one was relatively permissive, four were semi-permissive, and three were completely non-permissive for HIV-1 replication. When the levels of APOBEC3 expression were determined, all these clones retained similar low levels of APOBEC3DE, APOBEC3F, APOBEC3G and APOBEC3H expression, and no APOBEC3B expression was detected. Since the vif from SIVmac can effectively neutralize APOBEC3B and APOBEC3H, recombinant HIV-1 expressing this SIV gene were created. However, these viruses still failed to replicate in CEM.NKR cells. We also confirmed that HIV-1 restriction in CEM.NKR was not due to a loss of calnexin expression. Conclusion Taken together, these results not only demonstrate that all these aforementioned anti-HIV APOBEC3 proteins do not contribute to this HIV-1 restriction, but also shed light on a novel and potent HIV-1 inhibitor in CEM.NKR cells.

  13. In vitro and in vivo analyses of a genetically—restricted antigen specific factor from mixed cell cultures of macrophage,T and B lymphocytes

    Institute of Scientific and Technical Information of China (English)



    An immunostimulatory factor was identified to be secreted by antigen-pulsed macrophages.This factor was able to induce the generation of antigen specific T helper lymphocytes in vitro as well as in vivo.Further in vitro experiments testing for the genetic restriction of this factor indicated that it is a geneticallyrestricted antigen specific factor (ASF).The Cunningham plaque assay was used to quantify the generation of T helper lymphocytes by measuring the number of plaque forming cells after sequential incubations of antigen-qulsed macrophages with T lymphocytes,and then spleen cells,and finally the TNP-coated sheep red blood cells.

  14. Sleep Loss as a Factor to Induce Cellular and Molecular Inflammatory Variations (United States)

    Hurtado-Alvarado, Gabriela; Castillo-García, Stephanie Ariadne; Hernández, María Eugenia; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier; Gómez-González, Beatriz


    A reduction in the amount of time spent sleeping occurs chronically in modern society. Clinical and experimental studies in humans and animal models have shown that immune function is impaired when sleep loss is experienced. Sleep loss exerts a strong regulatory influence on peripheral levels of inflammatory mediators of the immune response. An increasing number of research projects support the existence of reciprocal regulation between sleep and low-intensity inflammatory response. Recent studies show that sleep deficient humans and rodents exhibit a proinflammatory component; therefore, sleep loss is considered as a risk factor for developing cardiovascular, metabolic, and neurodegenerative diseases (e.g., diabetes, Alzheimer's disease, and multiple sclerosis). Circulating levels of proinflammatory mediators depend on the intensity and duration of the method employed to induce sleep loss. Recognizing the fact that the concentration of proinflammatory mediators is different between acute and chronic sleep-loss may expand the understanding of the relationship between sleep and the immune response. The aim of this review is to integrate data from recent published reports (2002–2013) on the effects of sleep loss on the immune response. This review may allow readers to have an integrated view of the mechanisms involved in central and peripheral deficits induced by sleep loss. PMID:24367384

  15. Sleep Loss as a Factor to Induce Cellular and Molecular Inflammatory Variations

    Directory of Open Access Journals (Sweden)

    Gabriela Hurtado-Alvarado


    Full Text Available A reduction in the amount of time spent sleeping occurs chronically in modern society. Clinical and experimental studies in humans and animal models have shown that immune function is impaired when sleep loss is experienced. Sleep loss exerts a strong regulatory influence on peripheral levels of inflammatory mediators of the immune response. An increasing number of research projects support the existence of reciprocal regulation between sleep and low-intensity inflammatory response. Recent studies show that sleep deficient humans and rodents exhibit a proinflammatory component; therefore, sleep loss is considered as a risk factor for developing cardiovascular, metabolic, and neurodegenerative diseases (e.g., diabetes, Alzheimer's disease, and multiple sclerosis. Circulating levels of proinflammatory mediators depend on the intensity and duration of the method employed to induce sleep loss. Recognizing the fact that the concentration of proinflammatory mediators is different between acute and chronic sleep-loss may expand the understanding of the relationship between sleep and the immune response. The aim of this review is to integrate data from recent published reports (2002–2013 on the effects of sleep loss on the immune response. This review may allow readers to have an integrated view of the mechanisms involved in central and peripheral deficits induced by sleep loss.

  16. Allopurinol ameliorates thioacetamide-induced acute liver failure by regulating cellular redox-sensitive transcription factors in rats. (United States)

    Demirel, Ulvi; Yalniz, Mehmet; Aygün, Cem; Orhan, Cemal; Tuzcu, Mehmet; Sahin, Kazim; Ozercan, Ibrahim Hanifi; Bahçecioğlu, Ibrahim Halil


    Oxidative stress plays important role in the development of acute liver failure. In this study, we investigated effects of allopurinol (AP) upon thioacetamide (TAA)-induced liver injury and the potential mechanisms leading to amelioration in inflammation with AP treatment. Acute liver failure was induced by intraperitoneal administration of TAA (300 mg/kg/day for 2 days). Thirty-five rats were divided into five groups as control (group 1), TAA (group 2), TAA + 25AP (group 3), TAA + 50 AP (group 4), and TAA + 100AP (group 5). The number of animals in each group was seven. At the end of the study, histopathological, biochemical, and western blot analysis were done. TAA treatment significantly increased serum levels of aminotransferases, liver malondialdehyde (MDA), nuclear factor-kappa B (NF-қB ), activator protein-1 (AP-1), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) levels, and the necro-inflammation scores. Nevertheless, nuclear factor E2-related factor-2 and heme oxygenase-1 (HO-1) expressions in the liver were decreased by TAA. AP treatment significantly lowered the serum levels of aminotransferases (P < 0.01) and liver MDA, NF-κB, AP-1, TNF-α, COX-2, and IL-6 expressions (P < 0.05). Moreover, AP restored the liver Nrf2 and HO-1 expressions and improved the necro-inflammation scores significantly. AP improves oxidative stress-induced liver damage by regulating cellular redox-sensitive transcriptor factors and expression of pro-inflammatory and antioxidant defense mechanisms. AP probably exerts these beneficiary features by its free radical scavenging ability in a dose-dependent manner.

  17. PKCθ activation in pancreatic acinar cells by gastrointestinal hormones/neurotransmitters and growth factors is needed for stimulation of numerous important cellular signaling cascades (United States)

    Sancho, Veronica; Berna, Marc J.; Thill, Michelle; Jensen, R. T.


    The novel PKCθ isoform is highly expressed in T-cells, brain and skeletal muscle and originally thought to have a restricted distribution. It has been extensively studied in T-cells and shown to be important for apoptosis, T-cell activation and proliferation. Recent studies showed its presence in other tissues and importance in insulin signaling, lung surfactant secretion, intestinal barrier permeability, platelet and mast-cell functions. However, little information is available for PKCθ activation by gastrointestinal(GI) hormones/neurotransmitters and growth factors. In the present study we used rat pancreatic acinar cells to explore their ability to activate PKCθ and the possible interactions with important cellular mediators of their actions. Particular attention was paid to cholecystokinin(CCK), a physiological regulator of pancreatic function and important in pathological processes affecting acinar function, like pancreatitis. PKCθ-protein/mRNA were present in the pancreatic acini, and T538-PKCθ phosphorylation/activation was stimulated only by hormones/neurotransmitters activating phospholipase C. PKCθ was activated in time- and dose-related manner by CCK, mediated 30% by high-affinity CCKA-receptor activation. CCK stimulated PKCθ translocation from cytosol to membrane. PKCθ inhibition (by pseudostrate-inhibitor or dominant negative) inhibited CCK- and TPA-stimulation of PKD, Src, RafC, PYK2, p125FAK and IKKα/β, but not basal/stimulated enzyme secretion. Also CCK- and TPA-induced PKCθ activation produced an increment in PKCθ’s direct association with AKT, RafA, RafC and Lyn. These results show for the first time PKCθ presence in pancreatic acinar cells, its activation by some GI hormones/neurotransmitters and involvement in important cell signaling pathways mediating physiological responses (enzyme secretion, proliferation, apoptosis, cytokine expression, and pathological responses like pancreatitis and cancer growth). PMID:21810446

  18. Measurement of immunotargeted plasmonic nanoparticles' cellular binding: a key factor in optimizing diagnostic efficacy (United States)

    Fu, Kun; Sun, Jiantang; Bickford, Lissett R.; Lin, Alex W. H.; Halas, Naomi J.; Yu, Tse-Kuan; Drezek, Rebekah A.


    In this study, we use polarized light scattering to study immunotargeted plasmonic nanoparticles which bind to live SK-BR-3 human breast carcinoma cells. Gold nanoparticles can be conjugated to various biomolecules in order to target specific molecular signatures of disease. This specific targeting provides enhanced contrast in scattering-based optical imaging techniques. While there are papers which report the number of antibodies that bind per nanoparticle, there are almost no reports of the key factor which influences diagnostic or therapeutic efficacy using nanoparticles: the number of targeted nanoparticles that bind per cell. To achieve this goal, we have developed a 'negative' method of determining the binding concentration of those antibody/nanoparticle bioconjugates which are targeted specifically to breast cancer cells. Unlike previously reported methods, we collected unbound nanoparticle bioconjugates and measured the light scattering from dilute solutions of these particles so that quantitative binding information can be obtained. By following this process, the interaction effects of adjacent bound nanoparticles on the cell membrane can be avoided simply by measuring the light scattering from the unbound nanoparticles. Specifically, using nanoshells of two different sizes, we compared the binding concentrations of anti-HER2/nanoshell and anti-IgG/nanoshell bioconjugates targeted to HER2-positive SK-BR-3 breast cancer cells. The results indicate that, for anti-HER2/nanoshell bioconjugates, there are approximately 800-1600 nanoshells bound per cell; for anti-IgG/nanoshell bioconjugates, the binding concentration is significantly lower at nearly 100 nanoshells bound per cell. These results are also supported by dark-field microscopy images of the cells labeled with anti-HER2/nanoshell and anti-IgG/nanoshell bioconjugates.

  19. Measurement of immunotargeted plasmonic nanoparticles' cellular binding: a key factor in optimizing diagnostic efficacy

    Energy Technology Data Exchange (ETDEWEB)

    Fu Kun [Department of Bioengineering, Rice University, 6100 Main Street, MS-142, Houston, TX 77005 (United States); Sun Jiantang [Department of Bioengineering, Rice University, 6100 Main Street, MS-142, Houston, TX 77005 (United States); Bickford, Lissett R [Department of Bioengineering, Rice University, 6100 Main Street, MS-142, Houston, TX 77005 (United States); Lin, Alex W H [Department of Bioengineering, Rice University, 6100 Main Street, MS-142, Houston, TX 77005 (United States); Halas, Naomi J [Department of Electrical and Computer Engineering, Rice University, 6100 Main Street, MS-142, Houston, TX 77005 (United States); Yu, T-K [Department of Radiation Oncology, University of Texas, M D Anderson Cancer Center, Box 1202, 1515 Holcombe Boulevard, Houston, TX 77030 (United States); Drezek, Rebekah A [Department of Bioengineering, Rice University, 6100 Main Street, MS-142, Houston, TX 77005 (United States)


    In this study, we use polarized light scattering to study immunotargeted plasmonic nanoparticles which bind to live SK-BR-3 human breast carcinoma cells. Gold nanoparticles can be conjugated to various biomolecules in order to target specific molecular signatures of disease. This specific targeting provides enhanced contrast in scattering-based optical imaging techniques. While there are papers which report the number of antibodies that bind per nanoparticle, there are almost no reports of the key factor which influences diagnostic or therapeutic efficacy using nanoparticles: the number of targeted nanoparticles that bind per cell. To achieve this goal, we have developed a 'negative' method of determining the binding concentration of those antibody/nanoparticle bioconjugates which are targeted specifically to breast cancer cells. Unlike previously reported methods, we collected unbound nanoparticle bioconjugates and measured the light scattering from dilute solutions of these particles so that quantitative binding information can be obtained. By following this process, the interaction effects of adjacent bound nanoparticles on the cell membrane can be avoided simply by measuring the light scattering from the unbound nanoparticles. Specifically, using nanoshells of two different sizes, we compared the binding concentrations of anti-HER2/nanoshell and anti-IgG/nanoshell bioconjugates targeted to HER2-positive SK-BR-3 breast cancer cells. The results indicate that, for anti-HER2/nanoshell bioconjugates, there are approximately 800-1600 nanoshells bound per cell; for anti-IgG/nanoshell bioconjugates, the binding concentration is significantly lower at nearly 100 nanoshells bound per cell. These results are also supported by dark-field microscopy images of the cells labeled with anti-HER2/nanoshell and anti-IgG/nanoshell bioconjugates.

  20. Nucleoside drugs induce cellular differentiation by caspase-dependent degradation of stem cell factors.

    Directory of Open Access Journals (Sweden)

    Tanja Musch

    Full Text Available BACKGROUND: Stem cell characteristics are an important feature of human cancer cells and play a major role in the therapy resistance of tumours. Strategies to target cancer stem cells are thus of major importance for cancer therapy. Differentiation therapy by nucleoside drugs represents an attractive approach for the elimination of cancer stem cells. However, even if it is generally assumed that the activity of these drugs is mediated by their ability to modulate epigenetic pathways, their precise mode of action remains to be established. We therefore analysed the potential of three nucleoside analogues to induce differentiation of the embryonic cancer stem cell line NTERA 2 D1 and compared their effect to the natural ligand retinoic acid. METHODOLOGY/PRINCIPAL FINDINGS: All nucleoside analogues analyzed, but not retinoic acid, triggered proteolytic degradation of the Polycomb group protein EZH2. Two of them, 3-Deazaneplanocin A (DZNep and 2'-deoxy-5-azacytidine (decitabine, also induced a decrease in global DNA methylation. Nevertheless, only decitabine and 1beta-arabinofuranosylcytosine (cytarabine effectively triggered neuronal differentiation of NT2 cells. We show that drug-induced differentiation, in contrast to retinoic acid induction, is caused by caspase activation, which mediates depletion of the stem cell factors NANOG and OCT4. Consistent with this observation, protein degradation and differentiation could be counteracted by co-treatment with caspase inhibitors or by depletion of CASPASE-3 and CASPASE-7 through dsRNA interference. In agreement with this, OCT4 was found to be a direct in-vitro-target of CASPASE-7. CONCLUSIONS/SIGNIFICANCE: We show that drug-induced differentiation is not a consequence of pharmacologic epigenetic modulation, but is induced by the degradation of stem-cell-specific proteins by caspases. Our results thus uncover a novel pathway that induces differentiation of embryonic cancer stem cells and is triggered by

  1. Cellular intrinsic factors involved in the resistance of squamous cell carcinoma to photodynamic therapy. (United States)

    Gilaberte, Yolanda; Milla, Laura; Salazar, Nerea; Vera-Alvarez, Jesús; Kourani, Omar; Damian, Alejandra; Rivarola, Viviana; Roca, Maria José; Espada, Jesús; González, Salvador; Juarranz, Angeles


    Photodynamic therapy (PDT) is widely used to treat non-melanoma skin cancer. However, some patients affected with squamous cell carcinoma (SCC) do not respond adequately to PDT with methyl-δ-aminolevulinic acid (MAL-PDT) and the tumors acquire an infiltrative phenotype and became histologically more aggressive, less differentiated, and more fibroblastic. To search for potential factors implicated in SCC resistance to PDT, we have used the SCC-13 cell line (parental) and resistant SCC-13 cells obtained by repeated MAL-PDT treatments (5th and 10th PDT-resistant generations). Xenografts assays in immunodeficient mice showed that the tumors generated by resistant cells were bigger than those induced by parental cells. Comparative genomic hybridization array (aCGH) showed that the three cell types presented amplicons in 3p12.1 CADM2, 7p11.2 EFGR, and 11q13.3 CCND1 genes. The 5th and 10th PDT-resistant cells showed an amplicon in 5q11.2 MAP3K1, which was not present in parental cells. The changes detected by aCGH on CCND1, EFGR, and MAP3K1 were confirmed in extracts of SCC-13 cells by reverse-transcriptase PCR and by western blot, and by immunohistochemistry in human biopsies from persistent tumors after MAL-PDT. Our data suggest that genomic imbalances related to CCND1, EFGR, and particularly MAP3K1 seem to be involved in the development of the resistance of SCC to PDT.

  2. HIV-1 viral infectivity factor (Vif) alters processive single-stranded DNA scanning of the retroviral restriction factor APOBEC3G. (United States)

    Feng, Yuqing; Love, Robin P; Chelico, Linda


    APOBEC3G is a retroviral restriction factor that can inhibit the replication of human immunodeficiency virus, type 1 (HIV-1) in the absence of the viral infectivity factor (Vif) protein. Virion-encapsidated APOBEC3G can deaminate cytosine to uracil in viral (-)DNA, which leads to hypermutation and inactivation of the provirus. APOBEC3G catalyzes these deaminations processively on single-stranded DNA using sliding and jumping movements. Vif is thought to primarily overcome APOBEC3G through an interaction that mediates APOBEC3G ubiquitination and results in its proteasomal degradation. However, Vif may also inhibit APOBEC3G mRNA translation, virion encapsidation, and deamination activity. Here we investigated the molecular mechanism of VifIIIB- and VifHXB2-mediated inhibition of APOBEC3G deamination activity. Biochemical assays using a model HIV-1 replication assay and synthetic single-stranded or partially double-stranded DNA substrates demonstrated that APOBEC3G has an altered processive mechanism in the presence of Vif. Specifically, VifHXB2 inhibited the jumping and VifIIIB inhibited the sliding movements of APOBEC3G. The absence of such an effect by Vif on degradation-resistant APOBEC3G D128K indicates that a Vif-APOBEC3G interaction mediates this effect. That the partially processive APOBEC3G was less effective at inducing mutagenesis in a model HIV-1 replication assay suggests that Vif co-encapsidation with APOBEC3G can promote sublethal mutagenesis of HIV-1 proviral DNA.

  3. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    Energy Technology Data Exchange (ETDEWEB)

    Latham, Antony M.; Odell, Adam F. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Mughal, Nadeem A. [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Issitt, Theo; Ulyatt, Clare; Walker, John H. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Homer-Vanniasinkam, Shervanthi [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Ponnambalam, Sreenivasan, E-mail: [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom)


    Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: Black-Right-Pointing-Pointer Endothelial cells mount a stress response under conditions of low serum. Black

  4. Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay (United States)

    Park, Ok Hyun; Park, Joori; Yu, Mira; An, Hyoung-Tae; Ko, Jesang; Kim, Yoon Ki


    Glucocorticoid (GC) receptor (GR) has been shown recently to bind a subset of mRNAs and elicit rapid mRNA degradation. However, the molecular details of GR-mediated mRNA decay (GMD) remain unclear. Here, we demonstrate that GMD triggers rapid degradation of target mRNAs in a translation-independent and exon junction complex-independent manner, confirming that GMD is mechanistically distinct from nonsense-mediated mRNA decay (NMD). Efficient GMD requires PNRC2 (proline-rich nuclear receptor coregulatory protein 2) binding, helicase ability, and ATM-mediated phosphorylation of UPF1 (upstream frameshift 1). We also identify two GMD-specific factors: an RNA-binding protein, YBX1 (Y-box-binding protein 1), and an endoribonuclease, HRSP12 (heat-responsive protein 12). In particular, using HRSP12 variants, which are known to disrupt trimerization of HRSP12, we show that HRSP12 plays an essential role in the formation of a functionally active GMD complex. Moreover, we determine the hierarchical recruitment of GMD factors to target mRNAs. Finally, our genome-wide analysis shows that GMD targets a variety of transcripts, implicating roles in a wide range of cellular processes, including immune responses.

  5. Cellular Automata-based Chloride Ion Diffusion Simulation of Concrete Bridges under Multi-factor Coupling Actions

    Institute of Scientific and Technical Information of China (English)

    ZHU Jinsong; HE Likun


    Abstract In order to accurately simulate the diffusion of chloride ion in the existing concrete bridge and acquire the precise chloride ion concentration at given time,a cellular automata (CA)-based model is proposed.The process of chloride ion diffusion is analyzed by the CA-based method and a nonlinear solution of the Fick's second law is obtained.Considering the impact of various factors such as stress states,temporal and spatial variability of diffusion parameters and water-cement ratio on the process of chloride ion diffusion,the model of chloride ion diffusion under multi-factor coupling actions is presented.A chloride ion penetrating experiment reported in the literature is used to prove the effectiveness and reasonability of the present method,and a T-type beam is taken as an illustrative example to analyze the process of chloride ion diffusion in practical application.The results indicate that CA-based method can simulate the diffusion of chloride ion in the concrete structures with acceptable precision.

  6. Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus ofobesity-induced hypertensive rats. (United States)

    Kishi, Takuya; Hirooka, Yoshitaka; Nagayama, Tomomi; Isegawa, Kengo; Katsuki, Masato; Takesue, Ko; Sunagawa, Kenji


    In metabolic syndrome (MetS), previous studies have suggested that cognitive decline is worsened. Among the factors associated with cognition, decreased brain-derived neurotrophic factor (BDNF) in the hippocampus causes cognitive decline. We previously reported that exercise training with calorie restriction yielded protection against cognitive decline via BDNF in the hippocampus of hypertensive rats. The aim of the present study was to determine whether or not calorie restriction results in protection against cognitive decline via BDNF and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of MetS model rats. We divided dietary-induced obesity-prone and hypertensive rats (OP), as metabolic syndrome model rats, into three groups, fed with a high fat diet (HF), treated with calorie restriction (CR) plus vehicle, and treated with CR and ANA-12 (a TrkB antagonist) (CR+A). After treatment for 28 days, body weight, insulin, fasting blood glucose, adiponectin, systolic blood pressure, and oxidative stress in the hippocampus were significantly lower, and BDNF expression in the hippocampus was significantly higher in CR and CR+A than in HF. Cognitive performance determined by the Morris water maze test was significantly higher in CR than in HF, whereas the benefit was attenuated in CR+A. In conclusion, calorie restriction protects against cognitive decline via up-regulation of BDNF/TrkB through an antioxidant effect in the hippocampus of dietary-induced obesity rats.

  7. Behavioural changes are a major contributing factor in the reduction of sarcopenia in caloric-restricted ageing mice

    NARCIS (Netherlands)

    Norren, van K.; Rusli, F.; Dijk, van M.; Lute, C.; Nagel, J.C.; Dijk, F.J.; Dwarkasing, J.T.; Boekschoten, M.V.; Luiking, Y.; Witkamp, R.F.; Müller, M.R.; Steegenga, W.T.


    Background - In rodent models, caloric restriction (CR) with maintenance of adequate micronutrient supply has been reported to increase lifespan and to reduce age-induced muscle loss (sarcopenia) during ageing. In the present study, we further investigated effects of CR on the onset and severity of

  8. Analysis of Perceptions of Customers of Cellular Phone Users in India: Study with Prepaid Service Customers and Post Paid Customers Demographic Factors

    Directory of Open Access Journals (Sweden)

    S. Muthumani


    Full Text Available The primary objective of the study is to find out and analyze the customer perceptions on cellular phone services in India. Cellular phones are become the part of the life and the various barriers in the obtaining and usage of cellular services are lack of awareness, cost factor, perceptions of the customers on cellular phones etc. In addition the service quality, customer care, market competition brings lot of instability and reliability of the services. In turn it makes further confusion among the users. It paves an opportunity of providing limited services in the selective areas. It leads to a wide gap in the service quality and reliability between the urban and semi urban areas. It gives an opportunity to the researcher to survey on the facts and perceptions of the cellular phone users to find out the real situation and to suggest appropriate suggestions to overcome the issues in the market expansion and to improve the service quality of the cellular phone services in the sample area. To do this, the researcher selects a comparative approach. The data is collected by preparing a structured questionnaire and collected from the cellular phone users in the sample area. The study centered, in comparing the customers perceptions towards cellular phone services provided by the different operators in the states of India. The customers are from both urban and semi-urban places of India. In addition, customers were also classified on the basis of the type of services usage (i.e., post paid or pre paid. The basic parameters used for the purpose of comparing their perceptions are purpose of usage. The study has taken the demographic factors of respondents for analysis.

  9. Comparing the epidermal growth factor interaction with four different cell lines: intriguing effects imply strong dependency of cellular context.

    Directory of Open Access Journals (Sweden)

    Hanna Björkelund

    Full Text Available The interaction of the epidermal growth factor (EGF with its receptor (EGFR is known to be complex, and the common over-expression of EGF receptor family members in a multitude of tumors makes it important to decipher this interaction and the following signaling pathways. We have investigated the affinity and kinetics of (125I-EGF binding to EGFR in four human tumor cell lines, each using four culturing conditions, in real time by use of LigandTracer®.Highly repeatable and precise measurements show that the overall apparent affinity of the (125I-EGF - EGFR interaction is greatly dependent on cell line at normal culturing conditions, ranging from K(D ≈ 200 pM on SKBR3 cells to K(D≈8 nM on A431 cells. The (125I-EGF - EGFR binding curves (irrespective of cell line have strong signs of multiple simultaneous interactions. Furthermore, for the cell lines A431 and SKOV3, gefitinib treatment increases the (125I-EGF - EGFR affinity, in particular when the cells are starved. The (125I-EGF - EGFR interaction on cell line U343 is sensitive to starvation while as on SKBR3 it is insensitive to gefitinib and starvation.The intriguing pattern of the binding characteristics proves that the cellular context is important when deciphering how EGF interacts with EGFR. From a general perspective, care is advisable when generalizing ligand-receptor interaction results across multiple cell-lines.

  10. Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus. (United States)

    Lipovsky, Alex; Popa, Andreea; Pimienta, Genaro; Wyler, Michael; Bhan, Ashima; Kuruvilla, Leena; Guie, Marie-Aude; Poffenberger, Adrian C; Nelson, Christian D S; Atwood, Walter J; DiMaio, Daniel


    Despite major advances in our understanding of many aspects of human papillomavirus (HPV) biology, HPV entry is poorly understood. To identify cellular genes required for HPV entry, we conducted a genome-wide screen for siRNAs that inhibited infection of HeLa cells by HPV16 pseudovirus. Many retrograde transport factors were required for efficient infection, including multiple subunits of the retromer, which initiates retrograde transport from the endosome to the trans-Golgi network (TGN). The retromer has not been previously implicated in virus entry. Furthermore, HPV16 capsid proteins arrive in the TGN/Golgi in a retromer-dependent fashion during entry, and incoming HPV proteins form a stable complex with retromer subunits. We propose that HPV16 directly engages the retromer at the early or late endosome and traffics to the TGN/Golgi via the retrograde pathway during cell entry. These results provide important insights into HPV entry, identify numerous potential antiviral targets, and suggest that the role of the retromer in infection by other viruses should be assessed.

  11. The heat-shock factor is not activated in mammalian cells exposed to cellular phone frequency microwaves. (United States)

    Laszlo, Andrei; Moros, Eduardo G; Davidson, Teri; Bradbury, Matt; Straube, William; Roti Roti, Joseph


    There has been considerable interest in the biological effects of exposure to radiofrequency electromagnetic radiation, given the explosive growth of cellular telephone use, with the possible induction of malignancy being a significant concern. Thus the determination of whether nonthermal effects of radiofrequency electromagnetic radiation contribute to the process leading to malignancy is an important task. One proposed pathway to malignancy involves the induction of the stress response by exposures to cell phone frequency microwaves. The first step in the induction of the stress response is the activation of the DNA-binding activity of the specific transcription factor involved in this response, the heat-shock factor (HSF). The DNA-binding activity of HSF in hamster, mouse and human cells was determined after acute and continuous exposures to frequency domain multiple access (FDMA)- or code domain multiple access (CDMA)-modulated microwaves at low (0.6 W/kg) or high (approximately 5 W/kg) SARs at frequencies used for mobile communication. The DNA-binding activity of HSF was monitored using a gel shift assay; the calibration of this assay indicated that an increase of approximately 10% in the activation of the DNA-binding activity of HSF after a 1 degrees C increase in temperature could be detected. We failed to detect any increase in the DNA-binding ability of HSF in cultured mammalian cells as a consequence of any exposure tested, within the sensitivity of our assay. Our results do not support the notion that the stress response is activated as a consequence of exposure to microwaves of frequencies associated with mobile communication devices.

  12. Cellular Internalization of Fibroblast Growth Factor-12 Exerts Radioprotective Effects on Intestinal Radiation Damage Independently of FGFR Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Nakayama, Fumiaki, E-mail: [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan); Umeda, Sachiko [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan); Yasuda, Takeshi [Radiation Emergency Medicine Research Program, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba (Japan); Fujita, Mayumi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan); Asada, Masahiro [Signaling Molecules Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba (Japan); Meineke, Viktor [Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich (Germany); Imamura, Toru [Signaling Molecules Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba (Japan); Imai, Takashi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba (Japan)


    Purpose: Several fibroblast growth factors (FGFs) were shown to inhibit radiation-induced tissue damage through FGF receptor (FGFR) signaling; however, this signaling was also found to be involved in the pathogenesis of several malignant tumors. In contrast, FGF12 cannot activate any FGFRs. Instead, FGF12 can be internalized readily into cells using 2 cell-penetrating peptide domains (CPP-M, CPP-C). Therefore, this study focused on clarifying the role of FGF12 internalization in protection against radiation-induced intestinal injury. Methods and Materials: Each FGF or peptide was administered intraperitoneally to BALB/c mice in the absence of heparin 24 hours before or after total body irradiation with γ rays at 9 to 12 Gy. Several radioprotective effects were examined in the jejunum. Results: Administration of FGF12 after radiation exposure was as effective as pretreatment in significantly promoting intestinal regeneration, proliferation of crypt cells, and epithelial differentiation. Two domains, comprising amino acid residues 80 to 109 and 140 to 169 of FGF12B, were identified as being responsible for the radioprotective activity, so that deletion of both domains from FGF12B resulted in a reduction in activity. Interestingly, these regions included the CPP-M and CPP-C domains, respectively; however, CPP-C by itself did not show an antiapoptotic effect. In addition, FGF1, prototypic FGF, possesses a domain corresponding to CPP-M, whereas it lacks CPP-C, so the fusion of FGF1 with CPP-C (FGF1/CPP-C) enhanced cellular internalization and increased radioprotective activity. However, FGF1/CPP-C reduced in vitro mitogenic activity through FGFRs compared with FGF1, implying that FGFR signaling might not be essential for promoting the radioprotective effect of FGF1/CPP-C. In addition, internalized FGF12 suppressed the activation of p38α after irradiation, resulting in reduced radiation-induced apoptosis. Conclusions: These findings indicate that FGF12 can protect the

  13. Structures and short linear motif of disordered transcription factor regions provide clues to the interactome of the cellular hub Radical-Induced Cell Death1

    DEFF Research Database (Denmark)

    O'Shea, Charlotte; Staby, Lasse; Bendsen, Sidsel Krogh;


    point to larger networks of interactions, such as with proteins that serve as hubs for essential cellular functions. The stress-associated plant protein Radical-Induced Cell Death1 (RCD1) is one such hub, interacting with many transcription factors via their flexible IDRs. To identify the SLiM bound...

  14. Restricted Airspace (United States)

    Federal Laboratory Consortium — Redstone Technical Test Center has restricted airspace up to 30,000 feet ASL. Airspace encompasses R-2104 (Redstone). Airspace is used extensively for airborne/UAV...

  15. Expression and cellular localization of the transcription factor NeuroD1 in the developing and adult rat pineal gland. (United States)

    Castro, Analía E; Benitez, Sergio G; Farias Altamirano, Luz E; Savastano, Luis E; Patterson, Sean I; Muñoz, Estela M


    Circadian rhythms govern many aspects of mammalian physiology. The daily pattern of melatonin synthesis and secretion is one of the classic examples of circadian oscillations. It is mediated by a class of neuroendocrine cells known as pinealocytes which are not yet fully defined. An established method to evaluate functional and cytological characters is through the expression of lineage-specific transcriptional regulators. NeuroD1 is a basic helix-loop-helix transcription factor involved in the specification and maintenance of both endocrine and neuronal phenotypes. We have previously described developmental and adult regulation of NeuroD1 mRNA in the rodent pineal gland. However, the transcript levels were not influenced by the elimination of sympathetic input, suggesting that any rhythmicity of NeuroD1 might be found downstream of transcription. Here, we describe NeuroD1 protein expression and cellular localization in the rat pineal gland during development and the daily cycle. In embryonic and perinatal stages, protein expression follows the mRNA pattern and is predominantly nuclear. Thereafter, NeuroD1 is mostly found in pinealocyte nuclei in the early part of the night and in cytoplasm during the day, a rhythm maintained into adulthood. Additionally, nocturnal nuclear NeuroD1 levels are reduced after sympathetic disruption, an effect mimicked by the in vivo administration of α- and β-adrenoceptor blockers. NeuroD1 phosphorylation at two sites, Ser(274) and Ser(336) , associates with nuclear localization in pinealocytes. These data suggest that NeuroD1 influences pineal phenotype both during development and adulthood, in an autonomic and phosphorylation-dependent manner.

  16. Regulation of Ras exchange factors and cellular localization of Ras activation by lipid messengers in T cells

    Directory of Open Access Journals (Sweden)

    Jesse E. Jun


    Full Text Available The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and SOS-family GEFs.Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood.One large group of biomolecules critically involved in the control of Ras-GEFs´functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells.

  17. Effects of the breed, sex and age on cellular content and growth factor release from equine pure-platelet rich plasma and pure-platelet rich gel


    Giraldo Carlos E; López Catalina; Álvarez María E; Samudio Ismael J; Prades Marta; Carmona Jorge U


    Abstract Background There is no information on the effects of the breed, gender and age on the cellular content and growth factor (GF) release from equine pure-platelet rich plasma (P-PRP) and pure-platelet rich gel (P-PRG). The objectives of this study were: 1) to compare the cellular composition of P-PRP with whole blood and platelet poor plasma (PPP); 2) to compare the concentration of transforming GF beta 1 (TGF-β1) and platelet derived GF isoform BB (PDGF-BB) between P-PRP treated with n...

  18. Proteasomal degradation of TRIM5alpha during retrovirus restriction.

    Directory of Open Access Journals (Sweden)

    Christopher James Rold


    Full Text Available The host protein TRIM5alpha inhibits retroviral infection at an early post-penetration stage by targeting the incoming viral capsid. While the detailed mechanism of restriction remains unclear, recent studies have implicated the activity of cellular proteasomes in the restriction of retroviral reverse transcription imposed by TRIM5alpha. Here, we show that TRIM5alpha is rapidly degraded upon encounter of a restriction-susceptible retroviral core. Inoculation of TRIM5alpha-expressing human 293T cells with a saturating level of HIV-1 particles resulted in accelerated degradation of the HIV-1-restrictive rhesus macaque TRIM5alpha protein but not the nonrestrictive human TRIM5alpha protein. Exposure of cells to HIV-1 also destabilized the owl monkey restriction factor TRIMCyp; this was prevented by addition of the inhibitor cyclosporin A and was not observed with an HIV-1 virus containing a mutation in the capsid protein that relieves restriction by TRIMCyp IVHIV. Likewise, human TRIM5alpha was rapidly degraded upon encounter of the restriction-sensitive N-tropic murine leukemia virus (N-MLV but not the unrestricted B-MLV. Pretreatment of cells with proteasome inhibitors prevented the HIV-1-induced loss of both rhesus macaque TRIM5alpha and TRIMCyp proteins. We also detected degradation of endogenous TRIM5alpha in rhesus macaque cells following HIV-1 infection. We conclude that engagement of a restriction-sensitive retrovirus core results in TRIM5alpha degradation by a proteasome-dependent mechanism.

  19. Improvement in coronary heart disease risk factors during an intermittent fasting/calorie restriction regimen: Relationship to adipokine modulations

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    Kroeger Cynthia M


    Full Text Available Abstract Background The ability of an intermittent fasting (IF-calorie restriction (CR regimen (with or without liquid meals to modulate adipokines in a way that is protective against coronary heart disease (CHD has yet to be tested. Objective Accordingly, we examined the effects of an IFCR diet on adipokine profile, body composition, and markers of CHD risk in obese women. Methods Subjects (n = 54 were randomized to either the IFCR-liquid (IFCR-L or IFCR-food based (IFCR-F diet for 10 weeks. Results Greater decreases in body weight and waist circumference were noted in the IFCR-L group (4 ± 1 kg; 6 ± 1 cm versus the IFCR-F group (3 ± 1 kg; 4 ± 1 cm. Similar reductions (P Conclusion These findings suggest that IFCR with a liquid diet favorably modulates visceral fat and adipokines in a way that may confer protection against CHD.

  20. Maternal protein restriction induces alterations in hepatic tumor necrosis factor-α/CYP7A1 signaling and disorders regulation of cholesterol metabolism in the adult rat offspring. (United States)

    Liu, Xiaomei; Qi, Ying; Tian, Baoling; Chen, Dong; Gao, Hong; Xi, Chunyan; Xing, Yanlin; Yuan, Zhengwei


    It is well recognized that adverse events in utero impair fetal development and lead to the development of obesity and metabolic syndrome in adulthood. To investigate the mechanisms linking impaired fetal growth to increased cholesterol, an important clinical risk factor characterizing the metabolic syndrome and cardiovascular disease, we examined the impact of maternal undernutrition on tumor necrosis factor-α (TNF-α)/c-jun N-terminal kinase (JNK) signaling pathway and the cholesterol 7α-hydroxylase (CYP7A1) expression in the livers of the offspring with a protein restriction model. The male offspring with intrauterine growth restriction (IUGR) caused by the isocaloric low-protein diet showed decreased liver weight at birth and augmented circulation and hepatic cholesterol levels at 40 weeks of age. Maternal undernutrition significantly upregulated cytokine TNF-α expression and JNK phospholytion levels in the livers from fetal age to adulthood. Elevated JNK phospholytion could be linked to downregulated hepatocyte nuclear factor-4α and CYP7A1 expression, subsequently led to higher hepatic cholesterol. This work demonstrated that intrauterine malnutrition-induced IUGR might result in intrinsic disorder in hepatic TNF-α/CYP7A1 signaling, and contribute to the development of hypercholesterolemia in later life.

  1. Transcription factors MYOCD, SRF, Mesp1 and SMARCD3 enhance the cardio-inducing effect of GATA4, TBX5, and MEF2C during direct cellular reprogramming.

    Directory of Open Access Journals (Sweden)

    Nicolas Christoforou

    Full Text Available Transient overexpression of defined combinations of master regulator genes can effectively induce cellular reprogramming: the acquisition of an alternative predicted phenotype from a differentiated cell lineage. This can be of particular importance in cardiac regenerative medicine wherein the heart lacks the capacity to heal itself, but simultaneously contains a large pool of fibroblasts. In this study we determined the cardio-inducing capacity of ten transcription factors to actuate cellular reprogramming of mouse embryonic fibroblasts into cardiomyocyte-like cells. Overexpression of transcription factors MYOCD and SRF alone or in conjunction with Mesp1 and SMARCD3 enhanced the basal but necessary cardio-inducing effect of the previously reported GATA4, TBX5, and MEF2C. In particular, combinations of five or seven transcription factors enhanced the activation of cardiac reporter vectors, and induced an upregulation of cardiac-specific genes. Global gene expression analysis also demonstrated a significantly greater cardio-inducing effect when the transcription factors MYOCD and SRF were used. Detection of cross-striated cells was highly dependent on the cell culture conditions and was enhanced by the addition of valproic acid and JAK inhibitor. Although we detected Ca(2+ transient oscillations in the reprogrammed cells, we did not detect significant changes in resting membrane potential or spontaneously contracting cells. This study further elucidates the cardio-inducing effect of the transcriptional networks involved in cardiac cellular reprogramming, contributing to the ongoing rational design of a robust protocol required for cardiac regenerative therapies.

  2. Expression of growth differentiation factor 6 in the human developing fetal spine retreats from vertebral ossifying regions and is restricted to cartilaginous tissues. (United States)

    Wei, Aiqun; Shen, Bojiang; Williams, Lisa A; Bhargav, Divya; Gulati, Twishi; Fang, Zhimin; Pathmanandavel, Sarennya; Diwan, Ashish D


    During embryogenesis vertebral segmentation is initiated by sclerotomal cell migration and condensation around the notochord, forming anlagen of vertebral bodies and intervertebral discs. The factors that govern the segmentation are not clear. Previous research demonstrated that mutations in growth differentiation factor 6 resulted in congenital vertebral fusion, suggesting this factor plays a role in development of vertebral column. In this study, we detected expression and localization of growth differentiation factor 6 in human fetal spinal column, especially in the period of early ossification of vertebrae and the developing intervertebral discs. The extracellular matrix proteins were also examined. Results showed that high levels of growth differentiation factor 6 were expressed in the nucleus pulposus of intervertebral discs and the hypertrophic chondrocytes adjacent to the ossification centre in vertebral bodies, where strong expression of proteoglycan and collagens was also detected. As fetal age increased, the expression of growth differentiation factor 6 was decreased correspondingly with the progress of ossification in vertebral bodies and restricted to cartilaginous regions. This expression pattern and the genetic link to vertebral fusion suggest that growth differentiation factor 6 may play an important role in suppression of ossification to ensure proper vertebral segmentation during spinal development.

  3. Relationship between fetal growth restriction and angiogenesis factors%胎儿生长受限与血管生成因子的关系

    Institute of Scientific and Technical Information of China (English)

    黄赟博; 刘倩倩; 余艳红


    Placenta is an important organ to maintain fetal growth, metabolism, maternal and fetal physiologic balance. Angiogenesis is a critical factor in placental development involved in fetal blood circulation and vascular changes in the endometrium and placenta. Angiogenesis is closely related to angiogenesis factors such as vascular endothelial growth factor and placenta growth factor. Fetal growth restriction threats the fetal health in gestation and also increases the long-term likeliness of several diseases. In this review, the authors summarize the findings in current studies of the relationship between angiogenesis factors and fetal growth restriction.%胎盘是胎儿生长发育、代谢循环及维持母胎生理平衡的重要脏器。血管形成是胎盘发育的关键,其不仅包括胎儿血液循环,还包括子宫内膜和胎盘的血管变化。血管的形成与血管生成因子如血管内皮生长因子(VEGF)、胎盘生长因子(PLGF)等密切相关。胎儿生长受限(FGR)属严重高危妊娠,不仅对胎儿在妊娠期的健康造成威胁,还会增加分娩后远期多种疾病的发病率。目前已有关于血管生成因子与胎儿生长受限之间的研究,现将两者之间的关系作一综述。

  4. Epigenetic regulation of caloric restriction in aging

    Directory of Open Access Journals (Sweden)

    Daniel Michael


    Full Text Available Abstract The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. The aging process is frequently affected by environmental factors, and caloric restriction is by far the most effective and established environmental manipulation for extending lifespan in various animal models. However, the precise mechanisms by which caloric restriction affects lifespan are still not clear. Epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. Two primary epigenetic codes, DNA methylation and histone modification, are believed to dynamically influence chromatin structure, resulting in expression changes of relevant genes. In this review, we assess the current advances in epigenetic regulation in response to caloric restriction and how this affects cellular senescence, aging and potential extension of a healthy lifespan in humans. Enhanced understanding of the important role of epigenetics in the control of the aging process through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases.

  5. Early Life Stress and Sleep Restriction as Risk Factors in PTSD: An Integrative Pre-Clinical Approach (United States)


    that CCK increases glutamatergic transmission in the DG (Sinton, 1988; Gabriel et al., 1996; Deng et al., 2010) as well as long-term potentiation (LTP...patterns of selected GABAergic and Glutamatergic factors in the ventral and dorsal hippocampus and in the BLA One-way ANOVA followed by post hoc...Table 2: Effects of an Exposure to Juvenile Stress, UWT and UWT reminder. Protein expression of GABAergic and glutamatergic factors was assessed in the

  6. Increased expression and dysregulated association of restriction factors and type I interferon in HIV, HCV mono- and co-infected patients. (United States)

    Zhu, Jia-Wu; Liu, Feng-Liang; Mu, Dan; Deng, De-Yao; Zheng, Yong-Tang


    Host restriction factors and type I interferon are important in limiting HIV and HCV infections, yet the role of HIV, HCV mono- and co-infection in regulating these antiviral genes expression is not clear. In this study, we measured the levels of TRIM5α, TRIM22, APOBEC3G, and IFN-α, -β mRNA expression in peripheral blood mononuclear cells of 43 HIV mono-infected, 70 HCV mono-infected and 64 HIV/HCV co-infected patients along with 98 healthy controls. We also quantified HIV and HCV viral loads in mono- and co-infected patients. The results showed that HCV, HIV mono- and co-infection differentially increased TRIM22, APOBEC3G, and IFN-α, -β mRNA expression while the mRNA expression of TRIMα was upregulated only by HCV-mono infection. HIV/HCV co-infection was associated with higher viral load, compared to either HIV or HCV mono-infection. Additionally, we showed TRIMα and TRIM22 positively correlated with IFN-α, -β, which could be dysregulated by HIV, HCV mono- and co-infection. Furthermore, we found TRIM22 negatively correlated with HCV viral load in mono-infected patients and APOBEC3G positively correlated with HCV viral load in co-infected patients. Collectively, our findings suggest the potential role of restriction factors in restricting HIV, HCV mono- and co-infection in vivo, which appears to be a therapeutic target for potential drug discovery.

  7. 制约建筑节能推进的因素探究%Exploring the Restrictive Factors to Promote the Construction of Energy-efficient

    Institute of Scientific and Technical Information of China (English)


    With the rapid development of the global economy, building problems especial y the energy consumption problem becomes more and more significant, and actively promoted the urgent task of energy-saving construction work. This paper thr-ough the analysis of the significance of energy-saving constru-ction work, analyzes the restricting factors to promote the con-struction of energy-saving, aims to break the restriction factor to promote the construction of energy-saving in China, to acce-lerate the construction of energy-saving, let building energy ef-ficiency become the people's livelihood project which benefit the nation and people.%  随着全球经济的快速发展,建筑带来的问题特别是能源消耗问题越来越显著,积极推进建筑节能工作任务紧迫。本文通过分析建筑节能工作的意义,剖析制约我国建筑节能推进的因素,旨在破除我国建筑节能推进的制约因素,加快我国建筑节能的步伐,让建筑节能成为利国利民的民生工程。

  8. Compound C prevents Hypoxia-Inducible Factor-1α protein stabilization by regulating the cellular oxygen availability via interaction with Mitochondrial Complex I

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    Hagen Thilo


    Full Text Available Abstract The transcription factor Hypoxia-Inducible Factor-1α is a master regulator of the cellular response to low oxygen concentration. Compound C, an inhibitor of AMP-activated kinase, has been reported to inhibit hypoxia dependent Hypoxia-Inducible Factor-1α activation via a mechanism that is independent of AMP-activated kinase but dependent on its interaction with the mitochondrial electron transport chain. The objective of this study is to characterize the interaction of Compound C with the mitochondrial electron transport chain and to determine the mechanism through which the drug influences the stability of the Hypoxia-Inducible Factor-1α protein. We found that Compound C functions as an inhibitor of complex I of the mitochondrial electron transport chain as demonstrated by its effect on mitochondrial respiration. It also prevents hypoxia-induced Hypoxia-Inducible Factor-1α stabilization in a dose dependent manner. In addition, Compound C does not have significant effects on reactive oxygen species production from complex I via both forward and reverse electron flux. This study provides evidence that similar to other mitochondrial electron transport chain inhibitors, Compound C regulates Hypoxia-Inducible Factor-1α stability by controlling the cellular oxygen concentration.

  9. Effect of feed restriction and initial body weight on growth performance, body composition, and hormones in male pigs immunized against gonadotropin-releasing factor. (United States)

    Moore, K L; Mullan, B P; Kim, J C; Payne, H G; Dunshea, F R


    Pigs immunized against gonadotropin-releasing factor (GnRF) have increased carcass fatness compared to entire males; however, the timing of this increase in fatness after the second immunization against GnRF has not been determined. An experiment was conducted to identify and compare the growth performance, body composition, and physiological changes in immunocastrated males (IC males) at different BW and feeding levels. A total of 64 pigs were used in a 2 × 2 × 2 factorial experiment with the treatments being 1) sex (entire males or IC males), 2) initial BW (45.9 kg [light] or 78.3 kg [heavy]), and 3) feeding regime (2.5 times maintenance [restricted] or ad libitum). The pigs were individually housed, and the diets were fed for 4 wk after the second immunization against GnRF until slaughter at either 68.4 kg BW (light) or 105.8 kg BW (heavy). Immunocastrated males on a restricted feed intake had a lower ADG compared to entire males from d 15 to 28 and d 0 to 28 ( 0.011 and 0.011, respectively). Fat deposition was not affected by sex from d 0 to 14, but from d 15 to 28 IC males deposited 45 g/d more fat than entire males ( = 0.025). Immunocastrated male pigs fed ad libitum deposited 87 g/d more fat from d 15 to 28 than entire males fed ad libitum ( = 0.036). However, there was no difference in fat deposition between IC males and entire males when feed intake was restricted from d 15 to 28. Plasma urea nitrogen levels were greater in IC males compared to entire males from d 7 after the second immunization against GnRF ( 0.05 for d 7, 10, 14, 21, and 28). Plasma concentrations of IGF-1 were lower for IC males compared to entire males on d 3, 7, 10, and 28 ( 0.05 for all days). The following conclusions were made: 1) when pigs are immunized at a light BW (50 kg) and/or are on a restricted feed intake, they have a reduced propensity to deposit fat; however, the restriction in feed intake adversely affects growth rate. 2) The majority of fat deposition for males

  10. A genome-wide screen for spatially restricted expression patterns identifies transcription factors that regulate glial development

    NARCIS (Netherlands)

    Fu, H.; Cai, J.; Clevers, H.; Fast, E.; Gray, S.; Greenberg, R.; Jain, M.K.; Ma, Q.; Qiu, M.; Rowitch, D.H.; Taylor, C.; Stiles, C.D.


    Forward genetic screens in genetically accessible invertebrate organisms such as Drosophila melanogaster have shed light on transcription factors that specify formation of neurons in the vertebrate CNS. However, invertebrate models have, to date, been uninformative with respect to genes that specify

  11. Both viral E2 protein and the cellular factor PEBP2 regulate transcription via E2 consensus sites within the bovine papillomavirus type 4 long control region.


    Jackson, M E; Campo, M S


    The bovine papillomavirus type 4 (BPV4) long control region (LCR) contains three consensus binding sites, E2(1), E2(2), and E2(3) (ACCN6GGT), for the viral E2 transcription factor and a fourth degenerate site, dE2 (ATCN6GGT), which lies 3 bp upstream of E2(3). The E2(2) site was found to bind the cellular transcription factor PEBP2, and mutations at this site reduced basal promoter activity by as much as 60%, indicating an important role for PEBP2 in LCR function. Mutation of the E2(3) or dE2...

  12. The Primary Resistance of Helicobacter pylori in Taiwan after the National Policy to Restrict Antibiotic Consumption and Its Relation to Virulence Factors-A Nationwide Study.

    Directory of Open Access Journals (Sweden)

    Jyh-Ming Liou

    Full Text Available The Taiwan Government issued a policy to restrict antimicrobial usage since 2001. We aimed to assess the changes in the antibiotic consumption and the primary resistance of H. pylori after this policy and the impact of virulence factors on resistance.The defined daily dose (DDD of antibiotics was analyzed using the Taiwan National Health Insurance (NHI research database. H. pylori strains isolated from treatment naïve (N=1395 and failure from prior eradication therapies (N=360 from 9 hospitals between 2000 and 2012 were used for analysis. The minimum inhibitory concentration was determined by agar dilution test. Genotyping for CagA and VacA was determined by PCR method.The DDD per 1000 persons per day of macrolides reduced from 1.12 in 1997 to 0.19 in 2008, whereas that of fluoroquinolones increased from 0.12 in 1997 to 0.35 in 2008. The primary resistance of amoxicillin, clarithromycin, metronidazole, and tetracycline remained as low as 2.2%, 7.9%, 23.7%, and 1.9% respectively. However, the primary levofloxacin resistance rose from 4.9% in 2000-2007 to 8.3% in 2008-2010 and 13.4% in 2011-2012 (p=0.001. The primary resistance of metronidazole was higher in females than males (33.1% vs. 18.8%, p<0.001, which was probably attributed to the higher consumption of nitroimidazole. Neither CagA nor VacA was associated with antibiotic resistance.The low primary clarithromycin and metronidazole resistance of H. pylori in Taiwan might be attributed to the reduced consumption of macrolides and nitroimidazole after the national policy to restrict antimicrobial usage. Yet, further strategies are needed to restrict the consumption of fluoroquinolones in the face of rising levofloxacin resistance.

  13. Fetal growth restriction and the programming of heart growth and cardiac insulin-like growth factor 2 expression in the lamb (United States)

    Wang, Kimberley C W; Zhang, Lei; McMillen, I Caroline; Botting, Kimberley J; Duffield, Jaime A; Zhang, Song; Suter, Catherine M; Brooks, Doug A; Morrison, Janna L


    Abstract Reduced growth in fetal life together with accelerated growth in childhood, results in a ∼50% greater risk of coronary heart disease in adult life. It is unclear why changes in patterns of body and heart growth in early life can lead to an increased risk of cardiovascular disease in adulthood. We aimed to investigate the role of the insulin-like growth factors in heart growth in the growth-restricted fetus and lamb. Hearts were collected from control and placentally restricted (PR) fetuses at 137–144 days gestation and from average (ABW) and low (LBW) birth weight lambs at 21 days of age. We quantified cardiac mRNA expression of IGF-1, IGF-2 and their receptors, IGF-1R and IGF-2R, using real-time RT-PCR and protein expression of IGF-1R and IGF-2R using Western blotting. Combined bisulphite restriction analysis was used to assess DNA methylation in the differentially methylated region (DMR) of the IGF-2/H19 locus and of the IGF-2R gene. In PR fetal sheep, IGF-2, IGF-1R and IGF-2R mRNA expression was increased in the heart compared to controls. LBW lambs had a greater left ventricle weight relative to body weight as well as increased IGF-2 and IGF-2R mRNA expression in the heart, when compared to ABW lambs. No changes in the percentage of methylation of the DMRs of IGF-2/H19 or IGF-2R were found between PR and LBW when compared to their respective controls. In conclusion, a programmed increased in cardiac gene expression of IGF-2 and IGF-2R may represent an adaptive response to reduced substrate supply (e.g. glucose and/or oxygen) in order to maintain heart growth and may be the underlying cause for increased ventricular hypertrophy and the associated susceptibility of cardiomyocytes to ischaemic damage later in life. PMID:21807611

  14. Energy restriction and exercise modulate angiopoietins and vascular endothelial growth factor expression in the cavernous tissue of high-fat diet-fed rats

    Institute of Scientific and Technical Information of China (English)

    In(ě)s Tomada; Nuno Tomada; Henrique Almeida; Delminda Neves


    The purpose of the current study was to evaluate the effect of a high-fat (HF) diet,energy restriction and exercise on the expression of vascular endothelial growth factor (VEGF),angiopoietin (Ang) 1 and 2,and their receptors in rat corpus cavernosum (CC).Male Wistar rats were fed adlibitum with an HF diet for 8 or 16 weeks.After 8 weeks of the HF diet,a group of rats was subjected to energy restriction with or without exercise for 8 weeks.Control animals had free access to standard diet for the same period.After euthanasia,blood was collected and the penises removed for immunofluorescence assays (VEGF,VEGF receptor (VEGFR) 1 and 2,Ang1,Ang2 and Tie2) and semiquantification of VEGF,VEGFR1,VEGFR2,Ang1,Ang2,Tie2,endothelial nitric oxide synthase (eNOS) and Akt/phospho-Akt by Western blotting.HF diet-fed rats exhibited lower high-density lipoprotein cholesterol (HDL-c) levels,higher systolic blood pressure and an increased atherogenic index.A significant increase in Ang2 expression in the CC was verified and coupled to a decrease in VEGF and VEGFRs.The Akt pathway was activated by the HF diet.Energy restriction and exercise increased eNOS expression and restored most HF diet-induced modifications except for VEGFR2 expression.These results emphasize the role of diet on vascular function regulation,demonstrating that cavernous imbalance of VEGF/VEGFRs and Angs/rie2 systems occurs before serum lipid changes and obesity onset,antedating structural atherosclerotic features.

  15. Cellular automata

    CERN Document Server

    Codd, E F


    Cellular Automata presents the fundamental principles of homogeneous cellular systems. This book discusses the possibility of biochemical computers with self-reproducing capability.Organized into eight chapters, this book begins with an overview of some theorems dealing with conditions under which universal computation and construction can be exhibited in cellular spaces. This text then presents a design for a machine embedded in a cellular space or a machine that can compute all computable functions and construct a replica of itself in any accessible and sufficiently large region of t

  16. The critical role of personality and organizational factors as determinants of reactions to restricted and stressful environments. [undersea habitats (United States)

    Helmreich, Robert L.


    Research into the impact of personality factors on groups in various settings is reviewed as an introduction to a brief discussion of personality and group behavior research needs relevant to the space program. Significant findings of some earlier research are summarized, and methodological problems are touched on. The study of intergroup and intragroup conflict in a stressful environment, as exemplified particularly by undersea habitats, is seen as being of consequence for long-term space missions. It is concluded that adequate research can only be conducted as an adjunct to data collection from operational stressful environments, and not from laboratory experiments.

  17. A novel lineage transcription factor based analysis reveals differences in T helper cell subpopulation development in infected and intrauterine growth restricted (IUGR) piglets. (United States)

    Ebner, F; Rausch, S; Scharek-Tedin, L; Pieper, R; Burwinkel, M; Zentek, J; Hartmann, S


    Research in mouse and human clearly identified subsets of T helper (Th) cells based on nuclear expression of specific lineage transcription factors. In swine, however, transcription factor based detection of functional subpopulations of porcine Th cells by flow cytometry is so far limited to regulatory T cells via Foxp3. T-bet and GATA-3 are the transcription factors that regulate commitment to Th1 or Th2 cells, respectively. In this study we prove GATA-3 and T-bet expression in porcine CD4(+) cells polarized in vitro. Importantly, GATA-3 and T-bet expressing cells were detectable in pigs infected with pathogens associated with Th2 and Th1 immune responses. Increased frequencies of GATA-3 positive CD4(+) cells are found in vivo in pigs experimentally infected with the nematode Trichuris suis, whereas porcine reproductive and respiratory syndrome virus (PRRSV) infection elicited T-bet positive CD4(+) T cells. Analysing the immune status of pre-weaning piglets with intrauterine growth restriction (IUGR) we found an increased expression of Foxp3, T-bet and GATA-3 in CD4(+) and CD4(+)CD8(+) double-positive T cells in systemic and intestinal compartments of IUGR piglets. Hence, we established the detection of porcine Th1 and Th2 cells via T-bet and GATA-3 and show that the porcine lineage transcription factors are differentially regulated very early in life depending on the developmental status.

  18. The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis. (United States)

    Szretter, Kristy J; Samuel, Melanie A; Gilfillan, Susan; Fuchs, Anja; Colonna, Marco; Diamond, Michael S


    Sterile alpha and HEAT/Armadillo motif (SARM) is a highly conserved Toll/interleukin-1 receptor (TIR)-containing adaptor protein that is believed to negatively regulate signaling of the pathogen recognition receptors Toll-like receptor 3 (TLR3) and TLR4. To test its physiological function in the context of a microbial infection, we generated SARM(-/-) mice and evaluated the impact of this deficiency on the pathogenesis of West Nile virus (WNV), a neurotropic flavivirus that requires TLR signaling to restrict infection. Although SARM was preferentially expressed in cells of the central nervous system (CNS), studies with primary macrophages, neurons, or astrocytes showed no difference in viral growth kinetics. In contrast, viral replication was increased specifically in the brainstem of SARM(-/-) mice, and this was associated with enhanced mortality after inoculation with a virulent WNV strain. A deficiency of SARM was also linked to reduced levels of tumor necrosis factor alpha (TNF-alpha), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. Thus, SARM appears to be unique among the TIR adaptor molecules, since it functions to restrict viral infection and neuronal injury in a brain region-specific manner, possibly by modulating the activation of resident CNS inflammatory cells.

  19. Elongation factor P restricts Salmonella’s growth by controlling translation of a Mg2+ transporter gene during infection (United States)

    Choi, Eunna; Choi, Soomin; Nam, Daesil; Park, Shinae; Han, Yoontak; Lee, Jung-Shin; Lee, Eun-Jin


    When a ribosome translates mRNA sequences, the ribosome often stalls at certain codons because it is hard to translate. Consecutive proline codons are such examples that induce ribosome stalling and elongation factor P (EF-P) is required for the stalled ribosome to continue translation at those consecutive proline codons. We found that EF-P is required for translation of the mgtB gene encoding a Mg2+ transporter in the mgtCBR virulence operon from the intracellular pathogen Salmonella enterica serovar Typhimurium. Salmonella lacking EF-P decreases MgtB protein levels in a manner dependent on consecutive proline codons located in the mgtB coding region despite increasing transcription of the mgtCBR operon via the mgtP open reading frame in the leader RNA, resulting in an altered ratio between MgtC and MgtB proteins within the operon. Substitution of the consecutive proline codons to alanine codons eliminates EF-P-mediated control of the mgtB gene during infection and thus contributes to Salmonella’s survival inside macrophages where Salmonella experiences low levels of EF-P. This suggests that this pathogen utilizes a strategy to coordinate expression of virulence genes by an evolutionarily conserved translation factor. PMID:28181542

  20. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus.

    Directory of Open Access Journals (Sweden)

    I-Chueh Huang

    Full Text Available Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3 are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV hemagglutinin (HA protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP(1,2 of Marburg and Ebola filoviruses (MARV, EBOV. Consistent with these observations, interferon-β specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV and entry mediated by the SARS-CoV spike (S protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.

  1. Decoding Cellular Dynamics in Epidermal Growth Factor Signaling Using a New Pathway-Based Integration Approach for Proteomics and Transcriptomics Data (United States)

    Wachter, Astrid; Beißbarth, Tim


    Identification of dynamic signaling mechanisms on different cellular layers is now facilitated as the increased usage of various high-throughput techniques goes along with decreasing costs for individual experiments. A lot of these signaling mechanisms are known to be coordinated by their dynamics, turning time-course data sets into valuable information sources for inference of regulatory mechanisms. However, the combined analysis of parallel time-course measurements from different high-throughput platforms still constitutes a major challenge requiring sophisticated bioinformatic tools in order to ease biological interpretation. We developed a new pathway-based integration approach for the analysis of coupled omics time-series data, which we implemented in the R package pwOmics. Unlike many other approaches, our approach acknowledges the role of the different cellular layers of measurement and infers consensus profiles and time profile clusters for further biological interpretation. We investigated a time-course data set on epidermal growth factor stimulation of human mammary epithelial cells generated on the two layers of RNA and proteins. The data was analyzed using our new approach with a focus on feedback signaling and pathway crosstalk. We could confirm known regulatory patterns relevant in the physiological cellular response to epidermal growth factor stimulation as well as identify interesting new interactions in this signaling context, such as the regulatory influence of the connective tissue growth factor on transferrin receptor or the influence of growth arrest and DNA-damage-inducible alpha on the connective tissue growth factor. Thus, we show that integrated cross-platform analysis provides a deeper understanding of regulatory signaling mechanisms. Combined with time-course information it enables the characterization of dynamic signaling processes and leads to the identification of important regulatory interactions which might be dysregulated in disease

  2. Hepatic insulin-like growth-factor binding protein (igfbp) responses tofood restriction in Atlantic salmon smolts (United States)

    Breves, Jason P.; Phipps-Costin, Silas K.; Fujimoto, Chelsea K.; Einarsdottir, Ingibjörg E.; Regish, Amy M.; Björnsson, Björn Thrandur; McCormick, Stephen


    The growth hormone (Gh)/insulin-like growth-factor (Igf) system plays a central role in the regulation of growth in fishes. However, the roles of Igf binding proteins (Igfbps) in coordinating responses to food availability are unresolved, especially in anadromous fishes preparing for seaward migration. We assayed plasma Gh, Igf1, thyroid hormones and cortisol along with igfbp mRNA levels in fasted and fed Atlantic salmon ( Salmo salar ). Fish were fasted for 3 or 10 days near the peak of smoltification (late April to early May). Fasting reduced plasma glucose by 3 days and condition factor by 10 days. Plasma Gh, cortisol, and thyroxine (T 4 ) were not altered in response to fasting, whereas Igf1 and 3,5,3′-triiodo- l -thyronine (T 3 ) were slightly higher and lower than controls, respectively. Hepatic igfbp1b1 , - 1b2 , - 2a , - 2b1 and - 2b2 mRNA levels were not responsive to fasting, but there were marked increases in igfbp1a1 following 3 and 10 days of fasting. Fasting did not alter hepatic igf1or igf2 ; however, muscle igf1 was diminished by 10 days of fasting. There were no signs that fasting compromised branchial ionoregulatory functions, as indicated by unchanged Na + /K + -ATPase activity and ion pump/transporter mRNA levels. We conclude that dynamic hepatic igfbp1a1 and muscle igf1 expression participate in the modulation of Gh/Igf signaling in smolts undergoing catabolism.

  3. Formation of the embryonic organizer is restricted by the competitive influences of Fgf signaling and the SoxB1 transcription factors.

    Directory of Open Access Journals (Sweden)

    Cheng-Liang Kuo

    Full Text Available The organizer is one of the earliest structures to be established during vertebrate development and is crucial to subsequent patterning of the embryo. We have previously shown that the SoxB1 transcription factor, Sox3, plays a central role as a transcriptional repressor of zebrafish organizer gene expression. Recent data suggest that Fgf signaling has a positive influence on organizer formation, but its role remains to be fully elucidated. In order to better understand how Fgf signaling fits into the complex regulatory network that determines when and where the organizer forms, the relationship between the positive effects of Fgf signaling and the repressive effects of the SoxB1 factors must be resolved. This study demonstrates that both fgf3 and fgf8 are required for expression of the organizer genes, gsc and chd, and that SoxB1 factors (Sox3, and the zebrafish specific factors, Sox19a and Sox19b can repress the expression of both fgf3 and fgf8. However, we also find that these SoxB1 factors inhibit the expression of gsc and chd independently of their repression of fgf expression. We show that ectopic expression of organizer genes induced solely by the inhibition of SoxB1 function is dependent upon the activation of fgf expression. These data allow us to describe a comprehensive signaling network in which the SoxB1 factors restrict organizer formation by inhibiting Fgf, Nodal and Wnt signaling, as well as independently repressing the targets of that signaling. The organizer therefore forms only where Nodal-induced Fgf signaling overlaps with Wnt signaling and the SoxB1 proteins are absent.

  4. Identification of an HIV-1 replication inhibitor which rescues host restriction factor APOBEC3G in Vif-APOBEC3G complex. (United States)

    Zhang, Shaoyang; Zhong, Limei; Chen, Bing; Pan, Ting; Zhang, Xue; Liang, Liting; Li, Qianwen; Zhang, Ziying; Chen, Hui; Zhou, Jie; Luo, Haihua; Zhang, Hui; Bai, Chuan


    HIV-1 Vif protein is one of the most crucial accessory proteins for viral replication. It efficiently counteracts the important host restriction factor APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G, A3G) which is lethal to HIV-1 by causing G to A mutation of viral genome. Vif protein mediates degradation of APOBEC3G via the complicated protein-protein interactions of Vif, APOBEC3G, Elongin C/B and Cullin 5. The importance of Vif-APOBEC3G complex makes it a good potential target to develop new therapeutics of HIV-1. We identified a potent HIV-1 replication inhibitor (ZBMA-1, IC50 = 1.01 μM) that efficiently protected APOBEC3G protein by targeting Vif-APOBEC3G complex. The co-immunoprecipitation and docking studies indicated that compound ZBMA-1 affected the binding of Elongin C with Vif protein.

  5. Calorie restriction and stroke

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    Manzanero Silvia


    Full Text Available Abstract Stroke, a major cause of disability and mortality in the elderly, occurs when a cerebral blood vessel is occluded or ruptured, resulting in ischemic damage and death of brain cells. The injury mechanism involves metabolic and oxidative stress, excitotoxicity, apoptosis and inflammatory processes, including activation of glial cells and infiltration of leukocytes. In animal models, dietary energy restriction, by daily calorie reduction (CR or intermittent fasting (IF, extends lifespan and decreases the development of age-related diseases. Dietary energy restriction may also benefit neurons, as suggested by experimental evidence showing that CR and IF protect neurons against degeneration in animal models. Recent findings by our group and others suggest the possibility that dietary energy restriction may protect against stroke induced brain injury, in part by inducing the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF and basic fibroblast growth factor (bFGF; protein chaperones, including heat shock protein 70 (Hsp70 and glucose regulated protein 78 (GRP78; antioxidant enzymes, such as superoxide dismutases (SOD and heme oxygenase-1 (HO-1, silent information regulator T1 (SIRT1, uncoupling proteins and anti-inflammatory cytokines. This article discusses the protective mechanisms activated by dietary energy restriction in ischemic stroke.

  6. Interferon regulatory factor-two restricts expression of interferon-stimulated genes to the endometrial stroma and glandular epithelium of the ovine uterus. (United States)

    Choi, Y; Johnson, G A; Burghardt, R C; Berghman, L R; Joyce, M M; Taylor, K M; Stewart, M D; Bazer, F W; Spencer, T E


    Interferon tau (IFNtau) is the signal for maternal recognition of pregnancy in ruminants. The positive effects of IFNtau on IFN-stimulated gene (ISG) expression are mediated by ISG factor 3 (ISGF3), which is composed of signal transducer and activator of transcription (Stat) 1, Stat 2, and IFN regulatory factor-9 (IRF-9), and by gamma-activated factor (GAF), which is a Stat 1 homodimer. Induction of ISGs, such as ISG17 and 2',5'-oligoadenylate synthetase, by IFNtau during pregnancy is limited to the endometrial stroma (S) and glandular epithelium (GE) of the ovine uterus. The IRF-2, a potent transcriptional repressor of ISG expression, is expressed in the luminal epithelium (LE). This study determined effects of the estrous cycle, pregnancy, and IFNtau on expression of Stat 1, Stat 2, IRF-9, IRF-1, and IRF-2 genes in the ovine endometrium. In cyclic ewes, Stat 1, Stat 2, IRF-1, and IRF-9 mRNA and protein were detected at low levels in the S and GE. During pregnancy, expression of these genes increased only in the S and GE. Expression of IRF-2 was detected only in the LE and superficial GE (sGE) of both cyclic and pregnant ewes. In cyclic ewes, intrauterine administration of IFNtau stimulated Stat 1, Stat 2, IRF-9, and IRF-1 expression in the endometrium. Ovine IRF-2 repressed transcriptional activity driven by IFN-stimulated response elements that bind ISGF3, but not by gamma-activation sequences that bind GAF. These results suggest that IRF-2 in the LE and sGE restricts IFNtau induction of ISGs to the S and GE. In the S and GE, IFNtau hyperactivation of ISG expression likely involves formation and actions of the transcription factors ISGF3 and, perhaps, IRF-1.

  7. Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. (United States)

    Csiszar, Anna; Labinskyy, Nazar; Jimenez, Rosario; Pinto, John T; Ballabh, Praveen; Losonczy, Gyorgy; Pearson, Kevin J; de Cabo, Rafael; Ungvari, Zoltan


    Endothelial dysfunction, oxidative stress and inflammation are associated with vascular aging and promote the development of cardiovascular disease. Caloric restriction (CR) mitigates conditions associated with aging, but its effects on vascular dysfunction during aging remain poorly defined. To determine whether CR exerts vasoprotective effects in aging, aortas of ad libitum (AL) fed young and aged and CR-aged F344 rats were compared. Aging in AL-rats was associated with impaired acetylcholine-induced relaxation, vascular oxidative stress and increased NF-kappaB activity. Lifelong CR significantly improved endothelial function, attenuated vascular ROS production, inhibited NF-kappaB activity and down-regulated inflammatory genes. To elucidate the role of circulating factors in mediation of the vasoprotective effects of CR, we determined whether sera obtained from CR animals can confer anti-oxidant and anti-inflammatory effects in cultured coronary arterial endothelial cells (CAECs), mimicking the effects of CR. In CAECs cultured in the presence of AL serum TNFalpha elicited oxidative stress, NF-kappaB activation and inflammatory gene expression. By contrast, treatment of CAECs with CR serum attenuated TNFalpha-induced ROS generation and prevented NF-kappaB activation and induction of inflammatory genes. siRNA knockdown of SIRT1 mitigated the anti-oxidant and anti-inflammatory effects of CR serum. CR exerts anti-oxidant and anti-inflammatory vascular effects, which are likely mediated by circulating factors, in part, via a SIRT1-dependent pathway.

  8. Human immunodeficiency virus type 1 Tat increases the expression of cleavage and polyadenylation specificity factor 73-kilodalton subunit modulating cellular and viral expression. (United States)

    Calzado, Marco A; Sancho, Rocío; Muñoz, Eduardo


    The human immunodeficiency virus type 1 (HIV-1) Tat protein, which is essential for HIV gene expression and viral replication, is known to mediate pleiotropic effects on various cell functions. For instance, Tat protein is able to regulate the rate of transcription of host cellular genes and to interact with the signaling machinery, leading to cellular dysfunction. To study the effect that HIV-1 Tat exerts on the host cell, we identified several genes that were up- or down-regulated in tat-expressing cell lines by using the differential display method. HIV-1 Tat specifically increases the expression of the cleavage and polyadenylation specificity factor (CPSF) 73-kDa subunit (CPSF3) without affecting the expression of the 160- and 100-kDa subunits of the CPSF complex. This complex comprises four subunits and has a key function in the 3'-end processing of pre-mRNAs by a coordinated interaction with other factors. CPSF3 overexpression experiments and knockdown of the endogenous CPSF3 by mRNA interference have shown that this subunit of the complex is an important regulatory protein for both viral and cellular gene expression. In addition to the known CPSF3 function in RNA polyadenylation, we also present evidence that this protein exerts transcriptional activities by repressing the mdm2 gene promoter. Thus, HIV-1-Tat up-regulation of CPSF3 could represent a novel mechanism by which this virus increases mRNA processing, causing an increase in both cell and viral gene expression.

  9. Effect of triamcinolone acetonide ammonia bromine joint hydrochloric acid on patients with secretory otitis media and on body's inflammatory factor and cellular immunologic parameters

    Institute of Scientific and Technical Information of China (English)

    Quan-Fu Hu; Shao-Ji Ouyang; Rong-Wei Yao; Xue-Jiang Xu; Jin-Hua He; Li-Li Zhang


    Objective:To explore the clinical effect of triamcinolone acetonide ammonia bromine joint hydrochloric acid on patients with secretory otitis media and the influences on the body's inflammatory factors and cellular immunologic parameters.Methods:A total of 40 cases of single ear secretory otitis media patients of the same period in our hospital were randomly selected as experimental group, using triamcinolone acetonide ammonia bromine joint hydrochloric acid treatment; And 40 cases of single ear secretory otitis media patients of the same period were randomly selected as control group, using dexamethasone treatment. To observe the clinical efficacy of two groups of patients and detect the inflammatory factors and cellular immune index level of the two groups of patients before and after treatment.Results:The total effective rate(90%) of treatment group is significantly higher than that (80%) of control group (P0.05). After treatment, the serum and ear effusion inflammatory cytokines levels of the two groups were significantly lower than that before treatment (P0.05); The CD4+/CD8+ levels of experimental group were significantly higher than the control group (P0.05). Conclusions: The triamcinolone acetonide ammonia bromine joint hydrochloric acid treatment is more conducive to improve the immune function of the secretory otitis media patients and treatment effect, which has important clinical significance on the treatment of secretory otitis media patients.


    Directory of Open Access Journals (Sweden)

    A. A. Rezanov


    Full Text Available Statement of the problem. The quality of silicate porous concrete is largely determined by vapor-ization processes at the stage of the formation of the macrostructure of the obtained material. In the production of cellular concrete with the use of injection molding, the existing manufacturing technologies do not enable the expeditious handling of the vaporization process. This is why there is a growing need to develop additional efficient methods of handling the vaporization process thus improving cellular silicate concrete.Results. Based on modelling and detailed examination of the balance of pressure affecting devel-oping gas pores, mechanisms and factors governing a defect-free structure are found. An additional governing factor, which is a pressure of the external gaseous medium, was discovered. The approaches to handling the vaporization process have been developed and a plant fitted with a system of automatic control of vaporization process by conscious operative pressuring effect from the external gaseous phase on a poring mixture has been designed.Conclusions. Theoretical validation along with the results of the experimental study help to arrive at the conclusion about the efficiency of the suggested system in controlling vaporization that could provide a good addition to the traditional injection molding and make it more susceptible against varying characteristics of raw materials.

  11. Brain-derived neurotrophic factor induces neuron-like cellular differentiation of mesenchymal stem cells derived from human umbilical cord blood cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Lei Chen; Guozhen Hui; Zhongguo Zhang; Bing Chen; Xiaozhi Liu; Zhenlin Liu; Hongliang Liu; Gang Li; Zhiguo Su; Junfei Wang


    Human umbilical cord blood was collected from full-term deliveries scheduled for cesarean section. Mononuclear cells were isolated, amplified and induced as mesenchymal stem cells. Isolated mesenchymal stem cells tested positive for the marker CD29, CD44 and CD105 and negative for typical hematopoietic and endothelial markers. Following treatment with neural induction medium containing brain-derived neurotrophic factor for 7 days, the adherent cells exhibited neuron-like cellular morphology. Immunohistochemical staining and reverse transcription-PCR revealed that the induced mesenchymal stem cells expressed the markers for neuron-specific enolase and neurofilament. The results demonstrated that human umbilical cord blood-derived mesenchymal stem cells can differentiate into neuron-like cells induced by brain-derived neurotrophic factor in vitro.

  12. Different mutagenic potential of HIV-1 restriction factors APOBEC3G and APOBEC3F is determined by distinct single-stranded DNA scanning mechanisms.

    Directory of Open Access Journals (Sweden)

    Anjuman Ara


    Full Text Available The APOBEC3 deoxycytidine deaminase family functions as host restriction factors that can block replication of Vif (virus infectivity factor deficient HIV-1 virions to differing degrees by deaminating cytosines to uracils in single-stranded (-HIV-1 DNA. Upon replication of the (-DNA to (+DNA, the HIV-1 reverse transcriptase incorporates adenines opposite the uracils, thereby inducing C/G→T/A mutations that can functionally inactivate HIV-1. Although both APOBEC3F and APOBEC3G are expressed in cell types HIV-1 infects and are suppressed by Vif, there has been no prior biochemical analysis of APOBEC3F, in contrast to APOBEC3G. Using synthetic DNA substrates, we characterized APOBEC3F and found that similar to APOBEC3G; it is a processive enzyme and can deaminate at least two cytosines in a single enzyme-substrate encounter. However, APOBEC3F scanning movement is distinct from APOBEC3G, and relies on jumping rather than both jumping and sliding. APOBEC3F jumping movements were also different from APOBEC3G. The lack of sliding movement from APOBEC3F is due to an ¹⁹⁰NPM¹⁹² motif, since insertion of this motif into APOBEC3G decreases its sliding movements. The APOBEC3G NPM mutant induced significantly less mutations in comparison to wild-type APOBEC3G in an in vitro model HIV-1 replication assay and single-cycle infectivity assay, indicating that differences in DNA scanning were relevant to restriction of HIV-1. Conversely, mutation of the APOBEC3F ¹⁹¹Pro to ¹⁹¹Gly enables APOBEC3F sliding movements to occur. Although APOBEC3F ¹⁹⁰NGM¹⁹² could slide, the enzyme did not induce more mutagenesis than wild-type APOBEC3F, demonstrating that the unique jumping mechanism of APOBEC3F abrogates the influence of sliding on mutagenesis. Overall, we demonstrate key differences in the impact of APOBEC3F- and APOBEC3G-induced mutagenesis on HIV-1 that supports a model in which both the processive DNA scanning mechanism and preferred

  13. Effects of the breed, sex and age on cellular content and growth factor release from equine pure-platelet rich plasma and pure-platelet rich gel

    Directory of Open Access Journals (Sweden)

    Giraldo Carlos E


    Full Text Available Abstract Background There is no information on the effects of the breed, gender and age on the cellular content and growth factor (GF release from equine pure-platelet rich plasma (P-PRP and pure-platelet rich gel (P-PRG. The objectives of this study were: 1 to compare the cellular composition of P-PRP with whole blood and platelet poor plasma (PPP; 2 to compare the concentration of transforming GF beta 1 (TGF-β1 and platelet derived GF isoform BB (PDGF-BB between P-PRP treated with non-ionic detergent (P-PRP+NID, P-PRG (activated with calcium gluconate -CG-, PPP+NID, PPP gel (PPG, and plasma and; 3 to evaluate and to correlate the effect of the breed, gender and age on the cellular and GF concentration for each blood component. Forty adult horses, 20 Argentinean Creole Horses (ACH and, 20 Colombian Creole Horses (CCH were included. Data were analyzed by parametric (i.e.: t-test, one way ANOVA and non parametric (Kruskal-Wallis test, Wilcoxon test tests. Correlation analysis was also performed by using the Spearman and Pearson tests. A p ≤ 0.05 was set as significant for all tests. All the blood components were compared for platelet (PLT, leukocyte (WBC, TGF-β1 and PDGF-BB concentrations. The effect of the breed, gender and age on these variables was analyzed. A P ≤ 0.05 was accepted as significant for all the tests. Results PLT counts were 1.8 and 0.6 times higher in P-PRP than in whole blood and PPP, respectively; WBC counts were 0.5 and 0.1 times lower in P-PRP, in comparison with whole blood and PPP, respectively. TGF-β1 and PDGF-BB concentrations were 2.3 and 262 times higher, respectively, in P-PRG than in plasma, and 0.59 and 0.48 times higher, respectively, in P-PRG than in PPG. P-PRG derived from CCH females or young horses presented significantly (P Conclusions Our results indicated that P-PRP obtained by a manual method was affected by intrinsic factors such as the breed, gender and age. Equine practitioners should be

  14. Acute cellular rejection is a risk factor for bronchiolitis obliterans syndrome independent of post-transplant baseline FEV1

    DEFF Research Database (Denmark)

    Burton, C.M.; Iversen, M.; Carlsen, J.;


    BACKGROUND: Post-transplant baseline forced expiratory volume in 1 second (FEV(1)) constitutes a systematic bias in analyses of bronchiolitis obliterans syndrome (BOS). This retrospective study evaluates risk factors for BOS adjusting for the confounding of post-transplant baseline FEV(1). METHODS...

  15. Regulation of the hypertonic stress response and other cellular functions by the Rel-like transcription factor NFAT5. (United States)

    Aramburu, José; Drews-Elger, Katherine; Estrada-Gelonch, Anaïs; Minguillón, Jordi; Morancho, Beatriz; Santiago, Verónica; López-Rodríguez, Cristina


    Stress, be it from environmental factors or intrinsic to the cell as result of growth and metabolism, can be harmful to cells. Mammalian cells have developed numerous mechanisms to respond to diverse forms of stress. These mechanisms combine signaling cascades and activation of gene expression programs to orchestrate an adaptive response that will allow the cell to survive and resume its normal functioning. In this review we will focus on the transcription factor NFAT5, a fundamental regulator of the response to osmotic stress in mammalian cells. Identified in 1999, NFAT5 is the latest addition to the Rel family, which comprises the NF-kappaB and NFATc proteins. Though in some of its structural and functional features NFAT5 is a hybrid between these two major groups of Rel proteins, it has unique characteristics that make it stand on its own as a third type of Rel transcription factor. Since its discovery, NFAT5 has been studied mostly in the context of the hypertonicity stress response. The advent of mouse models deficient in NFAT5 and other recent advances have confirmed a fundamental osmoprotective role for this factor in mammals, but also revealed features that suggest it may have a wider range of functions.

  16. Cellular Nuclear Export Factors TAP and Aly Are Required for HDAg-L-mediated Assembly of Hepatitis Delta Virus. (United States)

    Huang, Hsiu-Chen; Lee, Chung-Pei; Liu, Hui-Kang; Chang, Ming-Fu; Lai, Yu-Heng; Lee, Yu-Ching; Huang, Cheng


    Hepatitis delta virus (HDV) is a satellite virus of hepatitis B virus (HBV). HDV genome encodes two forms of hepatitis delta antigen (HDAg), small HDAg (HDAg-S), which is required for viral replication, and large HDAg (HDAg-L), which is essential for viral assembly. HDAg-L is identical to HDAg-S except that it bears a 19-amino acid extension at the C terminus. Both HDAgs contain a nuclear localization signal (NLS), but only HDAg-L contains a CRM1-independent nuclear export signal at its C terminus. The nuclear export activity of HDAg-L is important for HDV particle formation. However, the mechanisms of HDAg-L-mediated nuclear export of HDV ribonucleoprotein are not clear. In this study, the host cellular RNA export complex TAP-Aly was found to form a complex with HDAg-L, but not with an export-defective HDAg-L mutant, in which Pro(205) was replaced by Ala. HDAg-L was found to colocalize with TAP and Aly in the nucleus. The C-terminal domain of HDAg-L was shown to directly interact with the N terminus of TAP, whereas an HDAg-L mutant lacking the NLS failed to interact with full-length TAP. In addition, small hairpin RNA-mediated down-regulation of TAP or Aly reduced nuclear export of HDAg-L and assembly of HDV virions. Furthermore, a peptide, TAT-HDAg-L(198-210), containing the 10-amino acid TAT peptide and HDAg-L(198-210), inhibited the interaction between HDAg-L and TAP and blocked HDV virion assembly and secretion. These data demonstrate that formation and release of HDV particles are mediated by TAP and Aly.

  17. Transcription factors Mat2 and Znf2 operate cellular circuits orchestrating opposite- and same-sex mating in Cryptococcus neoformans.

    Directory of Open Access Journals (Sweden)

    Xiaorong Lin


    Full Text Available Cryptococcus neoformans is a human fungal pathogen that undergoes a dimorphic transition from a unicellular yeast to multicellular hyphae during opposite sex (mating and unisexual reproduction (same-sex mating. Opposite- and same-sex mating are induced by similar environmental conditions and involve many shared components, including the conserved pheromone sensing Cpk1 MAPK signal transduction cascade that governs the dimorphic switch in C. neoformans. However, the homeodomain cell identity proteins Sxi1alpha/Sxi2a encoded by the mating type locus that are essential for completion of sexual reproduction following cell-cell fusion during opposite-sex mating are dispensable for same-sex mating. Therefore, identification of downstream targets of the Cpk1 MAPK pathway holds the key to understanding molecular mechanisms governing the two distinct developmental fates. Thus far, homology-based approaches failed to identify downstream transcription factors which may therefore be species-specific. Here, we applied insertional mutagenesis via Agrobacterium-mediated transformation and transcription analysis using whole genome microarrays to identify factors involved in C. neoformans differentiation. Two transcription factors, Mat2 and Znf2, were identified as key regulators of hyphal growth during same- and opposite-sex mating. Mat2 is an HMG domain factor, and Znf2 is a zinc finger protein; neither is encoded by the mating type locus. Genetic, phenotypic, and transcriptional analyses of Mat2 and Znf2 provide evidence that Mat2 is a downstream transcription factor of the Cpk1 MAPK pathway whereas Znf2 functions as a more terminal hyphal morphogenesis determinant. Although the components of the MAPK pathway including Mat2 are not required for virulence in animal models, Znf2, as a hyphal morphology determinant, is a negative regulator of virulence. Further characterization of these elements and their target circuits will reveal genes controlling biological

  18. Multiuser Cellular Network

    CERN Document Server

    Bao, Yi; Chen, Ming


    Modern radio communication is faced with a problem about how to distribute restricted frequency to users in a certain space. Since our task is to minimize the number of repeaters, a natural idea is enlarging coverage area. However, coverage has restrictions. First, service area has to be divided economically as repeater's coverage is limited. In this paper, our fundamental method is to adopt seamless cellular network division. Second, underlying physics content in frequency distribution problem is interference between two close frequencies. Consequently, we choose a proper frequency width of 0.1MHz and a relevantly reliable setting to apply one frequency several times. We make a few general assumptions to simplify real situation. For instance, immobile users yield to homogenous distribution; repeaters can receive and transmit information in any given frequency in duplex operation; coverage is mainly decided by antenna height. Two models are built up to solve 1000 users and 10000 users situations respectively....

  19. Evaluation of udder health parameters and risk factors for clinical mastitis in Dutch dairy herds in the context of a restricted antimicrobial usage policy. (United States)

    Santman-Berends, I M G A; Swinkels, J M; Lam, T J G M; Keurentjes, J; van Schaik, G


    study indicated that udder health had not deteriorated compared with udder health in previous Dutch studies where herd sizes were somewhat smaller and before the restrictions in antimicrobial use. Several of the risk factors that were found can be influenced by the farmer and can prevent the occurrence of CMI. Still, when cases of CM occur, treatment with antimicrobials might be necessary to cure the CM case and is beneficial for the overall udder health in the herd.

  20. Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

    Institute of Scientific and Technical Information of China (English)

    Amr M.GHALEB; Mandayam O.NANDAN; Sengthong CHANCHEVALAP; W.Brian DALTON; Irfan M.HISAMUDDIN; Vincent W.YANG


    Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverse regulatory functions in cell growth, proliferation, differentiation, and embryogenesis. KLF4 and KLF5 are two closely related members of the KLF family that have a similar tissue distribution in embryos and adults. However, the two KLFs often exhibit opposite effects on regulation of gene transcription, despite binding to similar, if not identical, cis-acting DNA sequences. In addition, KLF4 and 5 exert contrasting effects on cell proliferation in many instances; while KLF4is an inhibitor of cell growth, KLF5 stimulates proliferation. Here we review the biological properties and biochemical mechanisms of action of the two KLFs in the context of growth regulation.

  1. Cellular organization of pre-mRNA splicing factors in several tissues. Changes in the uterus by hormone action. (United States)

    George-Téllez, R; Segura-Valdez, M L; González-Santos, L; Jiménez-García, L F


    In the mammalian cell nucleus, splicing factors are distributed in nuclear domains known as speckles or splicing factor compartments (SFCs). In cultured cells, these domains are dynamic and reflect transcriptional and splicing activities. We used immunofluorescence and confocal microscopy to monitor whether splicing factors in differentiated cells display similar features. Speckled patterns are observed in rat hepatocytes, beta-cells, bronchial and intestine epithelia and also in three cell types of the uterus. Moreover, the number, distribution and sizes of the speckles vary among them. In addition, we studied variations in the circular form (shape) of speckles in uterine cells that are transcriptionally modified by a hormone action. During proestrus of the estral cycle, speckles are irregular in shape while in diestrus I they are circular. Experimentally, in castrated rats luminal epithelial cells show a pattern where speckles are dramatically rounded, but they recover their irregular shape rapidly after an injection of estradiol. The same results were observed in muscle and gland epithelial cells of the uterus. We concluded that different speckled patterns are present in various cells types in differentiated tissues and that these patterns change in the uterus depending upon the presence or absence of hormones such as estradiol.

  2. Poxvirus tumor necrosis factor receptor (TNFR)-like T2 proteins contain a conserved preligand assembly domain that inhibits cellular TNFR1-induced cell death. (United States)

    Sedger, Lisa M; Osvath, Sarah R; Xu, Xiao-Ming; Li, Grace; Chan, Francis K-M; Barrett, John W; McFadden, Grant


    The poxvirus tumor necrosis factor receptor (TNFR) homologue T2 has immunomodulatory properties; secreted myxoma virus T2 (M-T2) protein binds and inhibits rabbit TNF-alpha, while intracellular M-T2 blocks virus-induced lymphocyte apoptosis. Here, we define the antiapoptotic function as inhibition of TNFR-mediated death via a highly conserved viral preligand assembly domain (vPLAD). Jurkat cell lines constitutively expressing M-T2 were generated and shown to be resistant to UV irradiation-, etoposide-, and cycloheximide-induced death. These cells were also resistant to human TNF-alpha, but M-T2 expression did not alter surface expression levels of TNFRs. Previous studies indicated that T2's antiapoptotic function was conferred by the N-terminal region of the protein, and further examination of this region revealed a highly conserved N-terminal vPLAD, which is present in all poxvirus T2-like molecules. In cellular TNFRs and TNF-alpha-related apoptosis-inducing ligand (TRAIL) receptors (TRAILRs), PLAD controls receptor signaling competency prior to ligand binding. Here, we show that M-T2 potently inhibits TNFR1-induced death in a manner requiring the M-T2 vPLAD. Furthermore, we demonstrate that M-T2 physically associates with and colocalizes with human TNFRs but does not prevent human TNF-alpha binding to cellular receptors. Thus, M-T2 vPLAD is a species-nonspecific dominant-negative inhibitor of cellular TNFR1 function. Given that the PLAD is conserved in all known poxvirus T2-like molecules, we predict that it plays an important function in each of these proteins. Moreover, that the vPLAD confers an important antiapoptotic function confirms this domain as a potential target in the development of the next generation of TNF-alpha/TNFR therapeutics.

  3. 制约辽宁省居民消费能力提升的因素%Restrictive Factors To Enhance Consumption Capacity Of Liaoning Province Residents

    Institute of Scientific and Technical Information of China (English)



    Insufficient household consumption has become a great obstacle to develop economy.It also profoundly affects the coordinated development of investment,consumption and export.The overall consumption ability of liaoning province residents is insufficient.According to analysis,we suggest that unreasonable resident income distribution,lower consumption concept,lower expectation of social security in the future and imperfect consumption environment become restrictive factors to enhance ability of residents'consumption in liaoning and then we put forward countermeasures and suggestions.Finally we hope realize the new pattern of consumption,investment and export to drive economic growth.%居民消费不足已成为经济发展的巨大障碍,也影响着投资、消费、出口的协调发展. 辽宁省居民的总体消费能力不足,通过分析得出,居民收入分配不合理、消费理念偏低、未来保障预期低以及消费环境不完善等都成为制约辽宁居民消费能力提升的因素,据此提出对策建议,最终实现消费、投资、出口协同驱动经济增长的新格局.

  4. Development of a polymerase chain reaction-restriction fragment length polymorphism method for identification of the Fusarium genus using the transcription elongation factor-1α gene. (United States)

    Zarrin, Majid; Ganj, Farzaneh; Faramarzi, Sama


    Fusarium species are well-known plant pathogens and food contaminants that have also appeared as one of the most important groups of medically significant fungi. The sequences of the translation elongation factor (TEF)-1α gene have been broadly employed for species detection. A total of 50 strains of Fusarium spp., including environmental, clinical and reference isolates were used for the current study. The primer sets, Fu3f and Fu3r, were used to amplify an ~420-bp DNA fragment of the TEF-1α gene. Double digestion with two restriction enzymes, XhoI and SduI was used for discrimination of the Fusarium species in the TEF-1α gene fragment. Double digestion of the TEF-1α gene fragment from five clinically important Fusarium species were clearly differentiated from each other: The F. solani species complex, F. oxysporum species complex, F. verticillioides, F. proliferatum and F. fujikuroi. This method facilitates detection and enables verification of the Fusarium genus; therefore, it may be applied for disease control.

  5. The effects of the calcium-restricted diet of urolithiasis patients with absorptive hypercalciuria type II on risk factors for kidney stones and osteopenia

    NARCIS (Netherlands)

    Faassen, A. van; Ploeg, E.M.C. van der; Habets, H.M.L.; Meer, R. van der; Hermus, R.J.J.; Janknegt, R.A.


    The calcium (Ca)-restricted diet of urolithiasis patients with absorptive hypercalciuria type II may decrease Ca excretion but increase biochemical markers of risk for osteopenia. We randomly allocated 25 patients from six hospitals into an experimental group (Ca restriction to 500 mg/day, oxalate-r

  6. Cellular Telephone

    Institute of Scientific and Technical Information of China (English)



    Cellular phones, used in automobiles, airliners, and passenger trains, are basically low-power radiotelephones. Calls go through radio transmitters that are located within small geographical units called cells. Because each cell’s signals are too weak to interfere with those of other cells operating on the same fre-

  7. Attenuation of the suppressive activity of cellular splicing factor SRSF3 by Kaposi sarcoma-associated herpesvirus ORF57 protein is required for RNA splicing. (United States)

    Majerciak, Vladimir; Lu, Mathew; Li, Xiaofan; Zheng, Zhi-Ming


    Kaposi sarcoma-associated herpesvirus (KSHV) ORF57 is a multifunctional post-transcriptional regulator essential for viral gene expression during KSHV lytic infection. ORF57 requires interactions with various cellular proteins for its function. Here, we identified serine/arginine-rich splicing factor 3 (SRSF3, formerly known as SRp20) as a cellular cofactor involved in ORF57-mediated splicing of KSHV K8β RNA. In the absence of ORF57, SRSF3 binds to a suboptimal K8β intron and inhibits K8β splicing. Knockdown of SRSF3 promotes K8β splicing, mimicking the effect of ORF57. The N-terminal half of ORF57 binds to the RNA recognition motif of SRSF3, which prevents SRSF3 from associating with the K8β intron RNA and therefore attenuates the suppressive effect of SRSF3 on K8β splicing. ORF57 also promotes splicing of heterologous non-KSHV transcripts that are negatively regulated by SRSF3, indicating that the effect of ORF57 on SRSF3 activity is independent of RNA target. SPEN proteins, previously identified as ORF57-interacting partners, suppress ORF57 splicing activity by displacing ORF57 from SRSF3-RNA complexes. In summary, we have identified modulation of SRSF3 activity as the molecular mechanism by which ORF57 promotes RNA splicing.

  8. Tips and step-by-step protocol for the optimization of important factors affecting cellular enzyme-linked immunosorbent assay (CELISA). (United States)

    Morandini, R; Boeynaems, J M; Wérenne, J; Ghanem, G


    CELISA, or cellular enzyme-linked immunosorbent assay, is a powerful and easy to use technique to study cell surface antigens under different stimulations. Nevertheless, some factors must be discussed and optimized prior to reaching a reproducible CELISA. These include the choice of cell density, fixative agent, blocking agent, culture medium, optimal antibody dilutions, and incubation time. In this paper, we first present a short review of some references devoted to CELISA by means of a comparison of these parameters, followed by their description. Then, we describe and study these different parameters using practical examples comparing TNF-induced ICAM-1 expression as an end point, on HBL melanoma and HUVEC. These cell lines were also chosen because they differ in their ability to grow as discontinuous and continuous layers, respectively. Furthermore, we designed a comprehensive flow chart, as well as a complete step-by-step protocol for CELISA optimization.

  9. The effect of platelet-derived growth factor on the cellular response of the periodontium: an autoradiographic study on dogs. (United States)

    Wang, H L; Pappert, T D; Castelli, W A; Chiego, D J; Shyr, Y; Smith, B A


    Platelet-derived growth factor (PDGF) is a polypeptide growth factor considered to have a role in the proliferation and migration of fibroblasts at a wound healing site. The aim of this investigation was to determine if PDGF, when applied to root surfaces, would stimulate the proliferation of fibroblasts and further enhance regeneration. Six mongrel dogs with healthy periodontia were selected for this study. Using a closed wound surgical model, standardized 4 x 4 mm fenestration defects were created into dentin on the mid-facial of the mesial and distal roots of 4 mandibular posterior teeth in each quadrant. Each defect received either: 1) saline solution (C); 2) expanded polytetrafluoroethylene (ePTFE) membrane; 3) PDGF; or 4) ePTFE + PDGF. 3H-thymidine was administered 1 hour prior to animal sacrifice at 1, 3, and 7 days postsurgery. Each time period included 2 dogs with each dog undergoing the four different treatments. Slides were prepared for autoradiography. 3H-thymidine-labeled cells were counted and results were statistically analyzed using the Bonferroni (Dunn) t test on the SAS program. Results indicated PDGF enhanced fibroblast proliferation when compared to the groups without PDGF. Significant differences (P < 0.05) were noted at day 1 and 7 when PDGF and PDGF + GT were compared to C and GT groups. No significant differences were observed in labeled fibroblasts between the C and GT groups at any time period. These findings suggest that PDGF enhances fibroblast proliferation in early periodontal wound healing, whether used alone or in combination with the ePTFE membrane.

  10. Suppression of Transforming Growth Factor-β Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived From Human Pluripotent Stem Cells. (United States)

    Bai, Hao; Gao, Yongxing; Hoyle, Dixie L; Cheng, Tao; Wang, Zack Z


    : Transplantation of vascular cells derived from human pluripotent stem cells (hPSCs) offers an attractive noninvasive method for repairing the ischemic tissues and for preventing the progression of vascular diseases. Here, we found that in a serum-free condition, the proliferation rate of hPSC-derived endothelial cells is quickly decreased, accompanied with an increased cellular senescence, resulting in impaired gene expression of endothelial nitric oxide synthase (eNOS) and impaired vessel forming capability in vitro and in vivo. To overcome the limited expansion of hPSC-derived endothelial cells, we screened small molecules for specific signaling pathways and found that inhibition of transforming growth factor-β (TGF-β) signaling significantly retarded cellular senescence and increased a proliferative index of hPSC-derived endothelial cells. Inhibition of TGF-β signaling extended the life span of hPSC-derived endothelial and improved endothelial functions, including vascular network formation on Matrigel, acetylated low-density lipoprotein uptake, and eNOS expression. Exogenous transforming growth factor-β1 increased the gene expression of cyclin-dependent kinase inhibitors, p15(Ink4b), p16(Ink4a), and p21(CIP1), in endothelial cells. Conversely, inhibition of TGF-β reduced the gene expression of p15(Ink4b), p16(Ink4a), and p21(CIP1). Our findings demonstrate that the senescence of newly generated endothelial cells from hPSCs is mediated by TGF-β signaling, and manipulation of TGF-β signaling offers a potential target to prevent vascular aging.

  11. Comprehensive Identification of Kruppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming.

    Directory of Open Access Journals (Sweden)

    Hyojung Jeon

    Full Text Available Pluripotency is maintained in mouse embryonic stem (ES cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Krüppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naïve pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.

  12. Nutrient-deprivation autophagy factor-1 (NAF-1: biochemical properties of a novel cellular target for anti-diabetic drugs.

    Directory of Open Access Journals (Sweden)

    Sagi Tamir

    Full Text Available Nutrient-deprivation autophagy factor-1 (NAF-1 (synonyms: Cisd2, Eris, Miner1, and Noxp70 is a [2Fe-2S] cluster protein immune-detected both in endoplasmic reticulum (ER and mitochondrial outer membrane. It was implicated in human pathology (Wolfram Syndrome 2 and in BCL-2 mediated antagonization of Beclin 1-dependent autophagy and depression of ER calcium stores. To gain insights about NAF-1 functions, we investigated the biochemical properties of its 2Fe-2S cluster and sensitivity of those properties to small molecules. The structure of the soluble domain of NAF-1 shows that it forms a homodimer with each protomer containing a [2Fe-2S] cluster bound by 3 Cys and one His. NAF-1 has shown the unusual abilities to transfer its 2Fe-2S cluster to an apo-acceptor protein (followed in vitro by spectrophotometry and by native PAGE electrophoresis and to transfer iron to intact mitochondria in cell models (monitored by fluorescence imaging with iron fluorescent sensors targeted to mitochondria. Importantly, the drug pioglitazone abrogates NAF-1's ability to transfer the cluster to acceptor proteins and iron to mitochondria. Similar effects were found for the anti-diabetes and longevity-promoting antioxidant resveratrol. These results reveal NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs like pioglitazone and of the natural product resveratrol, both of which interact with the protein and stabilize its labile [2Fe-2S] cluster.

  13. Differential effects of Sp cellular transcription factors on viral promoter activation by varicella-zoster virus (VZV) IE62 protein. (United States)

    Khalil, Mohamed I; Ruyechan, William T; Hay, John; Arvin, Ann


    The immediate early (IE) 62 protein is the major varicella-zoster virus (VZV) regulatory factor. Analysis of the VZV genome revealed 40 predicted GC-rich boxes within 36 promoters. We examined effects of ectopic expression of Sp1-Sp4 on IE62- mediated transactivation of three viral promoters. Ectopic expression of Sp3 and Sp4 enhanced IE62 activation of ORF3 and gI promoters while Sp3 reduced IE62 activation of ORF28/29 promoter and VZV DNA replication. Sp2 reduced IE62 transactivation of gI while Sp1 had no significant influence on IE62 activation with any of these viral promoters. Electrophoretic mobility shift assays (EMSA) confirmed binding of Sp1 and Sp3 but not Sp2 and Sp4 to the gI promoter. Sp1-4 bound to IE62 and amino acids 238-258 of IE62 were important for the interaction with Sp3 and Sp4 as well as Sp1. This work shows that Sp family members have differential effects on IE62-mediated transactivation in a promoter-dependent manner.

  14. HIV-1 infection induces changes in expression of cellular splicing factors that regulate alternative viral splicing and virus production in macrophages

    Directory of Open Access Journals (Sweden)

    Purcell Damian FJ


    Full Text Available Abstract Background Macrophages are important targets and long-lived reservoirs of HIV-1, which are not cleared of infection by currently available treatments. In the primary monocyte-derived macrophage model of infection, replication is initially productive followed by a decline in virion output over ensuing weeks, coincident with a decrease in the levels of the essential viral transactivator protein Tat. We investigated two possible mechanisms in macrophages for regulation of viral replication, which appears to be primarily regulated at the level of tat mRNA: 1 differential mRNA stability, used by cells and some viruses for the rapid regulation of gene expression and 2 control of HIV-1 alternative splicing, which is essential for optimal viral replication. Results Following termination of transcription at increasing times after infection in macrophages, we found that tat mRNA did indeed decay more rapidly than rev or nef mRNA, but with similar kinetics throughout infection. In addition, tat mRNA decayed at least as rapidly in peripheral blood lymphocytes. Expression of cellular splicing factors in uninfected and infected macrophage cultures from the same donor showed an inverse pattern over time between enhancing factors (members of the SR family of RNA binding proteins and inhibitory factors (members of the hnRNP family. While levels of the SR protein SC35 were greatly up-regulated in the first week or two after infection, hnRNPs of the A/B and H groups were down-regulated. Around the peak of virus production in each culture, SC35 expression declined to levels in uninfected cells or lower, while the hnRNPs increased to control levels or above. We also found evidence for increased cytoplasmic expression of SC35 following long-term infection. Conclusion While no evidence of differential regulation of tat mRNA decay was found in macrophages following HIV-1 infection, changes in the balance of cellular splicing factors which regulate alternative

  15. Somatotropin as the non-ACTH factor of anterior pituitary origin for the maintenance of enhanced aldosterone secretory responsiveness of dietary sodium restriction in chronically hypophysectomized rats

    NARCIS (Netherlands)

    Lee, T.C.; Wied, D. de


    Somatotropin treatment in chronically hypophysectomized, sodium-deprived rats effectively restored to treated animals the distinct and enhanced aldosterone secretory responsiveness of the adrenal which characterizes the adrenals of intact rats subjected to dietary sodium restriction, but absent in c

  16. The Factors Restricting the Sustainable Development of the Borderland of Southwest China%西南边疆可持续发展制约因素研究

    Institute of Scientific and Technical Information of China (English)



    Sustainable development is a must in the strategic choices of all countries and regions of the world. Facing the transitional period and quick development, the borderland of China should also stick to this choice. The borderland of southwest China occupies a strategically important position but has a quite a few factors restricting its sustainable development like the poor transportation system, relatively slow social and economic development and a worsening ecology. The solutions to these problems include the adherence to the concept of scientific development, the control of the population growth and the improvement of the population quality, the optimizing of the industrial structure, strengthen self-reliance, protect the ecology and deal well with all the relationships in the social development.%可持续发展是当今世界和各地区长期发展战略的必然选择,对我国正处在急剧转型期和加速发展的边疆,更应坚持这一发展战略选择.西南边疆是我国地缘战略位置极为重要的地区,又是交通不便、产业结构层次低、社会经济发展滞后、贫困面大、生态恶化加剧的地区.针对西南边疆可持续发展面临的制约因素,必须坚持科学发展观,控制人口过快增长和提高人口素质,调整优化产业结构,增强自我发展能力,保护生态环境,正确处理好社会发展中的各种关系.

  17. 学风建设的制约因素和对策研究%Research on restrictive factors and countermeasures of the study style construction

    Institute of Scientific and Technical Information of China (English)



    学风问题在学校的生存和发展以及学生的成长成才过程中都处于重要的地位。影响和制约学风建设的因素主要有社会的、学校的、教师和学生本身的因素。靠完善的制度来规范学风建设,靠高尚的师德来引领学风建设,靠严格的管理来推进学风建设,靠榜样的示范作用带动学风建设,靠亲情的力量促进学风建设,是学风建设的有效对策和路径。%It is important problem of study style in the growth process of the survival and development of schools and students. Factors affecting and restricting the construction of study style are mainly social, school, teachers and students themselves. Relying on perfect system to regulate the construction of study style, by the noble morality to guide the construction of style of study, by strict management to promote the construction of style of study, an exemplary role model driven by the construction of study style, by the strength of family ties and promote the construction of study style, is the effective countermeasures and path of the construction of study style.

  18. Calorie restriction decreases murine and human pancreatic tumor cell growth, nuclear factor-κB activation, and inflammation-related gene expression in an insulin-like growth factor-1-dependent manner.

    Directory of Open Access Journals (Sweden)

    Alison E Harvey

    Full Text Available Calorie restriction (CR prevents obesity and has potent anticancer effects that may be mediated through its ability to reduce serum growth and inflammatory factors, particularly insulin-like growth factor (IGF-1 and protumorigenic cytokines. IGF-1 is a nutrient-responsive growth factor that activates the inflammatory regulator nuclear factor (NF-κB, which is linked to many types of cancers, including pancreatic cancer. We hypothesized that CR would inhibit pancreatic tumor growth through modulation of IGF-1-stimulated NF-κB activation and protumorigenic gene expression. To test this, 30 male C57BL/6 mice were randomized to either a control diet consumed ad libitum or a 30% CR diet administered in daily aliquots for 21 weeks, then were subcutaneously injected with syngeneic mouse pancreatic cancer cells (Panc02 and tumor growth was monitored for 5 weeks. Relative to controls, CR mice weighed less and had decreased serum IGF-1 levels and smaller tumors. Also, CR tumors demonstrated a 70% decrease in the expression of genes encoding the pro-inflammatory factors S100a9 and F4/80, and a 56% decrease in the macrophage chemoattractant, Ccl2. Similar CR effects on tumor growth and NF-κB-related gene expression were observed in a separate study of transplanted MiaPaCa-2 human pancreatic tumor cell growth in nude mice. In vitro analyses in Panc02 cells showed that IGF-1 treatment promoted NF-κB nuclear localization, increased DNA-binding of p65 and transcriptional activation, and increased expression of NF-κB downstream genes. Finally, the IGF-1-induced increase in expression of genes downstream of NF-κB (Ccdn1, Vegf, Birc5, and Ptgs2 was decreased significantly in the context of silenced p65. These findings suggest that the inhibitory effects of CR on Panc02 pancreatic tumor growth are associated with reduced IGF-1-dependent NF-κB activation.

  19. The collagen triple helix repeat containing 1 facilitates hepatitis B virus-associated hepatocellular carcinoma progression by regulating multiple cellular factors and signal cascades. (United States)

    Zhang, Rui; Cao, Yanhua; Bai, Lan; Zhu, Chengliang; Li, Rui; He, Hui; Liu, Yingle; Wu, Kailang; Liu, Fang; Wu, Jianguo


    Hepatitis B virus (HBV) infection is one of the major causes of acute and chronic liver diseases, fulminant hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HCC accounts for more than 85% of primary liver cancers and is the seventh most common cancer and the third leading cause of cancer-related deaths. However, the mechanism by which HBV induces HCC is largely unknown. Collagen triple helixes repeat containing 1 (CTHRC1) is a secreted protein and has characteristics of a circulating hormone with potentially broad implications for cell metabolism and physiology. CTHRC1 is associated with human cancers, but its effect on HCC is unknown. Here, we revealed that CTHRC1 expression is highly correlated with HCC progression in HBV-infected patients, and demonstrated that HBV stimulates CTHRC1 expression by activating nuclear factor-kappa B (NF-κB) and cAMP response element binding protein (CREB), through extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/c-JNK) pathway. In addition, CTHRC1 activates hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) through regulating phosphoinosmde-3-kinase/protein kinase B/mammalian target of rapamycin (PI-3K/AKT/mTOR) pathway. More interestingly, CTHRC1 enhances colony formation, migration, and invasion of hepatoma cells by regulating p53 and stimulating matrix metalloproteinase-9 (MMP-9) expression. In addition, knock-down of CTHRC1 results in the repression of HBV-associated carcinogenesis in nude mice. Thus, we revealed a novel mechanism by which HBV facilitates HCC development through activating the oncoprotein CTHRC1, which in turn enhances HBV-related HCC progression by stimulates colony formation, migration, and invasion of hepatoma cells through regulating multiple cellular factors and signal cascades.

  20. Replication-Coupled Recruitment of Viral and Cellular Factors to Herpes Simplex Virus Type 1 Replication Forks for the Maintenance and Expression of Viral Genomes (United States)

    Dembowski, Jill A.


    Herpes simplex virus type 1 (HSV-1) infects over half the human population. Much of the infectious cycle occurs in the nucleus of cells where the virus has evolved mechanisms to manipulate host processes for the production of virus. The genome of HSV-1 is coordinately expressed, maintained, and replicated such that progeny virions are produced within 4–6 hours post infection. In this study, we selectively purify HSV-1 replication forks and associated proteins from virus-infected cells and identify select viral and cellular replication, repair, and transcription factors that associate with viral replication forks. Pulse chase analyses and imaging studies reveal temporal and spatial dynamics between viral replication forks and associated proteins and demonstrate that several DNA repair complexes and key transcription factors are recruited to or near replication forks. Consistent with these observations we show that the initiation of viral DNA replication is sufficient to license late gene transcription. These data provide insight into mechanisms that couple HSV-1 DNA replication with transcription and repair for the coordinated expression and maintenance of the viral genome. PMID:28095497

  1. Cellular inhibitor of apoptosis protein-1 (cIAP1) can regulate E2F1 transcription factor-mediated control of cyclin transcription. (United States)

    Cartier, Jessy; Berthelet, Jean; Marivin, Arthur; Gemble, Simon; Edmond, Valérie; Plenchette, Stéphanie; Lagrange, Brice; Hammann, Arlette; Dupoux, Alban; Delva, Laurent; Eymin, Béatrice; Solary, Eric; Dubrez, Laurence


    The inhibitor of apoptosis protein cIAP1 (cellular inhibitor of apoptosis protein-1) is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-κB signaling pathways in the cytoplasm. However, in some primary cells and tumor cell lines, cIAP1 is expressed in the nucleus, and its nuclear function remains poorly understood. Here, we show that the N-terminal part of cIAP1 directly interacts with the DNA binding domain of the E2F1 transcription factor. cIAP1 dramatically increases the transcriptional activity of E2F1 on synthetic and CCNE promoters. This function is not conserved for cIAP2 and XIAP, which are cytoplasmic proteins. Chromatin immunoprecipitation experiments demonstrate that cIAP1 is recruited on E2F binding sites of the CCNE and CCNA promoters in a cell cycle- and differentiation-dependent manner. cIAP1 silencing inhibits E2F1 DNA binding and E2F1-mediated transcriptional activation of the CCNE gene. In cells that express a nuclear cIAP1 such as HeLa, THP1 cells and primary human mammary epithelial cells, down-regulation of cIAP1 inhibits cyclin E and A expression and cell proliferation. We conclude that one of the functions of cIAP1 when localized in the nucleus is to regulate E2F1 transcriptional activity.

  2. The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels. (United States)

    Miles, Anna L; Burr, Stephen P; Grice, Guinevere L; Nathan, James A


    Hypoxia Inducible transcription Factors (HIFs) are principally regulated by the 2-oxoglutarate and Iron(II) prolyl hydroxylase (PHD) enzymes, which hydroxylate the HIFα subunit, facilitating its proteasome-mediated degradation. Observations that HIFα hydroxylation can be impaired even when oxygen is sufficient emphasise the importance of understanding the complex nature of PHD regulation. Here, we use an unbiased genome-wide genetic screen in near-haploid human cells to uncover cellular processes that regulate HIF1α. We identify that genetic disruption of the Vacuolar H+ ATPase (V-ATPase), the key proton pump for endo-lysosomal acidification, and two previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115, stabilise HIF1α in aerobic conditions. Rather than preventing the lysosomal degradation of HIF1α, disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation. Iron supplementation directly restores PHD catalytic activity following V-ATPase inhibition, revealing important links between the V-ATPase, iron metabolism and HIFs.

  3. Mangiferin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-κB activity. (United States)

    Dilshara, Matharage Gayani; Kang, Chang-Hee; Choi, Yung Hyun; Kim, Gi-Young


    We investigated the effects of mangiferin on the expression and activity of metalloproteinase (MMP)-9 and the invasion of tumor necrosis factor (TNF)-α-stimulated human LNCaP prostate carcinoma cells. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that mangiferin significantly reversed TNF-α-induced mRNA and protein expression of MMP-9 expression. Zymography data confirmed that stimulation of cells with TNF-α significantly increased MMP-9 activity. However, mangiferin substantially reduced the TNF-α-induced activity of MMP-9. Additionally, a matrigel invasion assay showed that mangiferin significantly reduced TNF-α-induced invasion of LNCaP cells. Compared to untreated controls, TNF-α-stimulated LNCaP cells showed a significant increase in nuclear factor-κB (NF-κB) luciferase activity. However, mangiferin treatment markedly decreased TNF-α-induced NF-κB luciferase activity. Furthermore, mangiferin suppressed nuclear translocation of the NF-κB subunits p65 and p50. Collectively, our results indicate that mangiferin is a potential anti-invasive agent that acts by suppressing NF-κB-mediated MMP-9 expression.

  4. Logistic regression analysis on risk factors of fetal growth restriction%胎儿生长受限高危因素的Logistic回归分析

    Institute of Scientific and Technical Information of China (English)

    陈忠; 许建娟


    Objective: To explore the risk factors of fetal growth restriction (FGR) . Methods: A 1: 1 matched case - control study was conducted. The clinical data of 276 neonates with FGR (FGR group) and 276 neonates with normal weight (normal group) born in the hospital and the parturient women in 2011 were analyzed retrospectively. Results; There were statistically significant differences in maternal age, educational level, family monthly income, smoking, drinking tea, history of gestational infection, gestational complications, and fetal age of neonates between FGR group and normal group ( P < 0.05) . Taking neonatal weight as dependent variable, and taking the other factors as independent variables, non - conditional logistic regression analysis was conducted, the results showed that there were statistically significant differences in maternal age, educational level, family monthly income, smoking, drinking tea, history of gestational infection, gestational complications, and fetal age of neonates (P < 0.05) . Conclusion: High maternal age, low educational level, low family monthly income, smoking, drinking tea, history of gestational infection, gestational complications, and low fetal age of neonates are high risk factors of FGR. Active prevention targeting to the above - mentioned high risk factors during gestational period should be conducted to reduce the occurrence of FGR.%目的:探讨胎儿生长受限(FGR)发生的高危因素.方法:采用1∶1配比的病例对照研究设计,对2011年在该院分娩的276例FGR新生儿(FGR组)及276例正常体重新生儿(正常组)及其产妇病历资料进行回顾性分析.结果:FGR组与正常组在产妇年龄、文化程度、家庭月收入、吸烟、饮茶、妊娠期感染史、妊娠期合并症、妊娠期并发症、新生儿胎龄等单因素方面比较存在差异,差异有统计学意义(P<0.05);以新生儿体重为因变量,其他因素为自变量,进行非条件性的Logistic多因素分析,结果

  5. 我国扩大消费的制约因素及对策研究%Research on the restricting factors and countermeasures of expanding spending power

    Institute of Scientific and Technical Information of China (English)



    随着经济社会的进一步发展,传统经济发展模式的弊端逐渐显露出来。要克服传统经济发展模式的弊端,需要转变经济发展方式,建立以消费为主导,消费、投资和出口协调拉动的经济发展模式。通过论述经济与社会发展之间的关系,探讨制约我国扩大消费实践中存在的制约因素,并针对这些影响因素提出合理的政策建议。首先,论证建立以消费为主导的发展模式,是实现经济社会可持续发展的必由之路;其次,分别分析现行分配制度、经济发展模式和供给结构对扩大消费的制约作用;最后,将扩大消费的对策放在限制政府对市场的干预行为,提高居民的收入水平、完善消费品供给结构、提高农民收入、健全基本公共服务体系、稳定物价等6个方面。%With the development of economy and community, the traditional economic growth mode reveals its disadvantages. The proportion of consumption must be increased to get over the difficulty. This article looks for the restraining factors which hinder the expansion of consumption by analyzing the relationship between the economic and social development. First, we can arrive at conclusion from the analysis that it is the only way of social and economic sustainable develop- ment to establish consumption for the leading model of development; Second, the paper analyzes consumption restriction role of the distribution system, the model of economic development and the supply structure. Third, the article focuses the points of application on limiting the govern- ment to market intervention behavior;raising the income level of resident;perfecting goods supply structure;improving farmers' income;constructing basic public service system and stabilizing com- modity prices.

  6. Inhibition of a NEDD8 Cascade Restores Restriction of HIV by APOBEC3G.

    Directory of Open Access Journals (Sweden)

    David J Stanley


    Full Text Available Cellular restriction factors help to defend humans against human immunodeficiency virus (HIV. HIV accessory proteins hijack at least three different Cullin-RING ubiquitin ligases, which must be activated by the small ubiquitin-like protein NEDD8, in order to counteract host cellular restriction factors. We found that conjugation of NEDD8 to Cullin-5 by the NEDD8-conjugating enzyme UBE2F is required for HIV Vif-mediated degradation of the host restriction factor APOBEC3G (A3G. Pharmacological inhibition of the NEDD8 E1 by MLN4924 or knockdown of either UBE2F or its RING-protein binding partner RBX2 bypasses the effect of Vif, restoring the restriction of HIV by A3G. NMR mapping and mutational analyses define specificity determinants of the UBE2F NEDD8 cascade. These studies demonstrate that disrupting host NEDD8 cascades presents a novel antiretroviral therapeutic approach enhancing the ability of the immune system to combat HIV.

  7. Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain. (United States)

    Laflamme, N; Rivest, S


    Expression of the inhibitory factor kappaB alpha (IkappaB alpha) reflects the activity of nuclear factor kappaB(NF-kappaB) and is a powerful tool to investigate the regulation of the transcription factor within the CNS. IkappaB alpha mRNA was evaluated in the rat brain by means of in situ hybridization following different immunogenic stimuli; i.e., intraperitoneal (i.p.) and intravenous (i.v.) lipopolysaccharide (LPS), i.v. recombinant rat interleukin (IL) 1beta, IL-6, or tumor necrosis factor-alpha (TNF-alpha), and intramuscular (i.m.) turpentine injection, used here as a model of systemic localized inflammatory insult. Systemic LPS, IL-1beta, and TNF-alpha caused a rapid and transient transcriptional activation of IkappaB alpha along the blood vessels of the entire brain; the signal was very intense 30-60 min after the i.v. injections and returned to undetectable levels from 2 to 12 h depending on the challenge. Double-labeling procedure provided the anatomical evidence that IkappaB alpha-expressing cells within the microvasculature were essentially of the endothelial type, as they were immunoreactive to the von Willebrand factor. Scattered small cells were also found across the brain of LPS-, IL-1beta-, and TNF-alpha-injected rats at time 1-3 h, and microglial (OX-42)-immunoreactive cells were positive for the transcript. Such expression within parenchymal microglia was nevertheless not observed in the brain following a localized and sterile inflammatory insult. Indeed, i.m. turpentine administration stimulated IkappaB alpha transcription quite uniquely within the endothelium of the brain capillaries, an effect that paralleled the swelling of the injection site and lasted up to 24 h after the aggression. In contrast to these immunogenic challenges, i.v. IL-6 injection failed to activate the gene encoding IkappaB alpha in the rat brain. These results indicate that NF-kappaB may play a crucial role in specific cellular populations of the CNS to trigger

  8. Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag

    Directory of Open Access Journals (Sweden)

    Woods Matthew W


    Full Text Available Abstract Background The identification and characterization of several interferon (IFN-induced cellular HIV-1 restriction factors, defined as host cellular proteins or factors that restrict or inhibit the HIV-1 life cycle, have provided insight into the IFN response towards HIV-1 infection and identified new therapeutic targets for HIV-1 infection. To further characterize the mechanism underlying restriction of the late stages of HIV-1 replication, we assessed the ability of IFNbeta-induced genes to restrict HIV-1 Gag particle production and have identified a potentially novel host factor called HECT domain and RCC1-like domain-containing protein 5 (HERC5 that blocks a unique late stage of the HIV-1 life cycle. Results HERC5 inhibited the replication of HIV-1 over multiple rounds of infection and was found to target a late stage of HIV-1 particle production. The E3 ligase activity of HERC5 was required for blocking HIV-1 Gag particle production and correlated with the post-translational modification of Gag with ISG15. HERC5 interacted with HIV-1 Gag and did not alter trafficking of HIV-1 Gag to the plasma membrane. Electron microscopy revealed that the assembly of HIV-1 Gag particles was arrested at the plasma membrane, at an early stage of assembly. The mechanism of HERC5-induced restriction of HIV-1 particle production is distinct from the mechanism underlying HIV-1 restriction by the expression of ISG15 alone, which acts at a later step in particle release. Moreover, HERC5 restricted murine leukemia virus (MLV Gag particle production, showing that HERC5 is effective in restricting Gag particle production of an evolutionarily divergent retrovirus. Conclusions HERC5 represents a potential new host factor that blocks an early stage of retroviral Gag particle assembly. With no apparent HIV-1 protein that directly counteracts it, HERC5 may represent a new candidate for HIV/AIDS therapy.

  9. Long-duration effect of multi-factor stresses on the cellular biochemistry, oil-yielding performance and morphology of Nannochloropsis oculata. (United States)

    Wei, Likun; Huang, Xuxiong


    Microalga Nannochloropsis oculata is a promising alternative feedstock for biodiesel. Elevating its oil-yielding capacity is conducive to cost-saving biodiesel production. However, the regulatory processes of multi-factor collaborative stresses (MFCS) on the oil-yielding performance of N. oculata are unclear. The duration effects of MFCS (high irradiation, nitrogen deficiency and elevated iron supplementation) on N. oculata were investigated in an 18-d batch culture. Despite the reduction in cell division, the biomass concentration increased, resulting from the large accumulation of the carbon/energy-reservoir. However, different storage forms were found in different cellular storage compounds, and both the protein content and pigment composition swiftly and drastically changed. The analysis of four biodiesel properties using pertinent empirical equations indicated their progressive effective improvement in lipid classes and fatty acid composition. The variation curve of neutral lipid productivity was monitored with fluorescent Nile red and was closely correlated to the results from conventional methods. In addition, a series of changes in the organelles (e.g., chloroplast, lipid body and vacuole) and cell shape, dependent on the stress duration, were observed by TEM and LSCM. These changes presumably played an important role in the acclimation of N. oculata to MFCS and accordingly improved its oil-yielding performance.

  10. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways.

    Directory of Open Access Journals (Sweden)

    Tomoko Nishimura

    Full Text Available BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs have been widely used and are a major therapeutic advance in psychopharmacology. However, their pharmacology is quite heterogeneous. The SSRI fluvoxamine, with sigma-1 receptor agonism, is shown to potentiate nerve-growth factor (NGF-induced neurite outgrowth in PC 12 cells. However, the precise cellular and molecular mechanisms underlying potentiation by fluvoxamine are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of NGF-induced neurite outgrowth by fluvoxamine and sigma-1 receptor agonists. METHODS AND FINDINGS: The effects of three SSRIs (fluvoxamine, sertraline, paroxetine and three sigma-1 receptor agonists (SA4503, 4-phenyl-1-(4-phenylbutyl piperidine (PPBP, and dehydroepiandrosterone (DHEA-sulfate on NGF-induced neurite outgrowth in PC12 cells were examined. Also examined were the effects of the sigma-1 receptor antagonist NE-100, inositol 1,4,5-triphosphate (IP(3 receptor antagonist, and specific inhibitors of signaling pathways in the potentiation of NGF-induced neurite outgrowth by selective sigma-1 receptor agonist SA4503. Fluvoxamine (but not sertraline or paroxetine and the sigma-1 receptor agonists SA4503, PPBP, and DHEA-sulfate significantly potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. The potentiation by fluvoxamine and the three sigma-1 receptor agonists was blocked by co-administration of the selective sigma-1 receptor antagonist NE-100, suggesting that sigma-1 receptors play a role in blocking the enhancement of NGF-induced neurite outgrowth. Moreover, the potentiation by SA4503 was blocked by co-administration of the IP(3 receptor antagonist xestospongin C. In addition, the specific inhibitors of phospholipase C (PLC-gamma, phosphatidylinositol 3-kinase (PI3K, p38MAPK, c-Jun N-terminal kinase (JNK, and the Ras/Raf/mitogen-activated protein kinase (MAPK

  11. Extreme calorie restriction and energy source starvation in Saccharomyces cerevisiae represent distinct physiological states

    NARCIS (Netherlands)

    Boender, L.G.M.; Almering, M.J.H.; Dijk, M.; Van Maris, A.J.A.; De Winde, J.H.; Pronk, J.T.; Daran-Lapujade, P.


    Cultivation methods used to investigate microbial calorie restriction often result in carbon and energy starvation. This study aims to dissect cellular responses to calorie restriction and starvation in Saccharomyces cerevisiae by using retentostat cultivation. In retentostats, cells are continuousl

  12. Reduced Insulin/Insulin-like Growth Factor-1 Signaling and Dietary Restriction Inhibit Translation but Preserve Muscle Mass in Caenorhabditis elegans

    Energy Technology Data Exchange (ETDEWEB)

    Depuydt, Geert; Xie, Fang; Petyuk, Vladislav A.; Shanmugam, Nilesh; Smolders, Arne; Dhondt, Ineke; Brewer, Heather M.; Camp, David G.; Smith, Richard D.; Braeckman, Bart P.


    Reduced signaling through the C. elegans insulin/IGF1 like tyrosine kinase receptor daf2 and dietary restriction via bacterial dilution are two well-characterized lifespan-extending interventions that operate in parallel or through (partially) independent mechanisms. Using accurate mass and time tag LCMS/MS quantitative proteomics we detected that the abundance of a large number of ribosomal subunits is decreased in response to dietary restriction as well as in the daf2(e1370) insulin/IGF1 receptor mutant. In addition, general protein synthesis levels in these long-lived worms are repressed. Surprisingly, ribosomal transcript levels were not correlated to actual protein abundance, suggesting that posttranscriptional regulation determines ribosome content. Proteomics also revealed increased presence of many structural muscle cell components in long-lived worms, which appears to result from prioritized preservation of muscle cell volume in nutrient-poor conditions or low insulin-like signaling. Activation of DAF16, but not diet-restriction, stimulates mRNA expression of muscle-related genes to prevent muscle atrophy. Important daf2 specific proteome changes include overexpression of aerobic metabolism enzymes and a general activation of stress responsive and immune defense systems, while increased abundance of many protein subunits of the proteasome core complex is a DR-specific characteristic.

  13. Cellular rehabilitation of photobiomodulation (United States)

    Liu, Timon Cheng-Yi; Yuan, Jian-Qin; Wang, Yan-Fang; Xu, Xiao-Yang; Liu, Song-Hao


    Homeostasis is a term that refers to constancy in a system. A cell in homeostasis normally functions. There are two kinds of processes in the internal environment and external environment of a cell, the pathogenic processes (PP) which disrupts the old homeostasis (OH), and the sanogenetic processes (SP) which restores OH or establishes a new homeostasis (NH). Photobiomodualtion (PBM), the cell-specific effects of low intensity monochromatic light or low intensity laser irradiation (LIL) on biological systems, is a kind of modulation on PP or SP so that there is no PBM on a cell in homeostasis. There are two kinds of pathways mediating PBM, the membrane endogenetic chromophores mediating pathways which often act through reactive oxygen species, and membrane proteins mediating pathways which often enhance cellular SP so that it might be called cellular rehabilitation. The cellular rehabilitation of PBM will be discussed in this paper. It is concluded that PBM might modulate the disruption of cellular homeostasis induced by pathogenic factors such as toxin until OH has been restored or NH has been established, but can not change homeostatic processes from one to another one.

  14. A Canonical Correlation Analysis of AIDS Restriction Genes and Metabolic Pathways Identifies Purine Metabolism as a Key Cooperator

    Directory of Open Access Journals (Sweden)

    Hanhui Ye


    Full Text Available Human immunodeficiency virus causes a severe disease in humans, referred to as immune deficiency syndrome. Studies on the interaction between host genetic factors and the virus have revealed dozens of genes that impact diverse processes in the AIDS disease. To resolve more genetic factors related to AIDS, a canonical correlation analysis was used to determine the correlation between AIDS restriction and metabolic pathway gene expression. The results show that HIV-1 postentry cellular viral cofactors from AIDS restriction genes are coexpressed in human transcriptome microarray datasets. Further, the purine metabolism pathway comprises novel host factors that are coexpressed with AIDS restriction genes. Using a canonical correlation analysis for expression is a reliable approach to exploring the mechanism underlying AIDS.

  15. Receptor complementation and mutagenesis reveal SR-BI as an essential HCV entry factor and functionally imply its intra- and extra-cellular domains.

    Directory of Open Access Journals (Sweden)

    Marlène Dreux


    Full Text Available HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI, a major receptor of high-density lipoprotein (HDL, the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection.

  16. A Traffic Restriction Scheme for Enhancing Carpooling

    Directory of Open Access Journals (Sweden)

    Dong Ding


    Full Text Available For the purpose of alleviating traffic congestion, this paper proposes a scheme to encourage travelers to carpool by traffic restriction. By a variational inequity we describe travelers’ mode (solo driving and carpooling and route choice under user equilibrium principle in the context of fixed demand and detect the performance of a simple network with various restriction links, restriction proportions, and carpooling costs. Then the optimal traffic restriction scheme aiming at minimal total travel cost is designed through a bilevel program and applied to a Sioux Fall network example with genetic algorithm. According to various requirements, optimal restriction regions and proportions for restricted automobiles are captured. From the results it is found that traffic restriction scheme is possible to enhance carpooling and alleviate congestion. However, higher carpooling demand is not always helpful to the whole network. The topology of network, OD demand, and carpooling cost are included in the factors influencing the performance of the traffic system.

  17. Mechanism of Laser/light beam interaction at cellular and tissue level and study of the influential factors for the application of low level laser therapy



    After the discovery of laser therapy it was realized it has useful application of wound healing and reduce pain, but due to the poor understanding of the mechanism and dose response this technique remained to be controversial for therapeutic applications. In order to understand the working and effectiveness different experiments were performed to determine the laser beam effect at the cellular and tissue level. This article discusses the mechanism of beam interaction at tissues and cellular l...

  18. Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3) -- and vascular endothelial growth factor-mediated cellular invasion and tumor growth. (United States)

    Rivat, Christine; Christine, Rivat; Rodrigues, Sylvie; Sylvie, Rodrigues; Bruyneel, Erik; Erik, Bruyneel; Piétu, Geneviève; Geneviève, Piétu; Robert, Amélie; Amélie, Robert; Redeuilh, Gérard; Gérard, Redeuilh; Bracke, Marc; Marc, Bracke; Gespach, Christian; Christian, Gespach; Attoub, Samir; Samir, Attoub


    Signal transducer and activator of transcription (STAT) 3 is overexpressed or activated in most types of human tumors and has been classified as an oncogene. In the present study, we investigated the contribution of the STAT3s to the proinvasive activity of trefoil factors (TFF) and vascular endothelial growth factor (VEGF) in human colorectal cancer cells HCT8/S11 expressing VEGF receptors. Both intestinal trefoil peptide (TFF3) and VEGF, but not pS2 (TFF1), activate STAT3 signaling through Tyr(705) phosphorylation of both STAT3alpha and STAT3beta isoforms. Blockade of STAT3 signaling by STAT3beta, depletion of the STAT3alpha/beta isoforms by RNA interference, and pharmacologic inhibition of STAT3alpha/beta phosphorylation by cucurbitacin or STAT3 inhibitory peptide abrogates TFF- and VEGF-induced cellular invasion and reduces the growth of HCT8/S11 tumor xenografts in athymic mice. Differential gene expression analysis using DNA microarrays revealed that overexpression of STAT3beta down-regulates the VEGF receptors Flt-1, neuropilins 1 and 2, and the inhibitor of DNA binding/differentiation (Id-2) gene product involved in the neoplastic transformation. Taken together, our data suggest that TFF3 and the essential tumor angiogenesis regulator VEGF(165) exert potent proinvasive activity through STAT3 signaling in human colorectal cancer cells. We also validate new therapeutic strategies targeting STAT3 signaling by pharmacologic inhibitors and RNA interference for the treatment of colorectal cancer patients.

  19. Mechanism of Laser/light beam interaction at cellular and tissue level and study of the influential factors for the application of low level laser therapy

    CERN Document Server

    Khalid, Muhammad Zeeshan


    After the discovery of laser therapy it was realized it has useful application of wound healing and reduce pain, but due to the poor understanding of the mechanism and dose response this technique remained to be controversial for therapeutic applications. In order to understand the working and effectiveness different experiments were performed to determine the laser beam effect at the cellular and tissue level. This article discusses the mechanism of beam interaction at tissues and cellular level with different light sources and dosimetry principles for clinical application of low level laser therapy. Different application techniques and methods currently in use for clinical treatment has also been reviewed.

  20. Fasting and Caloric Restriction in Cancer Prevention and Treatment. (United States)

    Brandhorst, Sebastian; Longo, Valter D

    Cancer is the second leading cause of death in the USA and among the leading major diseases in the world. It is anticipated to continue to increase because of the growth of the aging population and prevalence of risk factors such as obesity, smoking, and/or poor dietary habits. Cancer treatment has remained relatively similar during the past 30 years with chemotherapy and/or radiotherapy in combination with surgery remaining the standard therapies although novel therapies are slowly replacing or complementing the standard ones. According to the American Cancer Society, the dietary recommendation for cancer patients receiving chemotherapy is to increase calorie and protein intake. In addition, there are no clear guidelines on the type of nutrition that could have a major impact on cancer incidence. Yet, various forms of reduced caloric intake such as calorie restriction (CR) or fasting demonstrate a wide range of beneficial effects able to help prevent malignancies and increase the efficacy of cancer therapies. Whereas chronic CR provides both beneficial and detrimental effects as well as major compliance challenges, periodic fasting (PF), fasting-mimicking diets (FMDs), and dietary restriction (DR) without a reduction in calories are emerging as interventions with the potential to be widely used to prevent and treat cancer. Here, we review preclinical and preliminary clinical studies on dietary restriction and fasting and their role in inducing cellular protection and chemotherapy resistance.

  1. Investigation Analysis of the City Inhabitants Participate Community Sports Motivation and Its Restrictive Factors%城市居民参加社区体育动机及其制约因素的调查分析

    Institute of Scientific and Technical Information of China (English)



    Take the Jilin Province partial city community inhabitants as the sample,investigate the motivation and the restrictive factors from the questionnaire that city inhabitants participates in the community sports,using the mathematical statistic method,discussion the difference of the motivation and the restrictive factors that community inhabitants participates in community sports.Result show:24.1% city inhabitants participate in community sports above 3 time/week;The first three motivation that inhabitants participates in the community sports is the enhance physical,the leisure and entertainment,the fitness and loses weight;The restriction factors existence significant differences that the city inhabitants participate in community sports in physiology,psychology,facilities,society and so on.%以吉林省部分城市社区居民为样本,对城市居民参加社区体育动机及其制约因素进行问卷调查,运用数理统计方法探讨城市居民参加社区体育动机和制约因素的差异。结果显示:有24.1%的城市居民参加3次/周以上的社区体育活动;参加社区体育动机前三位的是增强体质、休闲娱乐、健美减肥;城市居民参加社区体育的制约因素在生理、心理、设施和社会等层面存在显著差异。

  2. An Analysis on Institutional Restriction Factor of Financial Holding Company Development in China%我国金融控股公司发展的制度性制约因素分析

    Institute of Scientific and Technical Information of China (English)



    我国没有专门的金融控股公司法,但是事实上存在各种类型的金融控股公司。制约金融控股股公司的发展的因素除法律因素外,还包括公司转投资限制、母公司融资限制和税收制度限制等。在分业监管体制下.我国金融控股公司立法很难有实质性突破,研究分析专门立法之外的因素更具有现实意义。%There is no special law on financial holding companies, but in fact there exist many kinds of financial holding compa- nies. Apart from legal factor, restrictions on company investment transfer, parent company financing and taxation system all restrict the development of financial holding companies. Under the separated supervision flame, making a law on financial holding companies is hard to make a material progress. Therefore, it is meaningful to study and analyze other factors beyond legal factor.

  3. Impacts of Left Lane Truck Restriction on Urban Freeways


    Yang, Choon-Heon; Regan, A C


    This paper examines the impacts of truck lane restriction on urban freeways using traffic simulation models. The study includes three main parts: Part (1) provides insights into conditions under which truck lane restrictions would work well; Part (2) identifies the best number of lanes to restrict and shows that this is an important factor in the success of lane restriction; Part (3) investigates potential impacts of truck lane restriction through a case study using a region with some of the ...

  4. Parameters and characteristics governing cellular internalization and trans-barrier trafficking of nanostructures

    Directory of Open Access Journals (Sweden)

    Murugan K


    Full Text Available Karmani Murugan, Yahya E Choonara, Pradeep Kumar, Divya Bijukumar, Lisa C du Toit, Viness Pillay Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Abstract: Cellular internalization and trans-barrier transport of nanoparticles can be manipulated on the basis of the physicochemical and mechanical characteristics of nanoparticles. Research has shown that these factors significantly influence the uptake of nanoparticles. Dictating these characteristics allows for the control of the rate and extent of cellular uptake, as well as delivering the drug-loaded nanosystem intra-cellularly, which is imperative for drugs that require a specific cellular level to exert their effects. Additionally, physicochemical characteristics of the nanoparticles should be optimal for the nanosystem to bypass the natural restricting phenomena of the body and act therapeutically at the targeted site. The factors at the focal point of emerging smart nanomedicines include nanoparticle size, surface charge, shape, hydrophobicity, surface chemistry, and even protein and ligand conjugates. Hence, this review discusses the mechanism of internalization of nanoparticles and ideal nanoparticle characteristics that allow them to evade the biological barriers in order to achieve optimal cellular uptake in different organ systems. Identifying these parameters assists with the progression of nanomedicine as an outstanding vector of pharmaceuticals. Keywords: nanoparticles, transport mechanisms, cellular uptake, size, shape, charge

  5. Restrictions and Proportionality

    DEFF Research Database (Denmark)

    Werlauff, Erik


    The article discusses three central aspects of the freedoms under European Community law, namely 1) the prohibition against restrictions as an important extension of the prohibition against discrimination, 2) a prohibition against exit restrictions which is just as important as the prohibition...... against host country restrictions, but which is often not recognised to the same extent by national law, and 3) the importance of also identifying and recognising an exit restriction, so that it is possible to achieve the required test of appropriateness and proportionality in relation to the rule...

  6. Calorie restriction minimizes activation of insulin signaling in response to glucose: potential involvement of the growth hormone-insulin-like growth factor 1 axis. (United States)

    Hayashi, Hiroko; Yamaza, Haruyoshi; Komatsu, Toshimitsu; Park, Seongjoon; Chiba, Takuya; Higami, Yoshikazu; Nagayasu, Takeshi; Shimokawa, Isao


    Calorie restriction (CR) may modulate insulin signaling in response to energy intake through suppression of the growth hormone (GH)-IGF-1 axis. We investigated the glucose-stimulated serum insulin response and subsequent alterations in insulin receptor (IR), Akt, and FoxO1 in the rat liver and quadriceps femoris muscle (QFM). Nine-month-old wild-type (W) male Wistar rats fed ad libitum (AL) or a 30% CR diet initiated at 6 weeks of age and GH-suppressed transgenic (Tg) rats fed AL were killed 15 min after intraperitoneal injection of glucose or saline. In W-AL rats, the serum insulin concentration was elevated by glucose injection. Concomitantly, the phosphorylated (p)-IR and p-Akt levels were increased in both tissues. The active FoxO1 level was decreased in the liver, but not significantly in the QFM. In W-CR and Tg-AL rats, the serum insulin response was lower, and no significant changes were noted for the p-IR, p-Akt, or active FoxO1 levels in the liver. In the QFM, the p-Akt level was increased in W-CR and Tg-AL rats with an insignificant elevation of p-IR levels. The phenotypic similarity of W-CR and Tg-AL rats suggest that CR minimizes activation of insulin signaling in response to energy intake mostly through the GH-IGF-1 axis.

  7. Expression of HIV-1 Vpu leads to loss of the viral restriction factor CD317/Tetherin from lipid rafts and its enhanced lysosomal degradation.

    Directory of Open Access Journals (Sweden)

    Ruth Rollason

    Full Text Available CD317/tetherin (aka BST2 or HM1.24 antigen is an interferon inducible membrane protein present in regions of the lipid bilayer enriched in sphingolipids and cholesterol (often termed lipid rafts. It has been implicated in an eclectic mix of cellular processes including, most notably, the retention of fully formed viral particles at the surface of cells infected with HIV and other enveloped viruses. Expression of the HIV viral accessory protein Vpu has been shown to lead to intracellular sequestration and degradation of tetherin, thereby counteracting the inhibition of viral release. There is evidence that tetherin interacts directly with Vpu, but it remains unclear where in the cell this interaction occurs or if Vpu expression affects the lipid raft localisation of tetherin. We have addressed these points using biochemical and cell imaging approaches focused on endogenous rather than ectopically over-expressed tetherin. We find i no evidence for an interaction between Vpu and endogenous tetherin at the cell surface, ii the vast majority of endogenous tetherin that is at the cell surface in control cells is in lipid rafts, iii internalised tetherin is present in non-raft fractions, iv expression of Vpu in cells expressing endogenous tetherin leads to the loss of tetherin from lipid rafts, v internalised tetherin enters early endosomes, and late endosomes, in both control cells and cells expressing Vpu, but the proportion of tetherin molecules destined for degradation rather than recycling is increased in cells expressing Vpu vi lysosomes are the primary site for degradation of endogenous tetherin in cells expressing Vpu. Our studies underlie the importance of studying endogenous tetherin and let us propose a model in which Vpu intercepts newly internalised tetherin and diverts it for lysosomal destruction rather than recycling to the cell surface.

  8. Role of bed nucleus of the stria terminalis corticotrophin-releasing factor receptors in frustration stress-induced binge-like palatable food consumption in female rats with a history of food restriction. (United States)

    Micioni Di Bonaventura, Maria Vittoria; Ciccocioppo, Roberto; Romano, Adele; Bossert, Jennifer M; Rice, Kenner C; Ubaldi, Massimo; St Laurent, Robyn; Gaetani, Silvana; Massi, Maurizio; Shaham, Yavin; Cifani, Carlo


    We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This "frustration stress" manipulation also activates the hypothalamic-pituitary-adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10-20 mg/kg) and BNST (25-50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist D-Phe-CRF(12-41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders.


    Institute of Scientific and Technical Information of China (English)

    XIE Huimin


    The limit languages of cellular automata are defined and theircomplexity are discussed. New tools, which include skew evolution, skew periodic string, trace string, some algebraic calculation method, and restricted membership problem, are developed through a discussion focusing on the limit language of an elementary cellular automata of rule 94.It is proved that this language is non-regular.

  10. Evidence that levels of the dimeric cellular transcription factor CP2 play little role in the activation of the HIV-1 long terminal repeat in vivo or following superinfection with herpes simplex virus type 1. (United States)

    Zhong, F; Swendeman, S L; Popik, W; Pitha, P M; Sheffery, M


    The dimeric transcription factor CP2 binds a sequence element found near the transcription start site of the human immunodeficiency virus (HIV-1) long terminal repeat. Several groups have suggested that cellular factors binding this element might play a role in modulating HIV-1 promoter activity in vivo. For example, induction of latent HIV-1 gene expression in response to superinfection by herpes simplex virus type 1 (HSV-1) or cytomegalovirus is thought to be mediated, in part, by factors binding the CP2 site. In this report we began to examine directly the relationship between CP2 and expression of the HIV-1 promoter. First, we tested what effect HSV-1 infection of T cells had on the cellular levels of CP2. The results showed that HSV-1 infection led to a significant reduction in the level of CP2 DNA binding activity and protein within 20 h. Next, we tested the effect of overexpressing either the wild-type factor or a dominant negative variant of CP2 on HIV-1 promoter activity in vivo. The results showed that CP2 had little effect or slightly repressed HIV-1 promoter activity in vivo. In addition, these expression constructs had little effect on the induction of HIV-1 promoter activity elicited by HSV-1 infection.

  11. 中国竞技排球发展制约因素的研究%Study on the Restrictive Factors of the Development of the Chinese Competitive Volleyball

    Institute of Scientific and Technical Information of China (English)

    古松; 钟秉枢


    By the method of questionnaire and factor analysis,the research takes the research objects of the officials of China Volleyball Management Center,volleyball scholar,national team coaches,coaches of men's and women's volleyball clubs participating in the National Volleyball League,international and national volleyball referees.Major restrictive factors in the development on the Chinese competitive volleyball have been researched and analyzed.The result shows that current major factors restricting the development of Chinese competitive volleyball are: management models,athletes' culture quality,volleyball club,training effect,the effect of reserve training and coaches.%采用问卷调查、因子分析法以中国排球管理中心相关领导,排球学者,国家队教练员,参加全国排球甲A联赛的各俱乐部男女排教练员和国际、国家级排球裁判员等为调查对象,对当前中国竞技排球发展过程中的主要制约因素进行研究并对各因素进行分析。结果显示,当前制约中国竞技排球发展的主要因素有:管理模式、运动员文化素质、排球俱乐部、训练影响、后备培养和教练员影响。

  12. Structural basis for the recognition of cellular mRNA export factor REF by herpes viral proteins HSV-1 ICP27 and HVS ORF57. (United States)

    Tunnicliffe, Richard B; Hautbergue, Guillaume M; Kalra, Priti; Jackson, Brian R; Whitehouse, Adrian; Wilson, Stuart A; Golovanov, Alexander P


    The herpesvirus proteins HSV-1 ICP27 and HVS ORF57 promote viral mRNA export by utilizing the cellular mRNA export machinery. This function is triggered by binding to proteins of the transcription-export (TREX) complex, in particular to REF/Aly which directs viral mRNA to the TAP/NFX1 pathway and, subsequently, to the nuclear pore for export to the cytoplasm. Here we have determined the structure of the REF-ICP27 interaction interface at atomic-resolution and provided a detailed comparison of the binding interfaces between ICP27, ORF57 and REF using solution-state NMR. Despite the absence of any obvious sequence similarity, both viral proteins bind on the same site of the folded RRM domain of REF, via short but specific recognition sites. The regions of ICP27 and ORF57 involved in binding by REF have been mapped as residues 104-112 and 103-120, respectively. We have identified the pattern of residues critical for REF/Aly recognition, common to both ICP27 and ORF57. The importance of the key amino acid residues within these binding sites was confirmed by site-directed mutagenesis. The functional significance of the ORF57-REF/Aly interaction was also probed using an ex vivo cytoplasmic viral mRNA accumulation assay and this revealed that mutants that reduce the protein-protein interaction dramatically decrease the ability of ORF57 to mediate the nuclear export of intronless viral mRNA. Together these data precisely map amino acid residues responsible for the direct interactions between viral adaptors and cellular REF/Aly and provide the first molecular details of how herpes viruses access the cellular mRNA export pathway.

  13. Psychological factors in analogous thinking and their restriction%类比思维的心理因素及其制约

    Institute of Scientific and Technical Information of China (English)



    AIM: To investigate the role of certain psychological factors in the process of new analogous combination on the basis of complete perceptual materials.METHODS: By means of evaluation of critical thinking, the psychological factors in the process of analogous thinking were investigated.RESULTS: In the process of analogous thinking, how to choose and reflect the analogous objects has its proper use of analogous mode of thinking. At the same time, it is also influenced by certain psychological factors.CONCLUSION: Analogous thinking plays an important role as thinking tool in the process of recognizing new things and solving new problems, or explaining abstract affair with simple reasons.%目的:探讨一定的心理因素在完整的知觉材料基础上进行新的类比组合过程中的作用.方法:以批判性思维的评价方法,对类比思维过程中心理因素进行研究.结果:在类比思维的过程中,如何选择、映射类比事物,不但有着正确的类比思维方法的运用,同时它也受到一定的心理因素的影响.结论:类比思维在认识新事物、解决新问题的过程中,或者以简单的道理说明抽象事理的过程中,都发挥着重要的思维工具作用.


    Institute of Scientific and Technical Information of China (English)

    徐海贤; 庄林德


    苏南地区现行的村镇企业生产经营模式、产品销售方式,农村建设用地使用机制、农民的观念意识等严重制约着农村城市化进程.本文通过对这些制约因素及农村城市化动力机制的分析,提出了加速苏南地区农村城市化的若干调控措施.%At the beginning of this century, some problems restricted thedevelopment of rural urbanization ,which include the present production and management patterns ,products selling modes in rural enterprises,rural land use mechanism and improvement of peasant 's idea. The paper analyses the restricted factors and the new mechanism of rural urbanization. Then the authors propose several countermeasures to push rural urbanization in South Jiangsu.

  15. Change in proportional protein intake in a 10-week energy-restricted low- or high-fat diet, in relation to changes in body size and metabolic factors

    DEFF Research Database (Denmark)

    Stocks, Tanja; Taylor, Moira A; Ängquist, Lars


    Objective: To investigate in a secondary analysis of a randomised trial the effects of a low-/high-fat diet and reported change from baseline in energy% from protein (prot%), in relation to changes in body size and metabolic factors. Methods: Obese adults (n = 771) were randomised to a 600 kcal e...... increased the percentage energy intake from protein showed the greatest reduction in weight and cholesterol, and a triglyceride reduction equally large to that of participants on a high-fat diet. Copyright © 2013 S. Karger GmbH, Freiburg.......Objective: To investigate in a secondary analysis of a randomised trial the effects of a low-/high-fat diet and reported change from baseline in energy% from protein (prot%), in relation to changes in body size and metabolic factors. Methods: Obese adults (n = 771) were randomised to a 600 kcal...... energy-deficient low-fat (20-25 fat%) or high-fat (40-45 fat%) diet over 10 weeks. Dietary intake data at baseline and during the intervention were available in 585 completers. We used linear regression to calculate the combined effects of randomised group and groups of prot% change (2) on outcomes...

  16. Restricting Factors of Foreign Language Teachers Professional Development and Its Countermeasures%高职外语教师专业发展的制约因素及对策

    Institute of Scientific and Technical Information of China (English)



    本文在对河北省3所高职高专院校英语教师的问卷调查的基础上,探究了高职高专英语教师的专业发展需求和制约专业发展的几个因素,并提出促进高职外语教师专业发展的相应对策。%Based on questionnaire survey in Hebei province 3 vocational college English teachers, this paper is to explore the needs and restrict factors of English teachers professional development in higher vocational colleges,and put forward the corresponding countermeasures to promote foreign language teacher professional development.

  17. Th1 stimulatory proteins of Leishmania donovani: comparative cellular and protective responses of rTriose phosphate isomerase, rProtein disulfide isomerase and rElongation factor-2 in combination with rHSP70 against visceral leishmaniasis. (United States)

    Jaiswal, Anil Kumar; Khare, Prashant; Joshi, Sumit; Kushawaha, Pramod Kumar; Sundar, Shyam; Dube, Anuradha


    In visceral leishmaniasis, the recovery from the disease is always associated with the generation of Th1-type of cellular responses. Based on this, we have previously identified several Th1-stimulatory proteins of Leishmania donovani -triose phosphate isomerase (TPI), protein disulfide isomerase (PDI) and elongation factor-2 (EL-2) etc. including heat shock protein 70 (HSP70) which induced Th1-type of cellular responses in both cured Leishmania patients/hamsters. Since, HSPs, being the logical targets for vaccines aimed at augmenting cellular immunity and can be early targets in the immune response against intracellular pathogens; they could be exploited as vaccine/adjuvant to induce long-term immunity more effectively. Therefore, in this study, we checked whether HSP70 can further enhance the immunogenicity and protective responses of the above said Th1-stimulatory proteins. Since, in most of the studies, immunogenicity of HSP70 of L. donovani was assessed in native condition, herein we generated recombinant HSP70 and tested its potential to stimulate immune responses in lymphocytes of cured Leishmania infected hamsters as well as in the peripheral blood mononuclear cells (PBMCs) of cured patients of VL either individually or in combination with above mentioned recombinant proteins. rLdHSP70 alone elicited strong cellular responses along with remarkable up-regulation of IFN-γ and IL-12 cytokines and extremely lower level of IL-4 and IL-10. Among the various combinations, rLdHSP70 + rLdPDI emerged as superior one augmenting improved cellular responses followed by rLdHSP70 + rLdEL-2. These combinations were further evaluated for its protective potential wherein rLdHSP70 + rLdPDI again conferred utmost protection (∼80%) followed by rLdHSP70 + rLdEL-2 (∼75%) and generated a strong cellular immune response with significant increase in the levels of iNOS transcript as well as IFN-γ and IL-12 cytokines which was further supported by the high level of IgG2 antibody

  18. Adipogenic placenta-derived mesenchymal stem cells are not lineage restricted by withdrawing extrinsic factors: developing a novel visual angle in stem cell biology. (United States)

    Hu, C; Cao, H; Pan, X; Li, J; He, J; Pan, Q; Xin, J; Yu, X; Li, J; Wang, Y; Zhu, D; Li, L


    Current evidence implies that differentiated bone marrow mesenchymal stem cells (BMMSCs) can act as progenitor cells and transdifferentiate across lineage boundaries. However, whether this unrestricted lineage has specificities depending on the stem cell type is unknown. Placental-derived mesenchymal stem cells (PDMSCs), an easily accessible and less invasive source, are extremely useful materials in current stem cell therapies. No studies have comprehensively analyzed the transition in morphology, surface antigens, metabolism and multilineage potency of differentiated PDMSCs after their dedifferentiation. In this study, we showed that after withdrawing extrinsic factors, adipogenic PDMSCs reverted to a primitive cell population and retained stem cell characteristics. The mitochondrial network during differentiation and dedifferentiation may serve as a marker of absent or acquired pluripotency in various stem cell models. The new population proliferated faster than unmanipulated PDMSCs and could be differentiated into adipocytes, osteocytes and hepatocytes. The cell adhesion molecules (CAMs) signaling pathway and extracellular matrix (ECM) components modulate cell behavior and enable the cells to proliferate or differentiate during the differentiation, dedifferentiation and redifferentiation processes in our study. These observations indicate that the dedifferentiated PDMSCs are distinguishable from the original PDMSCs and may serve as a novel source in stem cell biology and cell-based therapeutic strategies. Furthermore, whether PDMSCs differentiated into other lineages can be dedifferentiated to a primitive cell population needs to be investigated.

  19. Adipogenic placenta-derived mesenchymal stem cells are not lineage restricted by withdrawing extrinsic factors: developing a novel visual angle in stem cell biology (United States)

    Hu, C; Cao, H; Pan, X; Li, J; He, J; Pan, Q; Xin, J; Yu, X; Li, J; Wang, Y; Zhu, D; Li, L


    Current evidence implies that differentiated bone marrow mesenchymal stem cells (BMMSCs) can act as progenitor cells and transdifferentiate across lineage boundaries. However, whether this unrestricted lineage has specificities depending on the stem cell type is unknown. Placental-derived mesenchymal stem cells (PDMSCs), an easily accessible and less invasive source, are extremely useful materials in current stem cell therapies. No studies have comprehensively analyzed the transition in morphology, surface antigens, metabolism and multilineage potency of differentiated PDMSCs after their dedifferentiation. In this study, we showed that after withdrawing extrinsic factors, adipogenic PDMSCs reverted to a primitive cell population and retained stem cell characteristics. The mitochondrial network during differentiation and dedifferentiation may serve as a marker of absent or acquired pluripotency in various stem cell models. The new population proliferated faster than unmanipulated PDMSCs and could be differentiated into adipocytes, osteocytes and hepatocytes. The cell adhesion molecules (CAMs) signaling pathway and extracellular matrix (ECM) components modulate cell behavior and enable the cells to proliferate or differentiate during the differentiation, dedifferentiation and redifferentiation processes in our study. These observations indicate that the dedifferentiated PDMSCs are distinguishable from the original PDMSCs and may serve as a novel source in stem cell biology and cell-based therapeutic strategies. Furthermore, whether PDMSCs differentiated into other lineages can be dedifferentiated to a primitive cell population needs to be investigated. PMID:26986509

  20. Cellular immune responses towards regulatory cells. (United States)

    Larsen, Stine Kiær


    This thesis describes the results from two published papers identifying spontaneous cellular immune responses against the transcription factors Foxp3 and Foxo3. The tumor microenvironment is infiltrated by cells that hinder effective tumor immunity from developing. Two of these cell types, which have been linked to a bad prognosis for patients, are regulatory T cells (Treg) and tolerogenic dendritic cells (DC). Tregs inhibit effector T cells from attacking the tumor through various mechanisms, including secreted factors and cell-to-cell contact. Tregs express the transcription factor Foxp3, which is necessary for their development and suppressive activities. Tolerogenic DCs participate in creating an environment in the tumor where effector T cells become tolerant towards the tumor instead of attacking it. The transcription factor Foxo3 was recently described to be highly expressed by tolerogenic DCs and to programme their tolerogenic influence. This thesis describes for the first time the existence of spontaneous cellular immune responses against peptides derived from Foxp3 and Foxo3. We have detected the presence of cytotoxic T cells that recognise these peptides in an HLA-A2 restricted manner in cancer patients and for Foxp3 in healthy donors as well. In addition, we have demonstrated that the Foxp3- and Foxo3-specific CTLs recognize Foxp3- and Foxo3-expressing cancer cell lines and importantly, suppressive immune cells, namely Tregs and in vitro generated DCs. Cancer immunotherapy is recently emerging as an important treatment modality improving the survival of selected patients. The current progress is largely owing to targeting of the immune suppressive milieu that is dominating the tumor microenvironment. This is being done through immune checkpoint blockade with CTLA-4 and PD-1/PD-L1 antibodies and through lymphodepleting conditioning of patients and ex vivo activation of TILs in adoptive cell transfer. Several strategies are being explored for depletion of

  1. Flat Cellular (UMTS) Networks

    NARCIS (Netherlands)

    Bosch, H.G.P.; Samuel, L.G.; Mullender, S.J.; Polakos, P.; Rittenhouse, G.


    Traditionally, cellular systems have been built in a hierarchical manner: many specialized cellular access network elements that collectively form a hierarchical cellular system. When 2G and later 3G systems were designed there was a good reason to make system hierarchical: from a cost-perspective i

  2. Late gestational nutrient restriction

    DEFF Research Database (Denmark)

    Tygesen, Malin Plumhoff; Nielsen, Mette Olaf; Nørgaard, Peder;


    We investigated the effect of 50% nutrient restriction during the last 6 weeks of gestation on twin-pregnant ewes' plasma glucose, non-esterified fatty acid, ß-hydroxybutyrate, insulin, IGF-1 and leptin concentrations and the effects on lamb birth weight and ewes' lactation performance. Plasma...... metabolite and hormone concentrations in restricted ewes suggest that maternal tissues were being mobilised. Despite the ewes' adaptations their lambs weighed significantly less at birth. Furthermore, colostrum and milk yields were markedly reduced up until the latest measurement at 3 weeks post partum...

  3. Binding of cellular export factor REF/Aly by Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is not required for efficient KSHV lytic replication. (United States)

    Li, Da-Jiang; Verma, Dinesh; Swaminathan, Sankar


    Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is expressed early during lytic KSHV replication, enhances expression of many KSHV genes, and is essential for virus production. ORF57 is a member of a family of proteins conserved among all human and many animal herpesviruses that are multifunctional regulators of gene expression and act posttranscriptionally to increase accumulation of their target mRNAs. The mechanism of ORF57 action is complex and may involve effects on mRNA transcription, stability, and export. ORF57 directly binds to REF/Aly, a cellular RNA-binding protein component of the TREX complex that mediates RNA transcription and export. We analyzed the effects of an ORF57 mutation known to abrogate REF/Aly binding and demonstrate that the REF-binding mutant is impaired in activation of viral mRNAs and noncoding RNAs confined to the nucleus. Although the inability to bind REF leads to decreased ORF57 activity in enhancing gene expression, there is no demonstrable effect on nuclear export of viral mRNA or the ability of ORF57 to support KSHV replication and virus production. These data indicate that REF/Aly-ORF57 interaction is not essential for KSHV lytic replication but may contribute to target RNA stability independent of effects on RNA export, suggesting a novel role for REF/Aly in viral RNA metabolism.

  4. Detection of cis- and trans-acting factors in DNA structure-induced genetic instability using in silico and cellular approaches

    Directory of Open Access Journals (Sweden)

    Guliang Wang


    Full Text Available Sequences that can adopt alternative DNA structures (i.e. non-B DNA are very abundant in mammalian genomes, and recent studies have revealed many important biological functions of non-B DNA structures in chromatin remodeling, DNA replication, transcription, and genetic instability. Here, we provide results from an in-silico web-based search engine coupled with cell-based experiments to characterize the roles of non-B DNA conformations in genetic instability in eukaryotes. The purpose of this article is to illustrate strategies that can be used to identify and interrogate the biological roles of non-B DNA structures, particularly on genetic instability. We have included unpublished data using a short H-DNA-forming sequence from the human c-MYC promoter region as an example, and identified two different mechanisms of H-DNA-induced genetic instability in yeast and mammalian cells: a DNA replication-related model of mutagenesis; and a replication-independent cleavage model. Further, we identified candidate proteins involved in H-DNA-induced genetic instability by using a yeast genetic screen. A combination of in silico and cellular methods, as described here, should provide further insight into the contributions of non-B DNA structures in biological functions, genetic evolution, and disease development.

  5. On Cellular MIMO Channel Capacity (United States)

    Adachi, Koichi; Adachi, Fumiyuki; Nakagawa, Masao

    To increase the transmission rate without bandwidth expansion, the multiple-input multiple-output (MIMO) technique has recently been attracting much attention. The MIMO channel capacity in a cellular system is affected by the interference from neighboring co-channel cells. In this paper, we introduce the cellular channel capacity and evaluate its outage capacity, taking into account the frequency-reuse factor, path loss exponent, standard deviation of shadowing loss, and transmission power of a base station (BS). Furthermore, we compare the cellular MIMO downlink channel capacity with those of other multi-antenna transmission techniques such as single-input multiple-output (SIMO) and space-time block coded multiple-input single-output (STBC-MISO). We show that the optimum frequency-reuse factor F that maximizes 10%-outage capacity is 3 and both 50%- and 90%-outage capacities is 1 irrespective of the type of multi-antenna transmission technique, where q%-outage capacity is defined as the channel capacity that gives an outage probability of q%. We also show that the cellular MIMO channel capacity is always higher than those of SIMO and STBC-MISO.

  6. Oxidative stress action in cellular aging

    Directory of Open Access Journals (Sweden)

    Monique Cristine de Oliveira


    Full Text Available Various theories try to explain the biological aging by changing the functions and structure of organic systems and cells. During lifetime, free radicals in the oxidative stress lead to lipid peroxidation of cellular membranes, homeostasis imbalance, chemical residues formation, gene mutations in DNA, dysfunction of certain organelles, and the arise of diseases due to cell death and/or injury. This review describes the action of oxidative stress in the cells aging process, emphasizing the factors such as cellular oxidative damage, its consequences and the main protective measures taken to prevent or delay this process. Tests with antioxidants: vitamins A, E and C, flavonoids, carotenoids and minerals, the practice of caloric restriction and physical exercise, seeking the beneficial effects on human health, increasing longevity, reducing the level of oxidative stress, slowing the cellular senescence and origin of certain diseases, are discussed.Diferentes teorias tentam explicar o envelhecimento biológico através da alteração das funções e estrutura dos sistemas orgânicos e células. Ao longo da vida, os radicais livres presentes no estresse oxidativo conduzem à peroxidação dos lipídios das membranas celulares, desequilíbrio da homeostase, formação de resíduos químicos, mutações gênicas no DNA, disfunção de certas organelas, bem como ao surgimento de doenças devido à lesão e/ou morte celular. Nesta revisão descreve-se a ação do estresse oxidativo no processo de envelhecimento das células, enfatizando fatores como os danos oxidativos celulares, suas conseqüências e as principais medidas protetoras adotadas para se prevenir ou retardar este processo. Testes com antioxidantes: vitaminas A, E e C, flavonóides, carotenóides e minerais; a prática de restrição calórica e exercícios físicos, que buscam efeitos benéficos sobre a saúde humana, aumentando a longevidade, reduzindo o nível de estresse oxidativo

  7. Coagulant activity and cellular origin of circulating tissue factor exposing microparticles in cancer patients - two forms of TF-exposing microparticles

    NARCIS (Netherlands)

    Kleinjan, A.; Boing, A. N.; Di Nisio, M.; Twint, D.; Kamphuisen, P. W.; Nanayakkara, P.; Buller, H. R.; Nieuwland, R.


    Background: Because plasma of cancer patients presenting with venous thrombosis contains high numbers of tissue factor (TF)-exposing microparticles (TF-MP1), TF-MP have been causally linked to the occurrence of venous thrombosis in cancer patients. The relationship between numbers of TF-exposing MP

  8. Training Restricted Boltzmann Machines

    DEFF Research Database (Denmark)

    Fischer, Asja

    Restricted Boltzmann machines (RBMs) are probabilistic graphical models that can also be interpreted as stochastic neural networks. Training RBMs is known to be challenging. Computing the likelihood of the model parameters or its gradient is in general computationally intensive. Thus, training...

  9. Bilinear Fourier restriction theorems

    CERN Document Server

    Demeter, Ciprian


    We provide a general scheme for proving $L^p$ estimates for certain bilinear Fourier restrictions outside the locally $L^2$ setting. As an application, we show how such estimates follow for the lacunary polygon. In contrast with prior approaches, our argument avoids any use of the Rubio de Francia Littlewood--Paley inequality.

  10. A Herpesvirus Protein Selectively Inhibits Cellular mRNA Nuclear Export. (United States)

    Gong, Danyang; Kim, Yong Hoon; Xiao, Yuchen; Du, Yushen; Xie, Yafang; Lee, Kevin K; Feng, Jun; Farhat, Nisar; Zhao, Dawei; Shu, Sara; Dai, Xinghong; Chanda, Sumit K; Rana, Tariq M; Krogan, Nevan J; Sun, Ren; Wu, Ting-Ting


    Nuclear mRNA export is highly regulated to ensure accurate cellular gene expression. Viral inhibition of cellular mRNA export can enhance viral access to the cellular translation machinery and prevent anti-viral protein production but is generally thought to be nonselective. We report that ORF10 of Kaposi's sarcoma-associated herpesvirus (KSHV), a nuclear DNA virus, inhibits mRNA export in a transcript-selective manner to control cellular gene expression. Nuclear export inhibition by ORF10 requires an interaction with an RNA export factor, Rae1. Genome-wide analysis reveals a subset of cellular mRNAs whose nuclear export is blocked by ORF10 with the 3' UTRs of ORF10-targeted transcripts conferring sensitivity to export inhibition. The ORF10-Rae1 interaction is important for the virus to express viral genes and produce infectious virions. These results suggest that a nuclear DNA virus can selectively interfere with RNA export to restrict host gene expression for optimal replication.

  11. Analysis of Risk Factors for Fetal Growth Restriction and Delivery Timing%胎儿生长受限危险因素及分娩时机的分析

    Institute of Scientific and Technical Information of China (English)

    崔世红; 孙俊燕; 陈娟; 李园园; 杭中霞; 申琳娜; 职云晓; 高亚南


    Objective:To explore the related risk factors for fetal growth restriction and time to termination of pregnancy.Method:The clinical data of 173 neonates with FGR(FGR group),180 neonates with normal weight(normal group) and the parturient women in the Third Affiliated Hospital of Zhengzhou University were selected from January 2013 to November 2014,they were analyzed retrospectively.Result:The high risk factors of fetal growth restriction were: gestational hypertension disease (P=0.000,OR=20.440,95%CI 8.499-49.156),oligohydramnios(P=0.000, OR=5.652,95%CI 2.195-14.555),gestational diabetes(P=0.018,OR=2.763,95%CI 1.192-6.400) and anemia (P=0.032,OR=1.708,95%CI 1.047-2.786).With the gestational age greater, the weight of the newborn was higher, the prognosis was better,the differences were statistically significant(P<0.05).Conclusion:Gestational hypertension disease, oligohydramnios, gestational diabetes and anemia are high risk factors of fetal growth restriction.To strengthen pregnancy care and custody,the standard treatment of obstetric complications, timely termination of pregnancy is main measures to reduce perinatal mortality.%目的:探讨胎儿生长受限的相关危险因素及终止妊娠时机。方法:对2013年1月-2014年11月在郑州大学第三附属医院分娩的173例FGR新生儿(FGR组)及180例正常体重新生儿(对照组)及其产妇病历资料进行回顾性分析。结果:胎儿生长受限的高危因素有:妊娠期高血压疾病(P=0.000,OR=20.440,95%CI 8.499~49.156)、羊水过少(P=0.000,OR=5.652,95%CI 2.195~14.555)、妊娠期糖尿病(P=0.018, OR=2.763,95%CI 1.192~6.400)和贫血(P=0.032,OR=1.708,95%CI 1.047~2.786)。孕周越大,新生儿体重越重,预后越好,差异均有统计学意义(P<0.05)。结论:妊娠期高血压疾病、羊水过少、妊娠期糖尿病、贫血是胎儿生长受限的高危因素,加强孕期保健及监护,规范治疗产科并发症

  12. Dietary restriction: could it be considered as speed bump on tumor progression road? (United States)

    Cangemi, Antonina; Fanale, Daniele; Rinaldi, Gaetana; Bazan, Viviana; Galvano, Antonio; Perez, Alessandro; Barraco, Nadia; Massihnia, Daniela; Castiglia, Marta; Vieni, Salvatore; Bronte, Giuseppe; Mirisola, Mario; Russo, Antonio


    Dietary restrictions, including fasting (or long-term starvation), calorie restriction (CR), and short-term starvation (STS), are considered a strong rationale that may protect against various diseases, including age-related diseases and cancer. Among dietary approaches, STS, in which food is not consumed during designed fasting periods but is typically not restricted during designated feeding periods, seems to be more suitable, because other dietary regimens involving prolonged fasting periods could worsen the health conditions of cancer patients, being they already naturally prone to weight loss. Until now, the limited amount of available data does not point to a single gene, pathway, or molecular mechanism underlying the benefits to the different dietary approaches. It is well known that the healthy effect is mediated in part by the reduction of nutrient-related pathways. The calorie restriction and starvation (long- and short-term) also suppress the inflammatory response reducing the expression, for example, of IL-10 and TNF-α, mitigating pro-inflammatory gene expression and increasing anti-inflammatory gene expression. The dietary restriction may regulate both genes involved in cellular proliferation and factors associated to apoptosis in normal and cancer cells. Finally, dietary restriction is an important tool that may influence the response to chemotherapy in preclinical models. However, further data are needed to correlate dietary approaches with chemotherapeutic treatments in human models. The aim of this review is to discuss the effects of various dietary approaches on the cancer progression and therapy response, mainly in preclinical models, describing some signaling pathways involved in these processes.

  13. Quantitative, functional and biochemical alterations in the peritoneal cells of mice exposed to whole-body gamma-irradiation. 1. Changes in cellular protein, adherence properties and enzymatic activities associated with platelet-activating factor formation and inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Steel, L.K.; Hughes, H.N.; Walden, T.L. Jr.


    Changes in total number, differentials, cell protein, adherence properties, acetyl-CoA transferase and acetylhydrolase activities, prostaglandin E/sub 2/ and leukotriene C/sub 4/ production, as well as Ca/sup 2+/ ionophore A23187 stimulation were examined in resident peritoneal cells isolated from mice 2 h to 10 days postexposure to a single dose (7, 10 or 12 Gy) of gamma-radiation. Radiation dose-related reductions in macrophage and lymphocyte numbers and increases in cellular protein and capacity to adhere to plastic surfaces were evident. In vivo irradiation also elevated the activities of acetyltransferase and acetyl-CoA hydrolase (catalysing platelet-activating factor biosynthesis and inactivation, respectively) in adherent and nonadherent peritoneal cells, particularly 3-4 days postexposure. Blood plasma from irradiated animals did not reflect the increased cellular acetyl-hydrolase activity. Prostaglandin E/sub 2/ and leukotriene C/sub 4/ synthesis were elevated postexposure, suggesting increased substrate (arachidonate) availability and increased cyclooxygenase and lipoxygenase activities. Ionophore stimulation of enzyme activities and eicosanoid release also differed in irradiated peritoneal cells.

  14. Restricted and quasi-toral restricted Lie-Rinehart algebras

    Directory of Open Access Journals (Sweden)

    Sun Bing


    Full Text Available In this paper, we introduce the definition of restrictable Lie-Rinehart algebras, the concept of restrictability is by far more tractable than that of a restricted Lie-Rinehart algebra. Moreover, we obtain some properties of p-mappings and restrictable Lie-Rinehart algebras. Finally, we give some sufficient conditions for the commutativity of quasi-toral restricted Lie-Rinehart algebras and study how a quasi-toral restricted Lie-Rinehart algebra with zero center and of minimal dimension should be.

  15. Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling. (United States)

    Wang, Yuqin; Fukuda, Tomohiko; Isaji, Tomoya; Lu, Jishun; Gu, Wei; Lee, Ho-Hsun; Ohkubo, Yasuhito; Kamada, Yoshihiro; Taniguchi, Naoyuki; Miyoshi, Eiji; Gu, Jianguo


    Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8(+/-) mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.

  16. Restriction of Helmholtz Model

    Directory of Open Access Journals (Sweden)

    V.M. Polunin


    Full Text Available The results of the experimental studies of physical mechanisms of energy dissipation in the oscillating system in which air cavity held by the forces of magnetic levitation is used as the elastic element, and magnetic fluid prepared on the basis of dispersing media with different viscosity level is used as the inertial element are considered in the article. Based on the obtained results the conclusion on the restriction of the applicability of Helmholtz equation, caused by boundary effects is made.

  17. License restrictions at Barnwell

    Energy Technology Data Exchange (ETDEWEB)

    Autry, V.R. [S.C. Dept. of Health and Environmental Control, Columbia, SC (United States). Bureau of Radiological Health


    The State of South Carolina was delegated the authority by the US Nuclear Regulatory Commission to regulate the receipt, possession, use and disposal of radioactive material as an Agreement State. Since 1970, the state has been the principal regulatory authority for the Barnwell Low-Level Waste Disposal Facility operated by Chem-Nuclear Systems, Inc. The radioactive material license issued authorizing the receipt and disposal of low-level waste contains numerous restrictions to ensure environmental protection and compliance with shallow land disposal performance criteria. Low-level waste has evolved from minimally contaminated items to complex waste streams containing high concentrations of radionuclides and processing chemicals which necessitated these restrictions. Additionally, some waste with their specific radionuclides and concentration levels, many classified as low-level radioactive waste, are not appropriate for shallow land disposal unless additional precautions are taken. This paper will represent a number of these restrictions, the rationale for them, and how they are being dealt with at the Barnwell disposal facility.

  18. Cellular neurothekeoma with melanocytosis. (United States)

    Wu, Ren-Chin; Hsieh, Yi-Yueh; Chang, Yi-Chin; Kuo, Tseng-Tong


    Cellular neurothekeoma (CNT) is a benign dermal tumor mainly affecting the head and neck and the upper extremities. It is characterized histologically by interconnecting fascicles of plump spindle or epithelioid cells with ample cytoplasm infiltrating in the reticular dermis. The histogenesis of CNT has been controversial, although it is generally regarded as an immature counterpart of classic/myxoid neurothekeoma, a tumor with nerve sheath differentiation. Two rare cases of CNT containing melanin-laden cells were described. Immunohistochemical study with NKI/C3, vimentin, epithelial membrane antigen, smooth muscle antigen, CD34, factor XIIIa, collagen type IV, S100 protein and HMB-45 was performed. Both cases showed typical growth pattern of CNT with interconnecting fascicles of epithelioid cells infiltrating in collagenous stroma. One of the nodules contained areas exhibiting atypical cytological features. Melanin-laden epithelioid or dendritic cells were diffusely scattered throughout one nodule, and focally present in the peripheral portion of the other nodule. Both nodules were strongly immunoreactive to NKI/C3 and vimentin, but negative to all the other markers employed. CNT harboring melanin-laden cells may pose diagnostic problems because of their close resemblance to nevomelanocytic lesions and other dermal mesenchymal tumors. These peculiar cases may also provide further clues to the histogenesis of CNT.

  19. The Examination of China’s New Medical Reform Based on Restrictive Factors in British Medical Reform%基于英国医改制约性因素审视我国新医改

    Institute of Scientific and Technical Information of China (English)



    As the first country established universal health insurance in the world, UK has been devoted to construct the fairness and welfare of National Health Service(NHS) with constant development and improvement. It focuses on the reform process of NHS since the beginning of this century and studies the deep factors restricted the reform, compared with the current situation of health care system under China’s new medical reform since 2006, putting forward enlightenment to China’s reform.%作为世界上最早建立全民医疗保障的国家,英国一直致力于其医疗服务系统(NHS)公平性与福利性的构建,不断进行发展与完善。文章重点关注本世纪以来NHS 的改革历程,研究影响其改革成效的深层次制约性因素,同时对照我国2006年启动新医疗改革后国内卫生医疗服务体系的现状,提出其对我国新医改的启示。

  20. 浅谈残疾儿童参与全民健身的制约因素及发展对策%Discussion on Restricting Factors and Developing Measurements of Disable Children Participating in National Fitness Activity

    Institute of Scientific and Technical Information of China (English)

    蔡勇刚; 张雷


    Through using the method of literature review, this paper makes analysis on restricting factors of disable children participating in national fitness activity from economy, policy, and cultural philosophy. Based on exiting problems, some measurements are put forward. The main purpose is to promote the physical fitness of disable children and provide the reference for national fitness development.%本文采用文献资料的研究方法,对残疾儿童参与全民健身的制约因素从经济、政策、思想文化意识三个角度进行分析,针对残疾儿童全面参与健身中遇到的问题,提出相应的对策和建议,旨在为残疾儿童提高身体素质、参与体育锻炼和全民健身的普及提供一定的理论参考依据。

  1. 高校学报数字出版的制约因素及其对策思考%On Restrictive Factors and Countermeasures of University Journal Digital Publishing

    Institute of Scientific and Technical Information of China (English)



    University Journal Digital Publishing is the requirement of the development of the times. However it is restricted by the fol-lowing factors: ideas,scientific evaluation mechanism,equipment and technology,and professional criteria,etc. In order to realize university journal digital publishing,the old ideas must be changed,the scientific evaluation mechanism be improved,the profit pat-tern of“double benefit”be carried out,the intensity of support be increased,the comprehensive qualities of editors and management personnel be promoted,and a shareable digital publishing platform be established.%高校学报数字出版是时代发展的要求。高校学报数字出版受思想观念、科研评价机制、设备和技术、行业标准等诸因素制约。要实现高校学报数字出版必须转变观念,完善科研评价机制,实行“双效益”的盈利模式,加大扶持力度,提升编辑和管理人员的综合素质,建立可共享的数字出版平台。

  2. Differential expression of HIV-1 interfering factors in monocyte-derived macrophages stimulated with polarizing cytokines or interferons (United States)

    Jiménez, Viviana Cobos; Booiman, Thijs; de Taeye, Steven W.; van Dort, Karel A.; Rits, Maarten A. N.; Hamann, Jörg; Kootstra, Neeltje A.


    HIV-1 replication in macrophages can be regulated by cytokines and infection is restricted in macrophages activated by type I interferons and polarizing cytokines. Here, we observed that the expression levels of the cellular factors Trim5α, CypA, APOBEC3G, SAMHD-1, Trim22, tetherin and TREX-1, and the anti-HIV miRNAs miR-28, miR-150, miR-223 and miR-382 was upregulated by IFN-α and IFN-β in macrophages, which may account for the inhibiting effect on viral replication and the antiviral state of these cells. Expression of these factors was also increased by IFN-γ +/- TNF-α, albeit to a lesser extent; yet, HIV-1 replication in these cells was not restricted at the level of proviral synthesis, indicating that these cellular factors only partially contribute to the observed restriction. IL-4, IL-10 or IL-32 polarization did not affect the expression of cellular factors and miRNAs, suggesting only a limited role for these cellular factors in restricting HIV-1 replication in macrophages.

  3. Expression of the ctenophore Brain Factor 1 forkhead gene ortholog (ctenoBF-1) mRNA is restricted to the presumptive mouth and feeding apparatus: implications for axial organization in the Metazoa (United States)

    Yamada, Atsuko; Martindale, Mark Q.


    Ctenophores are thoroughly modern animals whose ancestors are derived from a separate evolutionary branch than that of other eumetazoans. Their major longitudinal body axis is the oral-aboral axis. An apical sense organ, called the apical organ, is located at the aboral pole and contains a highly innervated statocyst and photodetecting cells. The apical organ integrates sensory information and controls the locomotory apparatus of ctenophores, the eight longitudinal rows of ctene/comb plates. In an effort to understand the developmental and evolutionary organization of axial properties of ctenophores we have isolated a forkhead gene from the Brain Factor 1 (BF-1) family. This gene, ctenoBF-1, is the first full-length nuclear gene reported from ctenophores. This makes ctenophores the most basal metazoan (to date) known to express definitive forkhead class transcription factors. Orthologs of BF-1 in vertebrates, Drosophila, and Caenorhabditis elegans are expressed in anterior neural structures. Surprisingly, in situ hybridizations with ctenoBF-1 antisense riboprobes show that this gene is not expressed in the apical organ of ctenophores. CtenoBF-1 is expressed prior to first cleavage. Transcripts become localized to the aboral pole by the 8-cell stage and are inherited by ectodermal micromeres generated from this region at the 16- and 32-cell stages. Expression in subsets of these cells persists and is seen around the edge of the blastopore (presumptive mouth) and in distinct ectodermal regions along the tentacular poles. Following gastrulation, stomodeal expression begins to fade and intense staining becomes restricted to two distinct domains in each tentacular feeding apparatus. We suggest that the apical organ is not homologous to the brain of bilaterians but that the oral pole of ctenophores corresponds to the anterior pole of bilaterian animals.

  4. Reversible quantum cellular automata

    CERN Document Server

    Schumacher, B


    We define quantum cellular automata as infinite quantum lattice systems with discrete time dynamics, such that the time step commutes with lattice translations and has strictly finite propagation speed. In contrast to earlier definitions this allows us to give an explicit characterization of all local rules generating such automata. The same local rules also generate the global time step for automata with periodic boundary conditions. Our main structure theorem asserts that any quantum cellular automaton is structurally reversible, i.e., that it can be obtained by applying two blockwise unitary operations in a generalized Margolus partitioning scheme. This implies that, in contrast to the classical case, the inverse of a nearest neighbor quantum cellular automaton is again a nearest neighbor automaton. We present several construction methods for quantum cellular automata, based on unitaries commuting with their translates, on the quantization of (arbitrary) reversible classical cellular automata, on quantum c...

  5. 限制刑事技术专业实战技能训练开展的因素及对策%The Factors Restricting Combat Skills Training of Criminal Technology Major and the Countermeasures

    Institute of Scientific and Technical Information of China (English)



    公安院校刑事技术专业的人才培养目标是理论基础扎实、专业知识系统并且实战能力强的应用型复合型刑侦人员,当前刑事犯罪的特点对刑侦人员的实战技能提出了更高的要求。实战技能训练作为培养和提升公安院校刑事技术专业学生实战技能的重要手段和途径,由于受到来自学生、教师以及学校等因素的限制并没有取得理想的教学效果,本文分析了这些因素产生的原因并提出了转变学生观念扭转学习态度,提升教师业务能力和水平,聘请公安机关刑事技术人员为实践教学教官,加强实验室建设,以及建立校外实践训练基地等相应对策。%The training goal of criminal technology major in public security college is to cultivate the practical and versatile talents who have solid theoretical background, professional knowledge system, and outstanding combat ability. However, the characteristics of new crime put forward a higher requirement for the actual combat ability of criminal investigators. As an important way to train and promote the criminal technology majors’ combat ability, the combat skills training fails to receive satisfied teaching effects out of some restrictions from students, teachers and the college. This paper analyses the reasons of these restricted factors and presents the countermeasures accordingly, such as changing the students’ learning idea and attitudes, improving the teachers’ proficiency and teaching level, appointing the criminal technicians in public security organs to be practicing teachers, improving the lab, establishing the practice training base outside school, etc.

  6. Targeting cellular drivers and counter-regulators of hyperglycaemia- and transforming growth factor-β1-associated profibrotic responses in diabetic kidney disease. (United States)

    Docherty, Neil G; Murphy, Madeline; Martin, Finian; Brennan, Eoin P; Godson, Catherine


    Diabetic kidney disease occurs in >30% of patients with type 2 diabetes mellitus and is characterized at source by a maladaptive response in the renal parenchyma to exposure to a glucotoxic-lipotoxic diabetic milieu that courses coincident with hypertension. The consequence of these maladaptive responses is progressive renal injury, which is exacerbated by the development of a chronic inflammatory infiltrate associated with the development of tubulointerstitial fibrosis. The evolution of tubulointerstitial fibrosis is correlated with the loss of functional renal mass and descent towards renal failure. Transforming growth factor-β1 (TGF-β1) is a recognized mediator of the profibrotic response of mesangial cells and renal tubular epithelial cells to hyperglycaemia. While euglycaemia remains the goal in the treatment of type 2 diabetes mellitus, the prevention, arrest and reversal of microvascular complications, such as diabetic kidney disease, may be assisted by pharmacological modulation of the effectors of glucotoxicity, such as TGF-β1. This review focuses on describing how, through reductionist in vitro experimentation focusing on TGF-β1-related responses to hyperglycaemia, we have identified induced in high glucose-1 (IHG-1), induced in high glucose-2 (IHG-2/Grem1) and the lipoxin-inducible microRNA let-7c as potential targets for harnessing new therapeutic approaches to limit the bioactivity of TGF-β1 in diabetic kidney disease.

  7. The cellular distribution of Na+/H+ exchanger regulatory factor 1 is determined by the PDZ-I domain and regulates the malignant progression of breast cancer (United States)

    Du, Guifang; Gu, Yanan; Hao, Chengcheng; Yuan, Zhu; He, Junqi; Jiang, Wen G.; Cheng, Shan


    The oncogenic role of ectopic expression of Na+/H+ exchanger regulatory factor 1 (NHERF1) was recently suggested. Here, we show that NHERF1 was upregulated in high grades compared with low grades. Increased NHERF1 expression was correlated with poor prognosis and poor survival. NHERF1 expression was higher in the nucleus of cancer cells than in contiguous non- mammary epithelial cells. A novel mutation, namely NHERF1 Y24S, was identified in human breast cancer tissues and shown to correspond to a conserved residue in the PDZ-I domain of NHERF1. Truncation and mutation of the PDZ-I domain of NHERF1 increased the nuclear distribution of the NHERF1 protein, and this redistribution was associated with the malignant phenotype of breast cancer cells, including growth, migration, and adhesion. The present results suggest a role for NHERF1 in the progression of breast cancer mediated by the nuclear distribution of the NHERF1 protein, as determined by the truncation or key site mutation of the PDZ-I domain. PMID:27097111

  8. The promoter of the white spot syndrome virus immediate-early gene WSSV108 is activated by the cellular KLF transcription factor. (United States)

    Liu, Wang-Jing; Lo, Chu-Fang; Kou, Guang-Hsiung; Leu, Jiann-Horng; Lai, Ying-Jang; Chang, Li-Kwan; Chang, Yun-Shiang


    A series of deletion and mutation assays of the white spot syndrome virus (WSSV) immediate-early gene WSSV108 promoter showed that a Krüppel-like factor (KLF) binding site located from -504 to -495 (relative to the transcription start site) is important for the overall level of WSSV108 promoter activity. Electrophoretic mobility shift assays further showed that overexpressed recombinant Penaeus monodon KLF (rPmKLF) formed a specific protein-DNA complex with the (32)P-labeled KLF binding site of the WSSV108 promoter, and that higher levels of Litopenaeus vannamei KLF (LvKLF) were expressed in WSSV-infected shrimp. A transactivation assay indicated that the WSSV108 promoter was strongly activated by rPmKLF in a dose-dependent manner. Lastly, we found that specific silencing of LvKLF expression in vivo by dsRNA injection dramatically reduced both WSSV108 expression and WSSV replication. We conclude that shrimp KLF is important for WSSV genome replication and gene expression, and that it binds to the WSSV108 promoter to enhance the expression of this immediate-early gene.

  9. Redox regulation of SIRT1 in inflammation and cellular senescence. (United States)

    Hwang, Jae-woong; Yao, Hongwei; Caito, Samuel; Sundar, Isaac K; Rahman, Irfan


    Sirtuin 1 (SIRT1) regulates inflammation, aging (life span and health span), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging, in which oxidative stress occurs. SIRT1 is regulated by a NAD(+)-dependent DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), and subsequent NAD(+) depletion by oxidative stress may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to posttranslational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65, and FOXO3, thereby enhancing the inflammatory, prosenescent, and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox posttranslational modifications of SIRT1 and its roles in PARP1 and NF-κB activation, and FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging, are discussed. Furthermore, we have also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases.

  10. The Epstein-Barr virus BZLF1 protein inhibits tumor necrosis factor receptor 1 expression through effects on cellular C/EBP proteins. (United States)

    Bristol, Jillian A; Robinson, Amanda R; Barlow, Elizabeth A; Kenney, Shannon C


    The Epstein-Barr virus immediate-early protein, BZLF1 (Z), initiates the switch between latent and lytic infection and plays an essential role in mediating viral replication. Z also inhibits expression of the major receptor for tumor necrosis factor (TNF), TNFR1, thus repressing TNF cytokine signaling, but the mechanism for this effect is unknown. Here, we demonstrate that Z prevents both C/EBPα- and C/EBPβ-mediated activation of the TNFR1 promoter (TNFR1p) by interacting directly with both C/EBP family members. We show that Z interacts directly with C/EBPα and C/EBPβ in vivo and that a Z mutant altered at alanine residue 204 in the bZIP domain is impaired for the ability to interact with both C/EBP proteins. Furthermore, we find that the Z(A204D) mutant is attenuated in the ability to inhibit the TNFR1p but mediates lytic viral reactivation and replication in vitro in 293 cells as well as wild-type Z. Although Z does not bind directly to the TNFR1p in EMSA studies, chromatin immunoprecipitation studies indicate that Z is complexed with this promoter in vivo. The Z(A204D) mutant has reduced interaction with the TNFR1p in vivo but is similar to wild-type Z in its ability to complex with the IL-8 promoter. Finally, we show that the effect of Z on C/EBPα- and C/EBPβ-mediated activation is promoter dependent. These results indicate that Z modulates the effects of C/EBPα and C/EBPβ in a promoter-specific manner and that in some cases (including that of the TNFR1p), Z inhibits C/EBPα- and C/EBPβ-mediated activation.

  11. Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma. (United States)

    Han, Kyung Seok; Raven, Peter A; Frees, Sebastian; Gust, Kilian; Fazli, Ladan; Ettinger, Susan; Hong, Sung Joon; Kollmannsberger, Cristian; Gleave, Martin E; So, Alan I


    Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC.

  12. Heterogeneous cellular networks

    CERN Document Server

    Hu, Rose Qingyang


    A timely publication providing coverage of radio resource management, mobility management and standardization in heterogeneous cellular networks The topic of heterogeneous cellular networks has gained momentum in industry and the research community, attracting the attention of standardization bodies such as 3GPP LTE and IEEE 802.16j, whose objectives are looking into increasing the capacity and coverage of the cellular networks. This book focuses on recent progresses,  covering the related topics including scenarios of heterogeneous network deployment, interference management i

  13. The cellular mobile telephone: social perception and real facts

    Directory of Open Access Journals (Sweden)

    Pedro Javier Galache Ríos


    Full Text Available The cellular mobil telephone has evolved, in a very short period of time, from a technology restricted and scarcely used to the universalitation of its use by all the societies.The social perception that cellular mobil telephone represents a public health risk has created the need of developing a great deal of scientific/tecnics studies and also the implementation of legislation that gaaranties the development and use of information with the uppermost aim of public health protection.

  14. Caloric restriction-associated remodeling of rat white adipose tissue: effects on the growth hormone/insulin-like growth factor-1 axis, sterol regulatory element binding protein-1, and macrophage infiltration. (United States)

    Chujo, Yoshikazu; Fujii, Namiki; Okita, Naoyuki; Konishi, Tomokazu; Narita, Takumi; Yamada, Atsushi; Haruyama, Yushi; Tashiro, Kosuke; Chiba, Takuya; Shimokawa, Isao; Higami, Yoshikazu


    The role of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis in the lifelong caloric restriction (CR)-associated remodeling of white adipose tissue (WAT), adipocyte size, and gene expression profiles was explored in this study. We analyzed the WAT morphology of 6-7-month-old wild-type Wistar rats fed ad libitum (WdAL) or subjected to CR (WdCR), and of heterozygous transgenic dwarf rats bearing an anti-sense GH transgene fed ad libitum (TgAL) or subjected to CR (TgCR). Although less effective in TgAL, the adipocyte size was significantly reduced in WdCR compared with WdAL. This CR effect was blunted in Tg rats. We also used high-density oligonucleotide microarrays to examine the gene expression profile of WAT of WdAL, WdCR, and TgAL rats. The gene expression profile of WdCR, but not TgAL, differed greatly from that of WdAL. The gene clusters with the largest changes induced by CR but not by Tg were genes involved in lipid biosynthesis and inflammation, particularly sterol regulatory element binding proteins (SREBPs)-regulated and macrophage-related genes, respectively. Real-time reverse-transcription polymerase chain reaction analysis confirmed that the expression of SREBP-1 and its downstream targets was upregulated, whereas the macrophage-related genes were downregulated in WdCR, but not in TgAL. In addition, CR affected the gene expression profile of Tg rats similarly to wild-type rats. Our findings suggest that CR-associated remodeling of WAT, which involves SREBP-1-mediated transcriptional activation and suppression of macrophage infiltration, is regulated in a GH-IGF-1-independent manner.

  15. Analysis of restricting factors of long-term care of stroke survivors in community%社区脑卒中患者长期保健的制约因素分析

    Institute of Scientific and Technical Information of China (English)

    张亚奇; 张振香; 陈颖; 刘腊梅; 张秋实


    Objective To investigate the restricting factors of long-term care of stroke survivors in community.Methods The phenomenological methodology was adopted in the study.Sixteen stroke survivors were interviewed.Data were analyzed by Colaizzi's method.Results Three themes were found,including physical barriers,incorrect attitude towards disease,and defects of community health service.Conclusions On the basis of improving technology and ability,medical workers in community should consider of supporting the patients with information of disease and useful resources in a variety of ways,and improving the patients" health literacy.%目的 探讨社区脑卒中患者康复保健的制约因素.方法 采用半结构访谈法对16例社区脑卒中患者进行一对一访谈,收集患者资料,并以Colaizzi 7步分析法分析资料.结果 通过分析整理和提炼主题,归纳出躯体障碍因素,不良疾病态度以及社区卫生服务不到位3个主题.结论社区医务人员应该在提高自身技术与能力的基础上,考虑以多种方式给予患者疾病知识和健康资源信息的支持和教育,提高患者健康素养.

  16. Restrictive Factors and Historical Significance of Rectification Movement in the Later Anti-Japanese War%抗战后期敌后整风的制约因素与历史意义

    Institute of Scientific and Technical Information of China (English)



    抗战后期,中共在全党开展整风学习运动。处在敌后的各根据地,尽管也都在规定时间内完成整风,但从当时的情况来看,这些根据地的整风受到诸多因素的制约,如党员干部对整风的重要性缺乏认识、敌后环境异常艰苦、党员与干部知识水平较低以及整风脱离实际等。分析敌后整风情况,无论从认识还是实践上,对于如今的党建工作也有一定的启发意义。%In the latter part of the Anti-Japanese War, the Chinese Communists Party carried out the rectification movement. Although the rectification was completed in a short time, from the point of view of the situation at that time, the rectification movement was restricted by many factors , such as the lack of understanding of importance of Party members and cadres ,the difficult environment in the enemy’s rear area, low level of knowledge and rectification from the reality etc. Analysis of rectification situation both from behind enemy lines, understanding and practice, also have certain enlightening significance for today ’s rectification learning.


    Institute of Scientific and Technical Information of China (English)



    在现代社会,公民积极主动地参与政府的公共政策,除了基于自身利益追求的参与动机外,实现和促进与全体社会成员相联系的公共利益也是一个重要动机。改革开放以后,在公民个体的政策参与逐渐增多的同时,我国以民间组织为主体的各种利益团体参与政府公共政策的活动也逐渐增多。同时在我国公民的公共政策参与过程中存在的问题也十分突出。公共政策参与中公民层面的制约因素主要包括参与意识不强、参与能力不足和参与的组织化程度不高3个方面。%In modern society, citizens actively participate in the government' s public policies. In addition to participation based on the pursuit of self-interests, the achieving and promoting of the public interest involving all members of society can be another important motivation. After the reform and opening up, an increasing number of individual citizens participate in policies and meanwhile more various interest groups in China take part in more policy-related activities with civil organizations as the main body. There exist some prominent problems in the participating process. The factors restricting citizens from participating in public policy include weak sense of participation, lack of capacity for involvement and participation and low degree of organization.

  18. 贫困地区民营经济发展的制约因素及对策分析%Restricting Factors for the Growth of Private Economy in Poverty-Stricken Areas and the Strategy

    Institute of Scientific and Technical Information of China (English)

    彭贞贞; 马骥


    民营经济发展水平低是贫困地区经济发展不发达的重要原因。制约贫困地区民营经济发展的因素有脱贫致富的思想、人力资源状况、金融生态环境和技术创新水平等。促进贫困地区民营经济发展与脱贫致富必须根据民营经济产业发展需求,大力发展职业教育;优化环境,承接产业转移;创新贫困地区新型城镇化发展机制,推动地区民营经济发展;大力发展交通基础设施,破解民营经济发展瓶颈;创新民营企业管理,做大做强民营经济。%Inadequate development of the private economy is a major reason of economic underdevelopment in poverty-driven areas. Fac-tors restricting the growth of the private economy in these areas include people's lack of eagerness for creating a fortune, human resource shortage, and the poor financial environment and technological innovation ability. To shake off poverty, the areas must develop the private economy by proactively develop vocational education, improve environment for carrying on industry transfer, innovate new-type urbaniza-tion mechanism, enhance the transportation infrastructure construction, and innovate the management of private enterprises.

  19. Granulocyte-macrophage stimulating factor (GM-CSF increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy

    Directory of Open Access Journals (Sweden)

    Martinez Micaela


    Full Text Available Abstract Background Advanced cancer and chemotherapy are both associated with immune system suppression. We initiated a clinical trial in patients receiving chemotherapy for metastatic colorectal cancer to determine if administration of GM-CSF in this setting was immunostimulatory. Methods Between June, 2003 and January, 2007, 20 patients were enrolled in a clinical trial (NCT00257322 in which they received 500 ug GM-CSF daily for 4 days starting 24 hours after each chemotherapy cycle. There were no toxicities or adverse events reported. Blood was obtained before chemotherapy/GM-CSF administration and 24 hours following the final dose of GM-CSF and evaluated for circulating dendritic cells and adaptive immune cellular subsets by flow cytometry. Peripheral blood mononuclear cell (PBMC expression of γ-interferon and T-bet transcription factor (Tbx21 by quantitative real-time PCR was performed as a measure of Th1 adaptive cellular immunity. Pre- and post-treatment (i.e., chemotherapy and GM-CSF samples were evaluable for 16 patients, ranging from 1 to 5 cycles (median 3 cycles, 6 biologic sample time points. Dendritic cells were defined as lineage (- and MHC class II high (+. Results 73% of patients had significant increases in circulating dendritic cells of ~3x for the overall group (5.8% to 13.6%, p = 0.02 and ~5x excluding non-responders (3.2% to 14.5%, p Tbx21 levels declined by 75% following each chemotherapy cycle despite administration of GM-CSF (p = 0.02. PBMC γ-interferon expression, however was unchanged. Conclusions This clinical trial confirms the suppressive effects of chemotherapy on Th1 cellular immunity in patients with metastatic colorectal cancer but demonstrates that mid-cycle administration of GM-CSF can significantly increase the proportion of circulating dendritic cells. As the role of dendritic cells in anti-tumor immunity becomes better defined, GM-CSF administration may provide a non-toxic intervention to augment this arm

  20. Sponging of Cellular Proteins by Viral RNAs


    Charley, Phillida A.; Wilusz, Jeffrey


    Viral RNAs accumulate to high levels during infection and interact with a variety of cellular factors including miRNAs and RNA-binding proteins. Although many of these interactions exist to directly modulate replication, translation and decay of viral transcripts, evidence is emerging that abundant viral RNAs may in certain cases serve as a sponge to sequester host non coding RNAs and proteins. By effectively reducing the ability of cellular RNA binding proteins to regulate host cell gene exp...

  1. Nanostructured cellular networks. (United States)

    Moriarty, P; Taylor, M D R; Brust, M


    Au nanocrystals spin-coated onto silicon from toluene form cellular networks. A quantitative statistical crystallography analysis shows that intercellular correlations drive the networks far from statistical equilibrium. Spin-coating from hexane does not produce cellular structure, yet a strong correlation is retained in the positions of nanocrystal aggregates. Mechanisms based on Marangoni convection alone cannot account for the variety of patterns observed, and we argue that spinodal decomposition plays an important role in foam formation.

  2. Very strict selectional restrictions

    CERN Document Server

    Laporte, Eric; Dias, Maria Carmelita P


    We discuss the characteristics and behaviour of two parallel classes of verbs in two Romance languages, French and Portuguese. Examples of these verbs are Port. abater [gado] and Fr. abattre [b\\'etail], both meaning "slaughter [cattle]". In both languages, the definition of the class of verbs includes several features: - They have only one essential complement, which is a direct object. - The nominal distribution of the complement is very limited, i.e., few nouns can be selected as head nouns of the complement. However, this selection is not restricted to a single noun, as would be the case for verbal idioms such as Fr. monter la garde "mount guard". - We excluded from the class constructions which are reductions of more complex constructions, e.g. Port. afinar [instrumento] com "tune [instrument] with".

  3. Modulation of Cellular Transcription Factor Activity

    DEFF Research Database (Denmark)


    A novel class of compounds, known as peptide nucleic acids, form double-stranded structures with one another and with ssDNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  4. Differences between disease-associated endoplasmic reticulum aminopeptidase 1 (ERAP1) isoforms in cellular expression, interactions with tumour necrosis factor receptor 1 (TNF-R1) and regulation by cytokines. (United States)

    Yousaf, N; Low, W Y; Onipinla, A; Mein, C; Caulfield, M; Munroe, P B; Chernajovsky, Y


    Endoplasmic reticulum aminopeptidase 1 (ERAP1) processes peptides for major histocompatibility complex (MHC) class I presentation and promotes cytokine receptor ectodomain shedding. These known functions of ERAP1 may explain its genetic association with several autoimmune inflammatory diseases. In this study, we identified four novel alternatively spliced variants of ERAP1 mRNA, designated as ΔExon-11, ΔExon-13, ΔExon-14 and ΔExon-15. We also observed a rapid and differential modulation of ERAP1 mRNA levels and spliced variants in different cell types pretreated with lipopolysaccharide (LPS). We have studied three full-length allelic forms of ERAP1 (R127-K528, P127-K528, P127-R528) and one spliced variant (ΔExon-11) and assessed their interactions with tumour necrosis factor receptor 1 (TNF-R1) in transfected cells. We observed variation in cellular expression of different ERAP1 isoforms, with R127-K528 being expressed at a much lower level. Furthermore, the cellular expression of full-length P127-K528 and ΔExon-11 spliced variant was enhanced significantly when co-transfected with TNF-R1. Isoforms P127-K528, P127-R528 and ΔExon-11 spliced variant associated with TNF-R1, and this interaction occurred in a region within the first 10 exons of ERAP1. Supernatant-derived vesicles from transfected cells contained the full-length and ectodomain form of soluble TNF-R1, as well as carrying the full-length ERAP1 isoforms. We observed marginal differences between TNF-R1 ectodomain levels when co-expressed with individual ERAP1 isoforms, and treatment of transfected cells with tumour necrosis factor (TNF), interleukin (IL)-1β and IL-10 exerted variable effects on TNF-R1 ectodomain cleavage. Our data suggest that ERAP1 isoforms may exhibit differential biological properties and inflammatory mediators could play critical roles in modulating ERAP1 expression, leading to altered functional activities of this enzyme.

  5. Restrictions to HIV-1 replication in resting CD4+T lymphocytes

    Institute of Scientific and Technical Information of China (English)

    Xiaoyu Pan; Hanna-Mari Baldauf; Oliver T Keppler; Oliver T Fackler


    CD4+ T lymphocytes represent the main target cell population of human immunodeficiency virus (HIV).In an activated state,CD4+ T cells residing in lymphoid organs are a major reservoir of ongoing HIV-1 replication in infected individuals.In contrast,resting CD4+ T cells are highly resistant to productive HIV-1 infection,yet are massively depleted during disease progression and represent a substantial latent reservoir for the virus in vivo.Barriers preventing replication of HIV-1 in resting CD4+ T cells include a rigid layer of cortical actin and,early after HIV-1entry,a block that limits reverse transcription of incoming viral RNA genomes.Defining the molecular bases of these restrictions has remained one of the central open questions in HIV research.Recent advances unraveled mechanisms by which HIV-1 bypasses the entry block and established the host cell restriction factor SAMHD1,a deoxynucleoside triphosphate triphosphohydrolase,as a central determinant of the cellular restriction to HIV-1 reverse transcription in resting CD4+ T cells.This review summarizes our current molecular and pathophysiological understanding of the multi-faceted interactions of HIV-1 with resting CD4+ T lymphocytes.

  6. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. (United States)

    Martin, Bronwen; Mattson, Mark P; Maudsley, Stuart


    The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span. CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease. A better understanding of the impact of CR and IF on the aging nervous system will likely lead to novel approaches for preventing and treating neurodegenerative disorders.

  7. Epigenetics and Cellular Metabolism (United States)

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao


    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. PMID:27695375

  8. Architected Cellular Materials (United States)

    Schaedler, Tobias A.; Carter, William B.


    Additive manufacturing enables fabrication of materials with intricate cellular architecture, whereby progress in 3D printing techniques is increasing the possible configurations of voids and solids ad infinitum. Examples are microlattices with graded porosity and truss structures optimized for specific loading conditions. The cellular architecture determines the mechanical properties and density of these materials and can influence a wide range of other properties, e.g., acoustic, thermal, and biological properties. By combining optimized cellular architectures with high-performance metals and ceramics, several lightweight materials that exhibit strength and stiffness previously unachievable at low densities were recently demonstrated. This review introduces the field of architected materials; summarizes the most common fabrication methods, with an emphasis on additive manufacturing; and discusses recent progress in the development of architected materials. The review also discusses important applications, including lightweight structures, energy absorption, metamaterials, thermal management, and bioscaffolds.

  9. Some applications and prospects of cellular automata in traffic problems

    NARCIS (Netherlands)

    Goldengorin, Boris; Makarenko, Alexander; Smelyanec, Natalia; Yacoubi, SE; Chopard, B; Bandini, S


    In this paper we deal with mathematical modeling of participants' movement based on cellular automata (CA). We describe some improvements of CA models of pedestrian motion taking into account the real geometrical constraints induced by a specific restricted space. Also some presumable optimization p

  10. Ecology from the Perspective of Analysis on the Factors Restricting Development of China′s Cartoon Periodicals%生态学视角下我国动漫类期刊发展制约因素探析

    Institute of Scientific and Technical Information of China (English)



    Anime journals as the front end of the animation industry chain,is the pioneer of the animation indus-try development.In recent years,the journal of the Chinese animation market presents the explosive growth of the deteriorating ecological environment at the same time.Elements in the system main body and anime have open,dynamic and network system,supporting policies lack of pertinence and operability,and publication man-agement system reform lags behind the policy environment;Animation industry chain of each node lack of con-tact,communication and cooperation,market orientation and layout is messy,homogeneity and low level compe-tition,the industry environment;Original animation works and journal editors and lack of business resources and environment is a major factor which restricts the healthy development of anime journals.%动漫期刊作为动漫产业链的前端,是动漫产业发展的先行者。近年来,中国动漫期刊市场呈现井喷式发展的同时其生态环境逐渐恶化。在动漫期刊这个系统主体和要素都具有开放性、动态性和网络化的系统中,扶持政策缺少针对性和可操作性以及出版市场秩序管理制度改革滞后的政策环境;动漫产业链各节点缺乏联系、沟通、合作,市场定位和布局凌乱,同质化低水平竞争的产业环境;动漫作品原创和期刊编辑、经营人才匮乏的资源环境是制约动漫期刊健康发展的主要因素。

  11. Restricted Factors and Countermeasures for the Development of Chinese Ice Hockey Players%我国冰球运动发展的制约因素及对策

    Institute of Scientific and Technical Information of China (English)

    宁文静; 王淑华


    冰球运动是一项冬季体育运动中唯一的球类集体项目,其运动水平可以代表一个国家冬季运动的总体水平。对我国冰球运动现状进行分析,找出目前我国冰球运动存在项目普及萎缩,后备人才短缺;培养体制不完善,场地、器材匮乏;教练员教练水平低,创新意识差;科技投入少,科学化训练水平低等制约因素。提出加大冰球运动后备人才培养力度;制定、完善冰球运动员培养、输送体制;提升冰球运动教练员的整体素质;强化冰球运动科学化训练体系等解决对策,为让冰球运动重新在中国的大地上蓬勃开展起来,打造中国冰球崭新的未来提供参考。%Ice hockey is the only team ball game of winter sports , its sports level can represent the winter sports level of a country .By analyzing the status of Chinese ice hockey , this paper has found out that there are many restricted factors of Chinese ice hockey , such as project popularization declining , shortages of re-served talents;training system is not perfect , lack of venues and equipments;low level of coaches , poor in-novation consciousness;low technology input , low level of scientific training .The paper puts forward that we should strengthen the reserved talents training of ice hockey; outline and perfect the training conveying system of ice hockey players;improve the overall quality of coaches;strengthen scientific training system of ice hockey and other solutions , in order to give a reference for having a great boom in ice hockey in China and creating a new future of Chinese ice hockey .

  12. Cellular blue naevus

    Directory of Open Access Journals (Sweden)

    Mittal R


    Full Text Available A 31-year-old man had asymptomatic, stationary, 1.5X2 cm, shiny, smooth, dark blue nodule on dorsum of right hand since 12-14 years. In addition he had developed extensive eruption of yellow to orange papulonodular lesions on extensors of limbs and buttocks since one and half months. Investigations confirmed that yellow papules were xanthomatosis and he had associated diabetes mellitus and hyperlipidaemia. Biopsy of blue nodule confirmed the clinical diagnosis of cellular blue naevus. Cellular blue naevus is rare and its association with xanthomatosis and diabetes mellitus were interesting features of above patients which is being reported for its rarity.

  13. Insulin-like growth factor 1 (IGF1) and its active peptide (1-3)IGF1 enhance the expression of synaptic markers in neuronal circuits through different cellular mechanisms.

    LENUS (Irish Health Repository)

    Corvin, Aiden P


    Insulin-like growth factor-1 (IGF1) and its active peptide (1-3)IGF1 modulate brain growth and plasticity and are candidate molecules for treatment of brain disorders. IGF1 N-terminal portion is naturally cleaved to generate the tri-peptide (1-3)IGF1 (glycine-praline-glutamate). IGF1 and (1-3)IGF have been proposed as treatment for neuropathologies, yet their effect on nerve cells has not been directly compared. In this study we examine the effects of IGF1 and (1-3)IGF1 in primary cortical cultures and measure the expression levels of markers for intracellular pathways and synaptic function. We find that both treatments activate the IGF1 receptor and enhance the expression of synaptic markers, however, they activate different intracellular pathways. Furthermore, (1-3)IGF1 administration increases the expression of endogenous IGF1, suggesting a direct interaction between the two molecules. The results show that the two molecules increase the expression of synaptic proteins through activating different cellular mechanisms.

  14. Property Rights, Restrictions and Responsibilities

    DEFF Research Database (Denmark)

    Enemark, Stig

    Land Administration Systems are the basis for conceptualizing rights, restrictions and responsibilities related to people, policies and places. Property rights are normally concerned with ownership and tenure whereas restrictions usually control use and activities on land. Responsibilities relate...... more to a social, ethical commitment or attitude to environmental sustainability and good husbandry. This paper provides an overall understanding of the concept of land administration systems for dealing with rights, restrictions and responsibilities in future spatially enabled government. Finally...

  15. Dietary Restriction and Nutrient Balance in Aging

    Directory of Open Access Journals (Sweden)

    Júlia Santos


    Full Text Available Dietary regimens that favour reduced calorie intake delay aging and age-associated diseases. New evidences revealed that nutritional balance of dietary components without food restriction increases lifespan. Particular nutrients as several nitrogen sources, proteins, amino acid, and ammonium are implicated in life and healthspan regulation in different model organisms from yeast to mammals. Aging and dietary restriction interact through partially overlapping mechanisms in the activation of the conserved nutrient-signalling pathways, mainly the insulin/insulin-like growth factor (IIS and the Target Of Rapamycin (TOR. The specific nutrients of dietary regimens, their balance, and how they interact with different genes and pathways are currently being uncovered. Taking into account that dietary regimes can largely influence overall human health and changes in risk factors such as cholesterol level and blood pressure, these new findings are of great importance to fully comprehend the interplay between diet and humans health.

  16. Cellular Response to Irradiation

    Institute of Scientific and Technical Information of China (English)

    LIU Bo; YAN Shi-Wei


    To explore the nonlinear activities of the cellular signaling system composed of one transcriptional arm and one protein-interaction arm, we use an irradiation-response module to study the dynamics of stochastic interactions.It is shown that the oscillatory behavior could be described in a unified way when the radiation-derived signal and noise are incorporated.

  17. 34周以下早产儿宫外生长发育迟缓发生的影响因素%Risk factors for extrauterine growth restriction in preterm infants with gestational age less than 34 weeks

    Institute of Scientific and Technical Information of China (English)

    曹玮; 张永红; 赵冬莹; 夏红萍; 朱天闻; 谢利娟


    ObjectiveTo investigate the correlated factors contributed to extrauterine growth restriction (EUGR) in preterm infants with the gestational age less than 34 weeks.MethodsA total of 694 preterm infants with the gestational ages less than 34 weeks were enrolled. They were classiifed into EUGR and non-EUGR groups by weight on discharge. The perinatal data, growth data, nutritional information and morbidities during hospitalization were compared between the two groups.ResultsEUGR on discharge occurred in 284 (40.9%) out of the 694 infants. The incidence of EUGR in intrauterine growth restriction (IUGR) infants was signiifcantly higher than in non-IUGR infants (P<0.01). The very low birth weight (VLBW) infants had a higher incidence of EUGR than non-VLBW infants (P<0.01). The incidence of EUGR increased with the decreases of gestational age at birth and birth weight (P<0.01). Compared with the non-EUGR group, the fasting time, the duration of parenteral nutrition, the time beginning to feed and the age to achieve full enteral feeds were signiifcantly greater in the EUGR group (P<0.01). The cumulative protein deifcit and cumulative caloric deifcit in the ifrst week of life in the EUGR group were higher than in the non-EUGR group (P<0.05). The incidences of respiratory distress syndrome, apnea, necrotizing enterocolitis and septicemia in the EUGR group were higher than in the non-EUGR group (P<0.05). The logistic regression analysis showed that birth weight, gestational age at birth and IUGR were the independent risk factors for EUGR.ConclusionsThe incidence of EUGR in infants with gestational age less than 34 weeks is high, especially in IUGR or VLBW infants. Early and aggressive nutritional strategy and prevention of apnea and septicemia may facilitate to reduce the occurrence of EUGR.%目的:研究34周以下早产儿宫外生长发育迟缓(EUGR)发生的相关因素。方法选取<34周早产儿694例,根据出院时体重分为EUGR组和非EUGR组,回顾

  18. 制约城市社区老年人参与健身活动的因素研究——基于解释结构模型视角%Research of the Individual Restricting Factors of Elderly Fitness Participation in Urban Community Based on ISM

    Institute of Scientific and Technical Information of China (English)



    This research based on ISM and analyzed the individual restricting factors of elderly fitness participation in urban community.It used the method of matrix to grading the restricting factors.Conclusion shows that the interpretative structural modeling can be classified by three grades.The purpose of this research was to provide strategy analysis and theoretical basis for community managers and elderly fitness activity promoters.%研究制约城市社区老年人健身参与的个人因素,利用ISM模型对各项指标进行分析,运用矩阵的方法对其分级。结果表明,构建的解释结构模型可以分为三级,从而为社区管理者和老年健身活动推广者提供策略分析和理论依据。

  19. Effects of sustained sleep restriction on mitogen-stimulated cytokines, chemokines and T helper 1/ T helper 2 balance in humans.

    Directory of Open Access Journals (Sweden)

    John Axelsson

    Full Text Available BACKGROUND: Recent studies suggest that acute sleep deprivation disrupts cellular immune responses by shifting T helper (Th cell activity towards a Th2 cytokine profile. Since little is known about more long-term effects, we investigated how five days of sleep restriction would affect pro-inflammatory, chemotactic, Th1- and Th2 cytokine secretion. METHODS: Nine healthy males participated in an experimental sleep protocol with two baseline sleep-wake cycles (sleep 23.00-07.00 h followed by 5 days with restricted sleep (03.00-07.00 h. On the second baseline day and on the fifth day with restricted sleep, samples were drawn every third hour for determination of cytokines/chemokines (tumor necrosis factor alpha (TNF-α, interleukin (IL -1β, IL-2, IL-4 and monocyte chemoattractant protein-1 (MCP-1 after in vitro stimulation of whole blood samples with the mitogen phytohemagglutinin (PHA. Also leukocyte numbers, mononuclear cells and cortisol were analysed. RESULTS: 5-days of sleep restriction affected PHA-induced immune responses in several ways. There was a general decrease of IL-2 production (p<.05. A shift in Th1/Th2 cytokine balance was also evident, as determined by a decrease in IL2/IL4 ratio. No other main effects of restricted sleep were shown. Two significant interactions showed that restricted sleep resulted in increased TNF-α and MCP-1 in the late evening and early night hours (p's<.05. In addition, all variables varied across the 24 h day. CONCLUSIONS: 5-days of sleep restriction is characterized by a shift towards Th2 activity (i.e. lower 1L-2/IL-4 ratio which is similar to the effects of acute sleep deprivation and psychological stress. This may have implications for people suffering from conditions characterized by excessive Th2 activity like in allergic disease, such as asthma, for whom restricted sleep could have negative consequences.

  20. 森林资源产权市场制约因素及对策分析——基于供求视角%Analysis on Forest Resource Property Market's Restriction Factors and Countermeasures: From the Perspective of Supply and Demand

    Institute of Scientific and Technical Information of China (English)

    乔永平; 聂影


    目前森林资源产权市场仍处于起步阶段,存在着众多制约市场供求双方的因素.制约需求的因素包括森林资源产权制度不完善、森林资源风险防范机制不健全、林业融资难、林业比较利益低;制约供给的因素包括政策法规不完善、信息不完备、交易成本高、非农就业机会少、社会保障制度不健全等;通过市场中介间接影响供求的因素包括市场中介组织缺乏等.本研究给出了强化森林资源产权市场机制的对策建议.%Current forest resource property market is still at the initial stage and there are many restricting factors that affect both the supply and the demand. The factors restricting the demand are forest resource property systems being imperfect, forest resource risk prevention mechanism being incomplete, forestry financing being difficult, forestry comparative rate of profit being low and so on; the factors restricting the supply include concerning law and policies being imperfect, information being incomplete, trading cost being high, non-agricultural job chance being low, social security system being imperfect and so on; to make it worse, imperfect intermediary organization turns out to be one of the restricting factors affect both the supply and the demand. This research offers some countermeasure suggestions of strengthening forest resource property market mechanism.

  1. Nutrient restrictive factors, nutrient absorption and accumulation of red kidney bean%红芸豆养分限制因子及养分吸收、积累和分配特征研究

    Institute of Scientific and Technical Information of China (English)

    韩彦龙; 晋凡生; 郑普山; 李晓平; 李洁; 李海金


    AbstractWith important economical and nutritional values, kidney bean (Phaseolus vuglaris) is one of the main grain crops in China. Recently, the planting area of red kidney bean has been gradually increasing in Shanxi Province, China. However, the nutrient absorption characteristics and limiting factors of kidney bean was still not very clear. Nitrogen (N), phosphorus (P) and potassium (K) are essential nutrients for plant growth, and knowledge on periodic uptake, accumulation and allocation of N, P and K in different organs of kidney bean is important to implement nutrient management practices to ensure its’ sustainable production. There were several studies on effect of the fertilization and nitrogen application on yield of kidney bean. However, few studies have investigated the nutrient accumulation and distribution characteristics of kidney bean. In this study, field experiment was conducted with different nutrient application (N absence, P absence, K absence, NPK application and no fertilizer) using the red kidney bean variety ‘British Red’ as the materials in 2014. The nutrient restrictive factors, dry matter accumulation and nutrient uptake and accumulation of red kidney bean were investigated. The samples of NPK application treatment at different growth stages were collected for determining dry matter and nutrient contents in different organs, to illustrate the law of nutrient absorption. This is beneficial to provide theoretical basis for rational fertilization and high yield cultivation of red kidney bean. The results showed that NPK application treatment significantly increased yield of red kidney bean compared to absence of N, P, or K and no fertilizer treatments. Compared to NPK application treatment, yields of N-, P- or K-absence decreased by 14.2%, 8.0% and 11.3%, respectively, which indicated that the order of nutrient restrictive factors of red kidney bean yield was N > K > P. The dry matter accumulation rate of red kidney bean increased

  2. Mechanisms of Salmonella Typhi Host Restriction. (United States)

    Spanò, Stefania


    Salmonella enterica serovar Typhi (S. Typhi) is the cause of typhoid fever, a life-threatening bacterial infection that is very common in the developing world. Recent spread of antimicrobial resistant isolates of S. Typhi makes typhoid fever, a global public health risk. Despite being a common disease, still very little is known about the molecular mechanisms underlying typhoid fever and S. Typhi pathogenesis. In contrast to other Salmonellae, S. Typhi can only infect humans. The molecular bases of this human restriction are mostly unknown. Recent studies identified a novel pathway that contributes to S. Typhi human restriction and is required for killing S. Typhi in macrophages of nonsusceptible species. The small Rab GTPase Rab32 and its guanine nucleotide exchange factor BLOC-3 are the critical components of this pathway. These proteins were already well known as important regulators of intracellular membrane transport. In particular, they are central for the transport of enzymes that synthetize melanin in pigment cells. The recent findings that Rab32 and BLOC-3 are required for S. Typhi host restriction point out to a novel mechanism restricting the growth of bacterial pathogen, dependent on the transport of still unknown molecule(s) to the S. Typhi vacuole. The identification of this novel antimicrobial pathway constitutes a critical starting point to study molecular mechanisms killing bacterial pathogens and possibly identify novel antimicrobial molecules.

  3. An Investigation on the Restricting Factors of Teachers' Professional——Development in the west Rural Areas of Guangdong Province%农村教师专业发展阻抗因素分析——基于粤西地区农村中小学教师的调查

    Institute of Scientific and Technical Information of China (English)

    文雪; 廖诗艳


    It is significant to understand the restricting factors of teachers' professional development for advancing teachers' professional development.The study investigats the restricting factors of teachers' professional development in the west rural areas of Guangdong province.Results show that there are a lot of insufficiencies of sustaining factors,ensuring factors,technical factors,motiving factors in rural teachers' professional developing.The suggestion is to advance the teachers' professional development by improving social conditions,constructing systems,leading professional development,and inspiring individual motivity.%了解教师专业发展的阻抗因素对有效促进教师专业发展具有重要意义。本研究对粤西地区农村教师专业发展阻抗因素进行了调查,结果表明,农村教师的专业发展存在着支撑性因素、保障性因素、技术性因素、动机性因素等的缺失。需要有针对性地从环境改善、制度建设、专业引领、动机激发等方面来促进教师的专业发展。

  4. Factores asociados a la infección celular por el virus de la necrosis pancreática infecciosa (IPNV Factors associated with cellular infection by the infectious pancreatic necrosis virus (IPNV

    Directory of Open Access Journals (Sweden)

    C Ortega


    Full Text Available El virus de la necrosis pancreática infecciosa (IPNV es una de las principales causas de pérdidas económicas en salmónidos de cultivo; la expresión temporal y las características de sus componentes han sido descritas en varios trabajos; sin embargo, el papel de las distintas proteínas en la patogénesis viral no ha sido completamente determinado. En este artículo se presenta una revisión bibliográfica de los procesos que permiten establecer la relación virus-célula, la replicación y diseminación de la infección, destacando el papel de los componentes virales en tales mecanismos y los efectos de su variabilidad sobre la virulencia viral, describiendo también los mecanismos moleculares que son característicos de los Birnavirusen relación a su replicación, traducción y maduración. Las respuestas y mecanismos de defensa del hospedero en contra de la infección viral son abordadas resaltando la importancia de la inmunidad inespecífica a través de la vía interferón como estimulador de la síntesis de proteínas antivirales y la implicancia de la apoptosis también como un mecanismo de defensa, pero que puede ser modulado por las proteínas del virus. El desarrollo del estado portador, considerado uno de los aspectos más importantes en la diseminación de IPNV, se aborda describiendo la participación de factores virales y celulares.The infectious pancreatic necrosis virus (IPNV is one of the main causes of economic losses in salmon farms. Its temporal expression and the characteristics of its components have been described in many studies, however, the role of proteins in viral pathogenesis has not been completely determined. The aim of this review is to detail the processes that allow the establishment of a virus-cell relationship, replication and dissemination of the infection, highlighting the role of the viral components in such mechanisms and the effect of their variability on viral virulence. The molecular mechanisms

  5. Molecular and Cellular Signaling

    CERN Document Server

    Beckerman, Martin


    A small number of signaling pathways, no more than a dozen or so, form a control layer that is responsible for all signaling in and between cells of the human body. The signaling proteins belonging to the control layer determine what kinds of cells are made during development and how they function during adult life. Malfunctions in the proteins belonging to the control layer are responsible for a host of human diseases ranging from neurological disorders to cancers. Most drugs target components in the control layer, and difficulties in drug design are intimately related to the architecture of the control layer. Molecular and Cellular Signaling provides an introduction to molecular and cellular signaling in biological systems with an emphasis on the underlying physical principles. The text is aimed at upper-level undergraduates, graduate students and individuals in medicine and pharmacology interested in broadening their understanding of how cells regulate and coordinate their core activities and how diseases ...

  6. Methionine restriction decreases endogenous oxidative molecular damage and increases mitochondrial biogenesis and uncoupling protein 4 in rat brain. (United States)

    Naudí, Alba; Caro, Pilar; Jové, Mariona; Gómez, José; Boada, Jordi; Ayala, Victoria; Portero-Otín, Manuel; Barja, Gustavo; Pamplona, Reinald


    Aging plays a central role in the occurrence of neurodegenerative diseases. Caloric restriction (CR) mitigates oxidative stress by decreasing the rate of generation of endogenous damage, a mechanism that can contribute to the slowing of the aging rate induced by this intervention. Various reports have recently linked methionine to aging, and methionine restriction (MetR) without energy restriction also increases life span. We have thus hypothesized that MetR can be responsible, at least in part, for the decrease in endogenous oxidative damage in CR. In this investigation we subjected male rats to exactly the same dietary protocol of MetR that is known to increase their life span. We have found that MetR: (1) decreases the mitochondrial complex I content and activity, as well as complex III content, while the complex II and IV, the mitochondrial flavoprotein apoptosis-inducing factor (AIF) and ATP content are unchanged; (2) increases the mitochondrial biogenesis factor PGC-1alpha; (3) increases the resistance of brain to metabolic and oxidative stress by increasing mitochondrial uncoupling protein 4 uncoupling protein 4 (UCP4); and (4) decreases mitochondrial oxidative DNA damage and all five different markers of protein oxidation measured and lowers membrane unsaturation in rat brain. No changes were detected for protein amino acid composition. These beneficial MetR-induced changes likely derived from metabolic reprogramming at the cellular and tissue level can play a key role in the protection against aging-associated neurodegenerative disorders.

  7. Repletion of TNFα or leptin in calorically restricted mice suppresses post-restriction hyperphagia (United States)

    Hambly, Catherine; Duncan, Jacqueline S.; Archer, Zoë A.; Moar, Kim M.; Mercer, Julian G.; Speakman, John R.


    SUMMARY The causes of post-restriction hyperphagia (PRH) represent a target for drug-based therapies to prevent obesity. However, the factors causing PRH are poorly understood. We show that, in mice, the extent of PRH was independent of the time under restriction, but depended on its severity, suggesting that PRH was driven by signals from altered body composition. Signals related to fat mass were important drivers. Circulating levels of leptin and TNFα were significantly depleted following caloric restriction (CR). We experimentally repleted their levels to match those of controls, and found that in both treatment groups the level of PRH was significantly blunted. These data establish a role for TNFα and leptin in the non-pathological regulation of energy homeostasis. Signals from adipose tissue, including but not limited to leptin and TNFα, regulate PRH and might be targets for therapies that support people engaged in CR to reduce obesity. PMID:21954068

  8. Environment Aware Cellular Networks

    KAUST Repository

    Ghazzai, Hakim


    The unprecedented rise of mobile user demand over the years have led to an enormous growth of the energy consumption of wireless networks as well as the greenhouse gas emissions which are estimated currently to be around 70 million tons per year. This significant growth of energy consumption impels network companies to pay huge bills which represent around half of their operating expenditures. Therefore, many service providers, including mobile operators, are looking for new and modern green solutions to help reduce their expenses as well as the level of their CO2 emissions. Base stations are the most power greedy element in cellular networks: they drain around 80% of the total network energy consumption even during low traffic periods. Thus, there is a growing need to develop more energy-efficient techniques to enhance the green performance of future 4G/5G cellular networks. Due to the problem of traffic load fluctuations in cellular networks during different periods of the day and between different areas (shopping or business districts and residential areas), the base station sleeping strategy has been one of the main popular research topics in green communications. In this presentation, we present several practical green techniques that provide significant gains for mobile operators. Indeed, combined with the base station sleeping strategy, these techniques achieve not only a minimization of the fossil fuel consumption but also an enhancement of mobile operator profits. We start with an optimized cell planning method that considers varying spatial and temporal user densities. We then use the optimal transport theory in order to define the cell boundaries such that the network total transmit power is reduced. Afterwards, we exploit the features of the modern electrical grid, the smart grid, as a new tool of power management for cellular networks and we optimize the energy procurement from multiple energy retailers characterized by different prices and pollutant

  9. Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome. (United States)

    Volek, Jeff S; Fernandez, Maria Luz; Feinman, Richard D; Phinney, Stephen D


    Abnormal fatty acid metabolism and dyslipidemia play an intimate role in the pathogenesis of metabolic syndrome and cardiovascular diseases. The availability of glucose and insulin predominate as upstream regulatory elements that operate through a collection of transcription factors to partition lipids toward anabolic pathways. The unraveling of the details of these cellular events has proceeded rapidly, but their physiologic relevance to lifestyle modification has been largely ignored. Here we highlight the role of dietary input, specifically carbohydrate intake, in the mechanism of metabolic regulation germane to metabolic syndrome. The key principle is that carbohydrate, directly or indirectly through the effect of insulin, controls the disposition of excess dietary nutrients. Dietary carbohydrate modulates lipolysis, lipoprotein assembly and processing and affects the relation between dietary intake of saturated fat intake and circulating levels. Several of these processes are the subject of intense investigation at the cellular level. We see the need to integrate these cellular mechanisms with results from low-carbohydrate diet trials that have shown reduced cardiovascular risk through improvement in hepatic, intravascular, and peripheral processing of lipoproteins, alterations in fatty acid composition, and reductions in other cardiovascular risk factors, notably inflammation. From the current state of the literature, however, low-carbohydrate diets are grounded in basic metabolic principles and the data suggest that some form of carbohydrate restriction is a candidate to be the preferred dietary strategy for cardiovascular health beyond weight regulation.

  10. [Glycotoxins and cellular dysfunction. A new mechanism for understanding the preventive effects of lifestyle modifications]. (United States)

    Michalsen, A; Bierhaus, A; Nawroth, P P; Dobos, G J


    Recently the AGE-RAGE interaction was identified as a potential mechanism underlying chronic and inflammatory diseases like atherosclerosis, diabetes mellitus and kidney disease. Advanced glycation end products (AGEs) are the derivatives of glucose-protein or glucose-lipid reactions and are mainly generated from the diet (depending on intensity of heating, cooking time and oxygenation). Binding of AGEs or other ligands to the AGE receptor (RAGE) results in cellular activation, i.e. increased expression of inflammatory mediators and oxidative stress. Diet-derived AGEs thus induce deleterious effects on tissues and the cardiovascular system. Recent research also found that other lifestyle factors are associated with pronounced inflammatory activation, e.g. psychosocial stress and smoking. In addition, each intake of meals is associated with proinflammatory cellular changes. The AGE-RAGE model and investigations of the underlying cellular mechanisms thus may lead to a better understanding of the health benefits of diets (Mediterranean diet, uncooked vegetarian diets), caloric restriction and intermittent fasting. The clinical impact of low-AGE diets and fasting and the interaction between stress and food intake should be further investigated in controlled trials.

  11. Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. (United States)

    Calabrese, Vittorio; Cornelius, Carolin; Cuzzocrea, Salvatore; Iavicoli, Ivo; Rizzarelli, Enrico; Calabrese, Edward J


    Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by co-ordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as carnosine, carnitines or polyphenols, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. In this review we discuss the most current and up to date

  12. Alteration of placental haemostatic mechanisms in idiopathic intrauterine growth restriction

    Directory of Open Access Journals (Sweden)

    Jaime Eduardo Bernal Villegas


    Full Text Available Intrauterine growth restriction is a complication of pregnancy with a high probability of perinatal morbidity and mortality. It appears tobe caused by abnormal development of placental vasculature. Haemostatic processes are important for the development of the placenta,and an imbalance between procoagulant and anticoagulant factors has been associated with risk of intrauterine growth restriction.Objective. To evaluate coagulation abnormalities in placenta of pregnancies complicated with idiopathic intrauterine growth restriction.Materials and methods. Five placentas from pregnancies with idiopathic intrauterine growth restriction were compared to 19 controls.We performed gross and histological examination of the placenta. Analysis was made of both mRNA expression by real-time PCRand protein by ELISA of tissue factor and thrombomodulin in placental tissue. Results. Results based on histological evaluation wereconsistent with an increased prothrombotic state in placentas from pregnancies with idiopathic intrauterine growth restriction, andthrombosis of chorionic vessels was the most important finding. The study showed an increased expression of tissue factor protein(p=0.0411 and an increase in the ratio of tissue factor/thrombomodulin mRNA (p=0.0411 and protein (p=0.0215 in placentas frompregnancies with idiopathic intrauterine growth restriction. There were no statistically significant differences neither between cases andcontrols in the mRNA levels of tissue factor or thrombomodulin nor at the protein level of thrombomodulin. Conclusion. Evidence ofalteration of local haemostatic mechanisms at the level of the placenta, including abnormal expression of tissue factor and tissue factor/thrombomodulin ratio, in pregnancies that occur with idiopathic intrauterine growth restriction is presented.

  13. Remarks on restricted Nevanlinna transforms

    CERN Document Server

    Jankowski, Lech


    The Nevanlinna transform K(z), of a measure and a real constant, plays an important role in the complex analysis and more recently in the free probability theory (boolean convolution). It is shown that its restriction k(it) (the restricted Nevanlinna transform) to the imaginary axis can be expressed as the Laplace transform of the Fourier transform (characteristic function) of the corresponding measure. Finally, a relation between the Voiculescu and the boolean convolution is indicated.

  14. Cellular communication through light.

    Directory of Open Access Journals (Sweden)

    Daniel Fels

    Full Text Available Information transfer is a fundamental of life. A few studies have reported that cells use photons (from an endogenous source as information carriers. This study finds that cells can have an influence on other cells even when separated with a glass barrier, thereby disabling molecule diffusion through the cell-containing medium. As there is still very little known about the potential of photons for intercellular communication this study is designed to test for non-molecule-based triggering of two fundamental properties of life: cell division and energy uptake. The study was performed with a cellular organism, the ciliate Paramecium caudatum. Mutual exposure of cell populations occurred under conditions of darkness and separation with cuvettes (vials allowing photon but not molecule transfer. The cell populations were separated either with glass allowing photon transmission from 340 nm to longer waves, or quartz being transmittable from 150 nm, i.e. from UV-light to longer waves. Even through glass, the cells affected cell division and energy uptake in neighboring cell populations. Depending on the cuvette material and the number of cells involved, these effects were positive or negative. Also, while paired populations with lower growth rates grew uncorrelated, growth of the better growing populations was correlated. As there were significant differences when separating the populations with glass or quartz, it is suggested that the cell populations use two (or more frequencies for cellular information transfer, which influences at least energy uptake, cell division rate and growth correlation. Altogether the study strongly supports a cellular communication system, which is different from a molecule-receptor-based system and hints that photon-triggering is a fine tuning principle in cell chemistry.

  15. Cellular automata: structures


    Ollinger, Nicolas


    Jury : François Blanchard (Rapporteur), Marianne Delorme (Directeur), Jarkko Kari (Président), Jacques Mazoyer (Directeur), Dominique Perrin, Géraud Sénizergues (Rapporteur); Cellular automata provide a uniform framework to study an important problem of "complex systems" theory: how and why do system with a easily understandable -- local -- microscopic behavior can generate a more complicated -- global -- macroscopic behavior? Since its introduction in the 40s, a lot of work has been done to ...

  16. Engineering Cellular Metabolism

    DEFF Research Database (Denmark)

    Nielsen, Jens; Keasling, Jay


    Metabolic engineering is the science of rewiring the metabolism of cells to enhance production of native metabolites or to endow cells with the ability to produce new products. The potential applications of such efforts are wide ranging, including the generation of fuels, chemicals, foods, feeds...... of metabolic engineering and will discuss how new technologies can enable metabolic engineering to be scaled up to the industrial level, either by cutting off the lines of control for endogenous metabolism or by infiltrating the system with disruptive, heterologous pathways that overcome cellular regulation....

  17. Failover in cellular automata

    CERN Document Server

    Kumar, Shailesh


    A cellular automata (CA) configuration is constructed that exhibits emergent failover. The configuration is based on standard Game of Life rules. Gliders and glider-guns form the core messaging structure in the configuration. The blinker is represented as the basic computational unit, and it is shown how it can be recreated in case of a failure. Stateless failover using primary-backup mechanism is demonstrated. The details of the CA components used in the configuration and its working are described, and a simulation of the complete configuration is also presented.

  18. Factors determining the stability, size distribution, and cellular accumulation of small, monodisperse chitosan nanoparticles as candidate vectors for anticancer drug delivery: application to the passive encapsulation of [14C]-doxorubicin

    Directory of Open Access Journals (Sweden)

    Masarudin MJ


    Full Text Available Mas Jaffri Masarudin,1 Suzanne M Cutts,2 Benny J Evison,3 Don R Phillips,2 Paul J Pigram4 1Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia; 2Department of Biochemistry, La Trobe University, Melbourne, Victoria, Australia; 3Department of Chemical Biology and Therapeutics, St Jude Children's Hospital, Memphis, TN, USA; 4Department of Physics, La Trobe University, Melbourne, Victoria, Australia Abstract: Development of parameters for the fabrication of nanosized vectors is pivotal for its successful administration in therapeutic applications. In this study, homogeneously distributed chitosan nanoparticles (CNPs with diameters as small as 62 nm and a polydispersity index (PDI of 0.15 were synthesized and purified using a simple, robust method that was highly reproducible. Nanoparticles were synthesized using modified ionic gelation of the chitosan polymer with sodium tripolyphosphate. Using this method, larger aggregates were mechanically isolated from single particles in the nanoparticle population by selective efficient centrifugation. The presence of disaggregated monodisperse nanoparticles was confirmed using atomic force microscopy. Factors such as anions, pH, and concentration were found to affect the size and stability of nanoparticles directly. The smallest nanoparticle population was ~62 nm in hydrodynamic size, with a low PDI of 0.15, indicating high particle homogeneity. CNPs were highly stable and retained their monodisperse morphology in serum-supplemented media in cell culture conditions for up to 72 hours, before slowly degrading over 6 days. Cell viability assays demonstrated that cells remained viable following a 72-hour exposure to 1 mg/mL CNPs, suggesting that the nanoparticles are well tolerated and highly suited for biomedical applications. Cellular uptake studies using fluorescein isothiocyanate-labeled CNPs showed that cancer cells


    Institute of Scientific and Technical Information of China (English)

    李锰; 杨峰


    For the purpose of investigating conditions of earthquake pregnancy,a heterogeneous 2-D single fault model with 81×81 cells is set up. By using cellular automata models and changing the model heterogeneity and correlation parameters respectively,we compute and get different synthetic event catalogues for analyzing general seismic activity and intensity distribution properties. The computation results show that different heterogeneous structures produce different seismic sequence types and G-R relation,so the heterogeneity is an important influencing factor on seismicity. Nevertheless ,both the coefficients of stress redistribution and local friction loss can also influence seimicity to some extent. It is possibly helpful for further understandings of earthquake process complexity.%基于细胞自动机模型,构建了由81×81个细胞单元组成非均匀二维单断层介质样本,研究了断层结构细观非均匀性以及相关模型参数变化对模拟输出结果和强度分布特征的影响.研究结果表明:结构非均匀性是影响地震活动性的控制性参量,随着非均匀程度的增强,地震事件数量增多,震级分布变得越来越均匀,破裂演化模式由相对“脆性”向“塑性”变化;介质结构的初始条件和应力加载的随机性对地震活动演化过程基本不产生影响,此外,应力降分配系数减小使b值主体线性段向大震级延伸;随着局部摩擦损耗系数增大,模拟地震事件的数量有所增加,大震级事件数量和震级衰减增强,b值主体线性区间变窄,使断层的变形破坏方式由相对“脆性”向“塑性”变化.这些对理解孕震过程的复杂性是有帮助的.

  20. Complexity, dynamic cellular network, and tumorigenesis. (United States)

    Waliszewski, P


    A holistic approach to tumorigenesis is proposed. The main element of the model is the existence of dynamic cellular network. This network comprises a molecular and an energetistic structure of a cell connected through the multidirectional flow of information. The interactions within dynamic cellular network are complex, stochastic, nonlinear, and also involve quantum effects. From this non-reductionist perspective, neither tumorigenesis can be limited to the genetic aspect, nor the initial event must be of molecular nature, nor mutations and epigenetic factors are mutually exclusive, nor a link between cause and effect can be established. Due to complexity, an unstable stationary state of dynamic cellular network rather than a group of unrelated genes determines the phenotype of normal and transformed cells. This implies relativity of tumor suppressor genes and oncogenes. A bifurcation point is defined as an unstable state of dynamic cellular network leading to the other phenotype-stationary state. In particular, the bifurcation point may be determined by a change of expression of a single gene. Then, the gene is called bifurcation point gene. The unstable stationary state facilitates the chaotic dynamics. This may result in a fractal dimension of both normal and tumor tissues. The co-existence of chaotic dynamics and complexity is the essence of cellular processes and shapes differentiation, morphogenesis, and tumorigenesis. In consequence, tumorigenesis is a complex, unpredictable process driven by the interplay between self-organisation and selection.

  1. Whole-transcriptome analysis of mouse adipose tissue in response to short-term caloric restriction. (United States)

    Kim, Seung-Soo; Choi, Kyung-Mi; Kim, Soyoung; Park, Taesun; Cho, In-Cheol; Lee, Jae-Won; Lee, Cheol-Koo


    Caloric restriction (CR) has been shown to extend the lifespan of many species by improving cellular function and organismal health. Additionally, fat reduction by CR may play an important role in lengthening lifespan and preventing severe age-related diseases. Interestingly, CR induced the greatest transcriptome change in the epididymal fat of mice in our study. In this transcriptome analysis, we identified and categorized 446 genes that correlated with CR level. We observed down-regulation of several signaling pathways, including insulin/insulin-like growth factor 1 (insulin/IGF-1), epidermal growth factor (EGF), transforming growth factor beta (TGF-β), and canonical wingless-type mouse mammary tumor virus integration site (Wnt). Many genes related to structural features, including extracellular matrix structure, cell adhesion, and the cytoskeleton, were down-regulated, with a strong correlation to the degree of CR. Furthermore, genes related to the cell cycle and adipogenesis were down-regulated. These biological processes are well-identified targets of insulin/IGF-1, EGF, TGF-β, and Wnt signaling. In contrast, genes involved in specific metabolic processes, including the tricarboxylic acid cycle and the electron transport chain were up-regulated. We performed in silico analysis of the promoter sequences of CR-responsive genes and identified two associated transcription factors, Paired-like homeodomain 2 (Pitx2) and Paired box gene 6 (Pax6). Our results suggest that strict regulation of signaling pathways is critical for creating the optimal energy homeostasis to extend lifespan.

  2. The VP1u Receptor Restricts Parvovirus B19 Uptake to Permissive Erythroid Cells (United States)

    Leisi, Remo; Von Nordheim, Marcus; Ros, Carlos; Kempf, Christoph


    Parvovirus B19 (B19V) is a small non-enveloped virus and known as the causative agent for the mild childhood disease erythema infectiosum. B19V has an extraordinary narrow tissue tropism, showing only productive infection in erythroid precursor cells in the bone marrow. We recently found that the viral protein 1 unique region (VP1u) contains an N-terminal receptor-binding domain (RBD), which mediates the uptake of the virus into cells of the erythroid lineage. To further investigate the role of the RBD in connection with a B19V-unrelated capsid, we chemically coupled the VP1u of B19V to the bacteriophage MS2 capsid and tested the internalization capacity of the bioconjugate on permissive cells. In comparison, we studied the cellular uptake and infection of B19V along the erythroid differentiation. The results showed that the MS2-VP1u bioconjugate mimicked the specific internalization of the native B19V into erythroid precursor cells, which further coincides with the restricted infection profile. The successful mimicry of B19V uptake demonstrates that the RBD in the VP1u is sufficient for the endocytosis of the viral capsid. Furthermore, the recombinant VP1u competed with B19V uptake into permissive cells, thus excluding a significant alternative uptake mechanism by other receptors. Strikingly, the VP1u receptor appeared to be expressed only on erythropoietin-dependent erythroid differentiation stages that also provide the necessary intracellular factors for a productive infection. Taken together, these findings suggest that the VP1u binds to a yet-unknown erythroid-specific cellular receptor and thus restricts the virus entry to permissive cells. PMID:27690083

  3. Cellular image classification

    CERN Document Server

    Xu, Xiang; Lin, Feng


    This book introduces new techniques for cellular image feature extraction, pattern recognition and classification. The authors use the antinuclear antibodies (ANAs) in patient serum as the subjects and the Indirect Immunofluorescence (IIF) technique as the imaging protocol to illustrate the applications of the described methods. Throughout the book, the authors provide evaluations for the proposed methods on two publicly available human epithelial (HEp-2) cell datasets: ICPR2012 dataset from the ICPR'12 HEp-2 cell classification contest and ICIP2013 training dataset from the ICIP'13 Competition on cells classification by fluorescent image analysis. First, the reading of imaging results is significantly influenced by one’s qualification and reading systems, causing high intra- and inter-laboratory variance. The authors present a low-order LP21 fiber mode for optical single cell manipulation and imaging staining patterns of HEp-2 cells. A focused four-lobed mode distribution is stable and effective in optical...

  4. Engineering Cellular Metabolism. (United States)

    Nielsen, Jens; Keasling, Jay D


    Metabolic engineering is the science of rewiring the metabolism of cells to enhance production of native metabolites or to endow cells with the ability to produce new products. The potential applications of such efforts are wide ranging, including the generation of fuels, chemicals, foods, feeds, and pharmaceuticals. However, making cells into efficient factories is challenging because cells have evolved robust metabolic networks with hard-wired, tightly regulated lines of communication between molecular pathways that resist efforts to divert resources. Here, we will review the current status and challenges of metabolic engineering and will discuss how new technologies can enable metabolic engineering to be scaled up to the industrial level, either by cutting off the lines of control for endogenous metabolism or by infiltrating the system with disruptive, heterologous pathways that overcome cellular regulation.

  5. Cellular basis of memory for addiction. (United States)

    Nestler, Eric J


    DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. Here, we review the types of molecular and cellular adaptations that occur in specific brain regions to mediate addiction-associated behavioral abnormalities. These include alterations in gene expression achieved in part via epigenetic mechanisms, plasticity in the neurophysiological functioning of neurons and synapses, and associated plasticity in neuronal and synaptic morphology mediated in part by altered neurotrophic factor signaling. Each of these types of drug-induced modifications can be viewed as a form of "cellular or molecular memory." Moreover, it is striking that most addiction-related forms of plasticity are very similar to the types of plasticity that have been associated with more classic forms of "behavioral memory," perhaps reflecting the finite repertoire of adaptive mechanisms available to neurons when faced with environmental challenges. Finally, addiction-related molecular and cellular adaptations involve most of the same brain regions that mediate more classic forms of memory, consistent with the view that abnormal memories are important drivers of addiction syndromes. The goal of these studies which aim to explicate the molecular and cellular basis of drug addiction is to eventually develop biologically based diagnostic tests, as well as more effective treatments for addiction disorders.

  6. Examining the properties and therapeutic potential of glial restricted precursors in spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    Kazuo Hayakawa; Christopher Haas; Itzhak Fischer


    In the aftermath of spinal cord injury, glial restricted precursors (GRPs) and immature astrocytes offer the potential to modulate the inlfammatory environment of the injured spinal cord and promote host axon re-generation. Nevertheless clinical application of cellular therapy for the repair of spinal cord injury requires strict quality-assured protocols for large-scale production and preservation that necessitates long-term in vitro expansion. Importantly, such processes have the potential to alter the phenotypic and functional properties and thus therapeutic potential of these cells. Furthermore, clinical use of cellular therapies may be limited by the inlfammatory microenvironment of the injured spinal cord, altering the phenotypic and functional properties of grafted cells. This report simulates the process of large-scale GRP production and demonstrates the permissive properties of GRP following long-termin vitro culture. Furthermore, we de-ifned the phenotypic and functional properties of GRP in the presence of inlfammatory factors, and call attention to the importance of the microenvironment of grafted cells, underscoring the importance of modulating the environment of the injured spinal cord.

  7. Numerical investigation on evolution of cylindrical cellular detonation

    Institute of Scientific and Technical Information of China (English)

    WANG Chun; JIANG Zong-lin; HU Zong-min; HAN Gui-lai


    Cylindrical cellular detonation is numerically investigated by solving twodimensional reactive Euler equations with a finite volume method on a two-dimensional self-adaptive unstructured mesh.The one-step reversible chemical reaction model is applied to simplify the control parameters of chemical reaction.Numerical results demonstrate the evolution of cellular cell splitting of cylindrical cellular detonation explored in experimentas.Split of cellular structures shows different features in the near-field and far-field from the initiation zone.Variation of the local curvature is a key factor in the behavior of cell split of cylindrical cellular detonation in propagation.Numerical results show that split of cellular structures comes from the self-organization of transverse waves corresponding to the development of small disturbances along the detonation front related to detonation instability.

  8. A Brief Study on Factors Restricting State Treasury Cash Management in China and Countermeasures%浅谈制约我国国库现金管理的因素及对策

    Institute of Scientific and Technical Information of China (English)



    The paper probes into the connotation and functions of the state treasury cash management and analyzes the major fac- tors which restrict the state treasury cash management. Some suggestions which strengthen the state treasury cash management are pro- posed such as constructing scientific budget management system, establishing developed government debt market and speeding up the construction of laws on state treasury.%本文探讨了国库现金管理的内涵及作用,分析了影响国库现金管理的主要因素。在此基础上,提出加强国库现金管理的相关建议:建立科学预算管理体系;建立发达的国债市场;加快国库法律制度建设等。

  9. Molecular motion in restricted geometries

    Indian Academy of Sciences (India)

    Siddharth Gautam; S Mitra; R Mukhopadhyay


    Molecular dynamics in restricted geometries is known to exhibit anomalous behaviour. Diffusion, translational or rotational, of molecules is altered significantly on confinement in restricted geometries. Quasielastic neutron scattering (QENS) offers a unique possibility of studying molecular motion in such systems. Both time scales involved in the motion and the geometry of motion can be studied using QENS. Molecular dynamics (MD) simulation not only provides insight into the details of the different types of motion possible but also does not suffer limitations of the experimental set-up. Here we report the effect of confinement on molecular dynamics in various restricted geometries as studied by QENS and MD simulations: An example where the QENS technique provided direct evidence of phase transition associated with change in the dynamical behaviour of the molecules is also discussed.

  10. Protein and Amino Acid Restriction, Aging and Disease: from yeast to humans


    Mirzaei, Hamed; Suarez, Jorge A.; Valter D Longo


    Many of the effects of dietary restriction (DR) on longevity and health span in model organisms have been linked to reduced protein and amino acid (AA) intake and the stimulation of specific nutrient signaling pathways. Studies in yeast have shown that addition of serine, threonine, and valine in media promotes cellular sensitization and aging by activating different but connected pathways. Protein or essential AA restriction extends both lifespan and healthspan in rodent models. In humans, p...

  11. Restricted TET2 Expression in Germinal Center Type B Cells Promotes Stringent Epstein-Barr Virus Latency. (United States)

    Wille, Coral K; Li, Yangguang; Rui, Lixin; Johannsen, Eric C; Kenney, Shannon C


    Epstein-Barr virus (EBV) latently infects normal B cells and contributes to the development of certain human lymphomas. Newly infected B cells support a highly transforming form (type III) of viral latency; however, long-term EBV infection in immunocompetent hosts is limited to B cells with a more restricted form of latency (type I) in which most viral gene expression is silenced by promoter DNA methylation. How EBV converts latency type is unclear, although it is known that type I latency is associated with a germinal center (GC) B cell phenotype, and type III latency with an activated B cell (ABC) phenotype. In this study, we have examined whether expression of TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells. We found that TET2 expression is inhibited in normal GC cells and GC type lymphomas. In contrast, TET2 is expressed in normal naive B cells and ABC type lymphomas. We also demonstrate that GC type cell lines have increased 5mC levels and reduced 5hmC levels in comparison to those of ABC type lines. Finally, we show that TET2 promotes the ability of the EBV transcription factor EBNA2 to convert EBV-infected cells from type I to type III latency. These findings demonstrate that TET2 expression is repressed in GC cells independent of EBV infection and suggest that TET2 promotes type III EBV latency in B cells with an ABC or naive phenotype by enhancing EBNA2 activation of methylated EBV promoters.IMPORTANCE EBV establishes several different types of viral latency in B cells. However, cellular factors that determine whether EBV enters the highly transforming type III latency, versus the more restricted type I latency, have not been well characterized. Here we show that TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells by

  12. Simulation of earthquakes with cellular automata

    Directory of Open Access Journals (Sweden)

    P. G. Akishin


    Full Text Available The relation between cellular automata (CA models of earthquakes and the Burridge–Knopoff (BK model is studied. It is shown that the CA proposed by P. Bak and C. Tang,although they have rather realistic power spectra, do not correspond to the BK model. We present a modification of the CA which establishes the correspondence with the BK model.An analytical method of studying the evolution of the BK-like CA is proposed. By this method a functional quadratic in stress release, which can be regarded as an analog of the event energy, is constructed. The distribution of seismic events with respect to this “energy” shows rather realistic behavior, even in two dimensions. Special attention is paid to two-dimensional automata; the physical restrictions on compression and shear stiffnesses are imposed.

  13. Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity (United States)

    Dalmasso, Giovanni; Marin Zapata, Paula Andrea; Brady, Nathan Ryan; Hamacher-Brady, Anne


    Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological and mobility dynamics are essential for maintaining mitochondrial functional homeostasis, and alterations both impact and reflect cellular stress states. Mitochondrial homeostasis is further dependent on production (biogenesis) and the removal of damaged mitochondria by selective autophagy (mitophagy). While mitochondrial function, dynamics, biogenesis and mitophagy are highly-integrated processes, it is not fully understood how systemic control in the cell is established to maintain homeostasis, or respond to bioenergetic demands. Here we used agent-based modeling (ABM) to integrate molecular and imaging knowledge sets, and simulate population dynamics of mitochondria and their response to environmental energy demand. Using high-dimensional parameter searches we integrated experimentally-measured rates of mitochondrial biogenesis and mitophagy, and using sensitivity analysis we identified parameter influences on population homeostasis. By studying the dynamics of cellular subpopulations with distinct mitochondrial masses, our approach uncovered system properties of mitochondrial populations: (1) mitochondrial fusion and fission activities rapidly establish mitochondrial sub-population homeostasis, and total cellular levels of mitochondria alter fusion and fission activities and subpopulation distributions; (2) restricting the directionality of mitochondrial mobility does not alter morphology subpopulation distributions, but increases network transmission dynamics; and (3) maintaining mitochondrial mass homeostasis and responding to bioenergetic stress requires the integration of mitochondrial dynamics with the cellular bioenergetic state. Finally, (4) our model suggests sources of, and stress conditions amplifying

  14. Legal restrictions and Investment Growth

    NARCIS (Netherlands)

    Lensink, B.W.; Scholtens, B.


    We analyze the impact of legal restrictions on investment growth at the firm level. With the help of a unique firm-level survey database, we analyze whether firm investments are related to the efficiency and quality of the judiciary. Furthermore, we analyze whether the investment behavior of large a

  15. Legal restrictions and investment growth

    NARCIS (Netherlands)

    Lensink, B.W.; Scholtens, B.


    We analyze the impact of legal restrictions on investment growth at the firm level. With the help of a unique firm-level survey database, we analyze whether firm investments are related to the efficiency and quality of the judiciary, Furthermore, we analyze whether the investment behavior of large a

  16. Restrictive dermopathy and fetal behaviour

    NARCIS (Netherlands)

    Mulder, EJH; Beemer, FA; Stoutenbeek, P


    We report three siblings from consecutive pregnancies affected with restrictive dermopathy (RD). During the second pregnancy, fetal behavioural development and growth were studied extensively using ultrasound at 1-4 week intervals. Dramatic and sudden changes occurred in fetal body movements and gro

  17. Restricted Morgan’s problem

    Institute of Scientific and Technical Information of China (English)

    陈树中; 曹立


    A new list of regular feedback invariant integers called right independent orders is introduced.That the restricted Morgan’s problem is equivalent to a kind of nonlinear algebraic equations is proved and the condition that the nonlinear algebraic equations degenerate into linear algebraic equations is given.

  18. Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction

    Directory of Open Access Journals (Sweden)

    Wood Richard J


    Full Text Available Abstract Background Diets that restrict carbohydrate (CHO have proven to be a successful dietary treatment of obesity for many people, but the degree of weight loss varies across individuals. The extent to which genetic factors associate with the magnitude of weight loss induced by CHO restriction is unknown. We examined associations among polymorphisms in candidate genes and weight loss in order to understand the physiological factors influencing body weight responses to CHO restriction. Methods We screened for genetic associations with weight loss in 86 healthy adults who were instructed to restrict CHO to a level that induced a small level of ketosis (CHO ~10% of total energy. A total of 27 single nucleotide polymorphisms (SNPs were selected from 15 candidate genes involved in fat digestion/metabolism, intracellular glucose metabolism, lipoprotein remodeling, and appetite regulation. Multiple linear regression was used to rank the SNPs according to probability of association, and the most significant associations were analyzed in greater detail. Results Mean weight loss was 6.4 kg. SNPs in the gastric lipase (LIPF, hepatic glycogen synthase (GYS2, cholesteryl ester transfer protein (CETP and galanin (GAL genes were significantly associated with weight loss. Conclusion A strong association between weight loss induced by dietary CHO restriction and variability in genes regulating fat digestion, hepatic glucose metabolism, intravascular lipoprotein remodeling, and appetite were detected. These discoveries could provide clues to important physiologic adaptations underlying the body mass response to CHO restriction.

  19. Cellular bioluminescence imaging. (United States)

    Welsh, David K; Noguchi, Takako


    Bioluminescence imaging of live cells has recently been recognized as an important alternative to fluorescence imaging. Fluorescent probes are much brighter than bioluminescent probes (luciferase enzymes) and, therefore, provide much better spatial and temporal resolution and much better contrast for delineating cell structure. However, with bioluminescence imaging there is virtually no background or toxicity. As a result, bioluminescence can be superior to fluorescence for detecting and quantifying molecules and their interactions in living cells, particularly in long-term studies. Structurally diverse luciferases from beetle and marine species have been used for a wide variety of applications, including tracking cells in vivo, detecting protein-protein interactions, measuring levels of calcium and other signaling molecules, detecting protease activity, and reporting circadian clock gene expression. Such applications can be optimized by the use of brighter and variously colored luciferases, brighter microscope optics, and ultrasensitive, low-noise cameras. This article presents a review of how bioluminescence differs from fluorescence, its applications to cellular imaging, and available probes, optics, and detectors. It also gives practical suggestions for optimal bioluminescence imaging of single cells.

  20. 30 CFR 56.11008 - Restricted clearance. (United States)


    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Restricted clearance. 56.11008 Section 56.11008 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR METAL AND NONMETAL MINE... Restricted clearance. Where restricted clearance creates a hazard to persons, the restricted clearance...

  1. 30 CFR 57.11008 - Restricted clearance. (United States)


    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Restricted clearance. 57.11008 Section 57.11008... Escapeways Travelways-Surface and Underground § 57.11008 Restricted clearance. Where restricted clearance creates a hazard to persons, the restricted clearance shall be conspicuously marked....

  2. 甘肃省少数民族地区包容性增长制约因素分析——基于“十二五”的历史方位%Analysis about restrictive Factors in Minority Area of GanSu's Inclusive Growth --Based on the Historical Position of the Period from the Year 2011 to 2015

    Institute of Scientific and Technical Information of China (English)



    包容性增长是“十二五”时期甘肃省少数民族地区发展面临的重大课题。经济基础薄弱、发展任务繁重、自然条件恶劣、地理区住劣势明显、基础设施落后、社会事业发展滞后、人才资源匮乏、制度不完善、社会不公是制约“十二五”时期少数民族地区包容性增长的主要因素。深入分析少数民族地区包容性增长的制约因素,是推动少数民族地区包容性增长的前提。%Inclusive growth is a great subject to minority area of GanSu in the period of the year 2011 to 2015. The unsubstantial economic foundation, heavy development task, bad natural conditions, evident geographical location disadvantages, behindhand infrastructure, hysteretic development of social undertakings, deficient resources of human talents, ineompletcd system and social injustice are major restrictive factors which will restrict minority area of Gansu's inclusive growth in the period from the year 2011 to 2015. In-depth analysis of the restrictive factors about minority area of GanSu's inclusive growth is the precondition of pushing forward minority area of GanSu's inclusive growth.

  3. 制约拓展训练课程在高校开设的因素分析及解决对策%On the Restrictive Factors of Outward Bound Training Course Development in Universities and Its Countermeasures

    Institute of Scientific and Technical Information of China (English)



    In recent years, outward bound training has been brought into the curriculum system by many colleges as a new course, but there are some problems such as the unsound curriculum system, contents of the course without specific aim, the low-teaching level and space facilities posing some safety hazards which seriously restrict the development of outward bound training in universities. For the above problems, this paper proposes appropriate countermeasures, aiming to offer some reference suggestions for the development and extension of outward bound training courses in Chinese universities.%近年来拓展训练作为一门新兴课程被很多高校纳入课程体系之中,但课程体系不健全、课程的内容针对性不强、课程师资薄弱、场地设施存在安全隐患等问题严重制约着其在高校的开展。本文针对以上问题提出相应对策,旨在为我国高校拓展训练课程开展和推广提供一些参考。

  4. Neuron-restrictive silencer factor (NRSF) represses cocaine- and amphetamine-regulated transcript (CART) transcription and antagonizes cAMP-response element-binding protein signaling through a dual NRSE mechanism. (United States)

    Zhang, Jing; Wang, Sihan; Yuan, Lin; Yang, Yinxiang; Zhang, Bowen; Liu, Qingbin; Chen, Lin; Yue, Wen; Li, Yanhua; Pei, Xuetao


    Cocaine- and amphetamine-regulated transcript (CART) peptide plays a pivotal role in neuroprotection against stroke-related brain injury. However, the regulatory mechanism on CART transcription, especially the repression mechanism, is not fully understood. Here, we show that the transcriptional repressor neuron-restrictive silencer elements (NRSF, also known as REST) represses CART expression through direct binding to two NRSF-binding elements (NRSEs) in the CART promoter and intron 1 (named pNRSE and iNRSE, respectively). EMSA show that NRSF binds to pNRSE and iNRSE directly in vitro. ChIP assays show that NRSF recruits differential co-repressor complexes including CoREST and HDAC1 to these NRSEs. The presence of both NRSEs is required for efficient repression of CART transcription as indicated by reporter gene assays. NRSF overexpression antagonizes forskolin-mediated up-regulation of CART mRNA and protein. Ischemia insult triggered by oxygen-glucose deprivation (OGD) enhances NRSF mRNA levels and then NRSF antagonizes the CREB signaling on CART activation, leading to augmented cell death. Depletion of NRSF in combination with forskolin treatment increases neuronal survival after ischemic insult. These findings reveal a novel dual NRSE mechanism by which NRSF represses CART expression and suggest that NRSF may serve as a therapeutic target for stroke treatment.

  5. Cellular receptors for plasminogen activators recent advances. (United States)

    Ellis, V


    The generation of the broad-specificity protease plasmin by the plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) is implicated in a variety of pathophysiological processes, including vascular fibrin dissolution, extracellular matrix degradation and remodeling, and cell migration. A mechanism for the regulation of plasmin generation is through binding of the plasminogen activators to specific cellular receptors: uPA to the glycolipid-anchored membrane protein urokinase-type plasminogen activator receptor (uPAR) and tPA to a number of putative binding sites. The uPA-uPAR complex can interact with a variety of ligands, including plasminogen, vitronectin, and integrins, indicating a multifunctional role for uPAR, regulating not only efficient and spatially restricted plasmin generation but also having the potential to modulate cell adhesion and signal transduction. The cellular binding of tPA, although less well characterized, also has the capacity to regulate plasmin generation and to play a significant role in vessel-wall biology. (Trends Cardiovasc Med 1997;7:227-234). © 1997, Elsevier Science Inc.

  6. Material and mechanical factors:new strategy in cellular neurogenesis

    Institute of Scientific and Technical Information of China (English)

    Hillary Stoll; Il Keun Kwon; Jung Yul Lim


    Since damaged neural circuits are not generally self-recovered, developing methods to stimulate neurogenesis is critically required. Most studies have examined the effects of soluble pharma-cological factors on the cellular neurogenesis. On the other hand, it is now recognized that the other extracellular factors, including material and mechanical cues, also have a strong potential to induce cellular neurogenesis. This article will review recent data on the material (chemical patterning, micro/nano-topography, carbon nanotube, graphene) and mechanical (static cue from substrate stiffness, dynamic cue from stretch and lfow shear) stimulations of cellular neuro-genesis. These approaches may provide new neural regenerative medicine protocols. Scaffolding material templates capable of triggering cellular neurogenesis can be explored in the presence of neurogenesis-stimulatory mechanical environments, and also with conventional soluble factors, to enhance axonal growth and neural network formation in neural tissue engineering.

  7. 高原地区胎盘VEGF在胎儿生长受限和巨大儿中的表达及意义%Expression of plateau area placenta vascular endothelial growth factor iIn fetal growth restriction And Great children and its significance

    Institute of Scientific and Technical Information of China (English)



    目的 血管内皮生长因子(VEGF)是一种对血管内皮细胞有特异高效的促有丝分裂因子,通过检测血管内皮生长因子在胎盘母面和子面的水平,探索胎儿生长受限和巨大儿的发病因素和发生的机制.方法 随机选择2010年1月至2011年2月在青海省妇女儿童医院足月分娩的足月小样儿(体重<2 500g的新生儿)50例产妇为宫内发育受限组,选择同期分娩体重≥4 000g新生儿50例产妇为巨大儿组;采用免疫组化链霉菌抗生物素蛋白-过氧化酶连接法(SP法)检测巨大儿(对照组)和胎儿生长受限患者(IUGR组)胎盘组织中VEGF的表达;巨大儿和IUGR组均为初产妇,两组孕妇年龄、孕周及体质量差异无显著性.结果 胎儿生长受限患者胎盘组织中VEGF阳性表达率低于巨大儿组,两者差异有统计学意义(P<0.05).结论 IUGR患者胎盘VEGF水平下降,可能是胎儿生长受限发病机理中的一个重要因素.%Objective Vascular endothelial growth factor is a vascular endothelial cell - specific and efficient mitogenic factor,by vascular endothelial growth factor in placenta parent surface and sub - surface level,to explore fetal growth restriction and a huge childrens risk factors and the mechanisms. Methods Randomly selected from January 2010 to February 2011 in our hospital term delivery of full - term small for gestational age ( body weight < 2500g neonates ) 50 cases of maternal intrauterine growth restriction group,select the new year birth weight ≥4000g children 50 cases of maternal child for the great group; Immunohistochemical streptavidin - biotin - peroxidase method (SP method) to detect a huge children ( control group) and patients with fetal growth restriction (IUGR group) placental tissue VEGF expression; Great children and the IUGR group were primipara,two groups of maternal age,gestational age and body mass difference was not statistically significant. Results Fetal growth restriction in placental

  8. Free fall and cellular automata

    Directory of Open Access Journals (Sweden)

    Pablo Arrighi


    Full Text Available Three reasonable hypotheses lead to the thesis that physical phenomena can be described and simulated with cellular automata. In this work, we attempt to describe the motion of a particle upon which a constant force is applied, with a cellular automaton, in Newtonian physics, in Special Relativity, and in General Relativity. The results are very different for these three theories.

  9. About Strongly Universal Cellular Automata

    Directory of Open Access Journals (Sweden)

    Maurice Margenstern


    Full Text Available In this paper, we construct a strongly universal cellular automaton on the line with 11 states and the standard neighbourhood. We embed this construction into several tilings of the hyperbolic plane and of the hyperbolic 3D space giving rise to strongly universal cellular automata with 10 states.

  10. Reactive Programming of Cellular Automata


    Boussinot, Frédéric


    Implementation of cellular automata using reactive programming gives a way to code cell behaviors in an abstract and modular way. Multiprocessing also becomes possible. The paper describes the implementation of cellular automata with the reactive programming language LOFT, a thread-based extension of C. Self replicating loops considered in artificial life are coded to show the interest of the approach.

  11. HIV restriction by APOBEC3 in humanized mice.

    Directory of Open Access Journals (Sweden)

    John F Krisko


    Full Text Available Innate immune restriction factors represent important specialized barriers to zoonotic transmission of viruses. Significant consideration has been given to their possible use for therapeutic benefit. The apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3 family of cytidine deaminases are potent immune defense molecules capable of efficiently restricting endogenous retroelements as well as a broad range of viruses including Human Immunodeficiency virus (HIV, Hepatitis B virus (HBV, Human Papilloma virus (HPV, and Human T Cell Leukemia virus (HTLV. The best characterized members of this family are APOBEC3G (A3G and APOBEC3F (A3F and their restriction of HIV. HIV has evolved to counteract these powerful restriction factors by encoding an accessory gene designated viral infectivity factor (vif. Here we demonstrate that APOBEC3 efficiently restricts CCR5-tropic HIV in the absence of Vif. However, our results also show that CXCR4-tropic HIV can escape from APOBEC3 restriction and replicate in vivo independent of Vif. Molecular analysis identified thymocytes as cells with reduced A3G and A3F expression. Direct injection of vif-defective HIV into the thymus resulted in viral replication and dissemination detected by plasma viral load analysis; however, vif-defective viruses remained sensitive to APOBEC3 restriction as extensive G to A mutation was observed in proviral DNA recovered from other organs. Remarkably, HIV replication persisted despite the inability of HIV to develop resistance to APOBEC3 in the absence of Vif. Our results provide novel insight into a highly specific subset of cells that potentially circumvent the action of APOBEC3; however our results also demonstrate the massive inactivation of CCR5-tropic HIV in the absence of Vif.

  12. 双重的约束:女性科技人才成长的制约因素分析%Double Constraints: Analysis of Restricting Factors in Female Talents' Growth in Science and Technology

    Institute of Scientific and Technical Information of China (English)



    近年来,我国的科技事业发展迅速。然而,科技人才队伍中的女性科技人才却发展较为缓慢,原因在于女性科技人才的发展受到了公私领域的双重约束即私人领域的家庭劳动、家庭决策、家庭教育投资以及公共领域的科技人才准入、培育和评价机制制约了女性科技人才的发展。在这种双重约束下,女性科技人才只能在具有性别排斥的科技领域中充当幕后支撑力量,相反,男性则在科技人才发展中占主导优势,成为主要的受惠群体。%The science and technology in China has developed rapidly in recent years. However, the development of female talents in science and technological is relatively slow. The admittance mechanism, cultivation mechanism, evalua tion mechanism in public domain and the housework, the family decision-making, the family education investment in the private sector restrict their development. As a result, female talents can just be the supporting power on backstage in the field of science and technology in which there is a gender rejection, on the contrary, the male talents dominate and benefit.

  13. MIMO Communication for Cellular Networks

    CERN Document Server

    Huang, Howard; Venkatesan, Sivarama


    As the theoretical foundations of multiple-antenna techniques evolve and as these multiple-input multiple-output (MIMO) techniques become essential for providing high data rates in wireless systems, there is a growing need to understand the performance limits of MIMO in practical networks. To address this need, MIMO Communication for Cellular Networks presents a systematic description of MIMO technology classes and a framework for MIMO system design that takes into account the essential physical-layer features of practical cellular networks. In contrast to works that focus on the theoretical performance of abstract MIMO channels, MIMO Communication for Cellular Networks emphasizes the practical performance of realistic MIMO systems. A unified set of system simulation results highlights relative performance gains of different MIMO techniques and provides insights into how best to use multiple antennas in cellular networks under various conditions. MIMO Communication for Cellular Networks describes single-user,...

  14. HIV-related travel restrictions: trends and country characteristics

    Directory of Open Access Journals (Sweden)

    Felicia Chang


    a finding that is relevant to migrant populations and travel medicine providers alike. Despite international pressure to remove travel restrictions, many countries continue to implement these restrictions for HIV-positive individuals on entry and stay. Since 2010, the United States and China have engaged in high profile removals. This may be indicative of an increasing trend, facilitated by various factors, including international advocacy and the setting of a UNAIDS goal to halve the number of countries with restrictions by 2015.

  15. The Influence Factors of Determination of Haematobacter sp. Cellular Fatty Acids%血液杆菌Haematobacter sp.细胞脂肪酸测定的影响因素

    Institute of Scientific and Technical Information of China (English)

    何蔚荭; 安明理; 陈国参; 贾彬; 吴晓磊; 王亚南


    Cellular fatty acid composition of strain HNMC11807, a novel species belong to Haematobacter sp., were detected by used Sherlock MIS system of MIDI company USA. The influence by different culture methods and cells growth conditions on cells fatty acid composition were explored in this article. Based on the bacterial cells cultured in varied medium such as in different medium components and in solid or liquid medium, the cellular fatty acid composition were respectively analysed and compared. On the same time, two standard systems in this instrument, conventional and fast, were used to run samples, and the detect results of the cellular fatty acid composition were compared respectively. As the results, the cells fatty acid composition was closely related with culture condition and a significant differences. The cellular fatty acid composition must be carried out in specified and unified culture conditions when this system was used in microbial classification.%应用美国MIDI公司Sherlock MIS系统检测一株归属于血液杆菌属的新菌种Haematobacter sp. HNMC11807的细胞脂肪酸组成,探讨不同培养方法和条件对其细胞脂肪酸组成的影响。采用不同培养条件培养微生物细胞,即不同的培养基组成、固液类型和培养时间;分析比较细胞脂肪酸检测结果存在的差异。同时对比分析仪器专用的两种检测体系,即常规标准和快速标准体系,对样品脂肪酸测定结果的影响。结果发现,细胞脂肪酸组成与其培养条件密切相关,且差异显著。因此,在应用该系统做微生物分类鉴定时,必需严格遵守特定的、统一的培养条件平行进行。

  16. Microfluidic Devices for the Measurement of Cellular Secretion (United States)

    Schrell, Adrian M.; Mukhitov, Nikita; Yi, Lian; Wang, Xue; Roper, Michael G.


    The release of chemical information from cells and tissues holds the key to understanding cellular behavior and dysfunction. The development of methodologies that can measure cellular secretion in a time-dependent fashion is therefore essential. Often these measurements are made difficult by the high-salt conditions of the cellular environment, the presence of numerous other secreted factors, and the small mass samples that are produced when frequent sampling is used to resolve secretory dynamics. In this review, the methods that we have developed for measuring hormone release from islets of Langerhans are dissected to illustrate the practical difficulties of studying cellular secretions. Other methods from the literature are presented that provide alternative approaches to particularly challenging areas of monitoring cellular secretion. The examples presented in this review serve as case studies and should be adaptable to other cell types and systems for unique applications.

  17. Reversibility of cellular aging by reprogramming through an embryonic-like state : a new paradigm for human cell rejuvenation

    Directory of Open Access Journals (Sweden)

    Jean-Marc Lemaitre


    Full Text Available Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs provides a unique opportunity to derive patient-specific stem cells with potential application in autologous tissue replacement therapies and without the ethical concerns of Embryonic Stem Cells (hESC. However, this strategy still suffers from several hurdles that need to be overcome before clinical applications. Among them, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. This suggests that aging might be an important limitation for therapeutic purposes for elderly individuals. Senescence is characterized by an irreversible cell cycle arrest in response to various forms of stress, including activation of oncogenes, shortened telomeres, DNA damage, oxidative stress, and mitochondrial dysfunction. To overcome this barrier, we developed an optimized 6-factor-based reprogramming protocol that is able to cause efficient reversing of cellular senescence and reprogramming into iPSCs. We demonstrated that iPSCs derived from senescent and centenarian fibroblasts have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESC. Finally, we demonstrate that re-differentiation led to rejuvenated cells with a reset cellular physiology, defining a new paradigm for human cell rejuvenation. We discuss the molecular mechanisms involved in cell reprogramming of senescent cells. 

  18. Cellular senescence and the aging brain. (United States)

    Chinta, Shankar J; Woods, Georgia; Rane, Anand; Demaria, Marco; Campisi, Judith; Andersen, Julie K


    Cellular senescence is a potent anti-cancer mechanism that arrests the proliferation of mitotically competent cells to prevent malignant transformation. Senescent cells accumulate with age in a variety of human and mouse tissues where they express a complex 'senescence-associated secretory phenotype' (SASP). The SASP includes many pro-inflammatory cytokines, chemokines, growth factors and proteases that have the potential to cause or exacerbate age-related pathology, both degenerative and hyperplastic. While cellular senescence in peripheral tissues has recently been linked to a number of age-related pathologies, its involvement in brain aging is just beginning to be explored. Recent data generated by several laboratories suggest that both aging and age-related neurodegenerative diseases are accompanied by an increase in SASP-expressing senescent cells of non-neuronal origin in the brain. Moreover, this increase correlates with neurodegeneration. Senescent cells in the brain could therefore constitute novel therapeutic targets for treating age-related neuropathologies.

  19. Cellular and Molecular Basis of Cerebellar Development

    Directory of Open Access Journals (Sweden)

    Salvador eMartinez


    Full Text Available Historically, the molecular and cellular mechanisms of cerebellar development were investigated through structural descriptions and studying spontaneous mutations in animal models and humans. Advances in experimental embryology, genetic engineering and neuroimaging techniques render today the possibility to approach the analysis of molecular mechanisms underlying histogenesis and morphogenesis of the cerebellum by experimental designs. Several genes and molecules were identified to be involved in the cerebellar plate regionalization, specification and differentiation of cerebellar neurons, as well as the establishment of cellular migratory routes and the subsequent neuronal connectivity. Indeed, pattern formation of the cerebellum requires the adequate orchestration of both key morphogenetic signals, arising from distinct brain regions, and local expression of specific transcription factors. Thus, the present review wants to revisit and discuss these morphogenetic and molecular mechanisms taking place during cerebellar development in order to understand causal processes regulating cerebellar cytoarchitecture, its highly topographically ordered circuitry and its role in brain function.

  20. Cellular systems biology profiling applied to cellular models of disease. (United States)

    Giuliano, Kenneth A; Premkumar, Daniel R; Strock, Christopher J; Johnston, Patricia; Taylor, Lansing


    Building cellular models of disease based on the approach of Cellular Systems Biology (CSB) has the potential to improve the process of creating drugs as part of the continuum from early drug discovery through drug development and clinical trials and diagnostics. This paper focuses on the application of CSB to early drug discovery. We discuss the integration of protein-protein interaction biosensors with other multiplexed, functional biomarkers as an example in using CSB to optimize the identification of quality lead series compounds.

  1. 76 FR 82179 - Drivers of CMVs: Restricting the Use of Cellular Phones (United States)


    ... following correction is made: Sec. 390.3 0 On page 75487, in Sec. 390.3, paragraph (f)(1), correct ``(g)(2)'' to ``(f)(2)''. Issued on: December 21, 2011. Larry Minor, Associate Administrator for Policy,...

  2. 75 FR 27672 - Restrictions on Railroad Operating Employees' Use of Cellular Telephones and Other Electronic... (United States)


    ..., 2005, to December 31, 2007. Based on the sampling method of the survey, findings were representative of... moderate to heavy traffic. This type of purposive sample served well the intentions of the study; however... data on driver electronic device use in the United States.\\6\\ Based on the sampling method of...

  3. 75 FR 59579 - Restrictions on Railroad Operating Employees' Use of Cellular Telephones and Other Electronic... (United States)


    ... driving. H. Other Efforts 1. State Action Texting while driving is prohibited in 30 States, the District... the Rulemaking F. Distracted Driving Impacts All Transportation Modes 1. Aviation 2. Rail 3... Naturalistic Driving Study 3. National Occupant Protection Use Survey (NOPUS) 4. Motor Vehicle Occupant...

  4. 76 FR 75470 - Drivers of CMVs: Restricting the Use of Cellular Phones (United States)


    ... demonstrated widespread support for a ban against texting and mobile telephone use while driving. Summit... telephone qualifies as texting (49 CFR 390.5) and, therefore, is already prohibited while driving (75 FR... distracted driving-related crashes, fatalities, and injuries involving drivers of CMVs. The Agencies...

  5. 75 FR 80014 - Drivers of CMVs: Restricting the Use of Cellular Phones (United States)


    ... and widespread support for a ban against texting and mobile telephone use while driving. Attendees...) that prohibits texting by CMV drivers. Finally, DOT held a second Distracted Driving Summit on... would improve safety on the Nation's highways by reducing the prevalence of distracted...

  6. Quality Dimensions, Value, Service Cost and Recommendation Behaviour: Evidence from the Nigerian Cellular Industry


    Abolaji Joachim Abiodun; Kenneth Sola Adeyemi; Adewale Omotayo Osibanjo


    The present study proposed and test a model that connects both affective and cognitive factors in cellular service to customers’ recommendation behavior. Results of the analysis of data collected through questionnaire from 293 respondents with cellular phones and active account in the Nigerian cellular industry indicate that core cellular service dimensions, service cost (price) and hedonic values are significant determinants of customers’ recommendation behavior. In addition, the study found...

  7. Electromagnetic Fields Restrictions and Approximation

    CERN Document Server

    Katsenelenbaum, Boris Z


    The fields scattered by metallic bodies or radiated by some types of antennas are created by the surfaces currents and therefore they are subject to some restrictions. The book is the first one where the properties of these fields are investigated in details. The properties have the important significance for the antenna synthesis, body shape reconstruction and other diffraction problems. The material of the book lies in the meetingpoint of the antenna theory, highfrequency electrodynamics and inverse scattering problems. The author is an internationally renowned investigator in the field of e

  8. A Course in Cellular Bioengineering. (United States)

    Lauffenburger, Douglas A.


    Gives an overview of a course in chemical engineering entitled "Cellular Bioengineering," dealing with how chemical engineering principles can be applied to molecular cell biology. Topics used are listed and some key references are discussed. Listed are 85 references. (YP)

  9. Avoidant/Restrictive Food Intake Disorder (United States)

    ... for the Professional Version Eating Disorders Definition of Eating Disorders Anorexia Nervosa Avoidant/Restrictive Food Intake Disorder Binge Eating ... about what they eat. Eating Disorders Definition of Eating Disorders Anorexia Nervosa Avoidant/Restrictive Food Intake Disorder Binge Eating ...

  10. Energy Landscape of Cellular Networks (United States)

    Wang, Jin


    Cellular Networks are in general quite robust and perform their biological functions against the environmental perturbations. Progresses have been made from experimental global screenings, topological and engineering studies. However, there are so far few studies of why the network should be robust and perform biological functions from global physical perspectives. In this work, we will explore the global properties of the network from physical perspectives. The aim of this work is to develop a conceptual framework and quantitative physical methods to study the global nature of the cellular network. The main conclusion of this presentation is that we uncovered the underlying energy landscape for several small cellular networks such as MAPK signal transduction network and gene regulatory networks, from the experimentally measured or inferred inherent chemical reaction rates. The underlying dynamics of these networks can show bi-stable as well as oscillatory behavior. The global shapes of the energy landscapes of the underlying cellular networks we have studied are robust against perturbations of the kinetic rates and environmental disturbances through noise. We derived a quantitative criterion for robustness of the network function from the underlying landscape. It provides a natural explanation of the robustness and stability of the network for performing biological functions. We believe the robust landscape is a global universal property for cellular networks. We believe the robust landscape is a quantitative realization of Darwinian principle of natural selection at the cellular network level. It may provide a novel algorithm for optimizing the network connections, which is crucial for the cellular network design and synthetic biology. Our approach is general and can be applied to other cellular networks.

  11. Mathematical Modeling of Cellular Metabolism. (United States)

    Berndt, Nikolaus; Holzhütter, Hermann-Georg


    Cellular metabolism basically consists of the conversion of chemical compounds taken up from the extracellular environment into energy (conserved in energy-rich bonds of organic phosphates) and a wide array of organic molecules serving as catalysts (enzymes), information carriers (nucleic acids), and building blocks for cellular structures such as membranes or ribosomes. Metabolic modeling aims at the construction of mathematical representations of the cellular metabolism that can be used to calculate the concentration of cellular molecules and the rates of their mutual chemical interconversion in response to varying external conditions as, for example, hormonal stimuli or supply of essential nutrients. Based on such calculations, it is possible to quantify complex cellular functions as cellular growth, detoxification of drugs and xenobiotic compounds or synthesis of exported molecules. Depending on the specific questions to metabolism addressed, the methodological expertise of the researcher, and available experimental information, different conceptual frameworks have been established, allowing the usage of computational methods to condense experimental information from various layers of organization into (self-) consistent models. Here, we briefly outline the main conceptual frameworks that are currently exploited in metabolism research.

  12. Study on the Main Restricting Factors and Countermeasures of the Development of the Disabled Fitness in Anhui Province%制约安徽省残疾人健身体育开展的主要因素及对策研究

    Institute of Scientific and Technical Information of China (English)

    陈华; 牛伟; 郝薇薇


    Definition of the disabled fitness and main factors restricting the development of Anhui Province disabled sports and fitness are analyzed; According to the relevant state policies, laws and regulations and the basic functions of sports, some suggestions and countermeasures of carring out disabled sports in Anhui Province are put forward.%  讨论了残疾人健身体育的涵义、制约安徽省残疾人健身体育活动开展的主要因素等问题。依据国家相关政策、法律、法规和制度及体育基本功能,提出了安徽省残疾人健身体育活动开展的建议与对策。

  13. 7 CFR 982.14 - Restricted hazelnuts. (United States)


    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Restricted hazelnuts. 982.14 Section 982.14... Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE HAZELNUTS GROWN IN OREGON AND WASHINGTON Order Regulating Handling Definitions § 982.14 Restricted hazelnuts. Restricted hazelnuts...

  14. Problem-Solving Test: Restriction Endonuclease Mapping (United States)

    Szeberenyi, Jozsef


    The term "restriction endonuclease mapping" covers a number of related techniques used to identify specific restriction enzyme recognition sites on small DNA molecules. A method for restriction endonuclease mapping of a 1,000-basepair (bp)-long DNA molecule is described in the fictitious experiment of this test. The most important fact needed to…

  15. Restriction Enzyme Mapping: A Simple Student Practical. (United States)

    Higgins, Stephen J.; And Others


    An experiment that uses the recombinant plasmid pX1108 to illustrate restriction mapping is described. The experiment involves three restriction enzymes and employs single and double restriction enzyme digestions. A list of needed materials, procedures, safety precautions, results, and discussion are included. (KR)

  16. Restrictive Imputation of Incomplete Survey Data

    NARCIS (Netherlands)

    Vink, G.


    This dissertation focuses on finding plausible imputations when there is some restriction posed on the imputation model. In these restrictive situations, current imputation methodology does not lead to satisfactory imputations. The restrictions, and the resulting missing data problems are real-life

  17. 29 CFR 18.56 - Restricted access. (United States)


    ... 29 Labor 1 2010-07-01 2010-07-01 true Restricted access. 18.56 Section 18.56 Labor Office of the... ADMINISTRATIVE LAW JUDGES General § 18.56 Restricted access. On his or her own motion, or on the motion of any party, the administrative law judge may direct that there be a restricted access portion of the...

  18. 28 CFR 68.51 - Restricted access. (United States)


    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Restricted access. 68.51 Section 68.51... ALIENS, UNFAIR IMMIGRATION-RELATED EMPLOYMENT PRACTICES, AND DOCUMENT FRAUD § 68.51 Restricted access. On... be a restricted access portion of the record to contain any material in the record to which...

  19. 47 CFR 1.1208 - Restricted proceedings. (United States)


    ... 47 Telecommunication 1 2010-10-01 2010-10-01 false Restricted proceedings. 1.1208 Section 1.1208... Restricted Proceedings § 1.1208 Restricted proceedings. Unless otherwise provided by the Commission or its... in all proceedings not listed as exempt in § 1.1204(b) or permit-but-disclose in § 1.1206(a) of...

  20. Querying Schemas With Access Restrictions

    CERN Document Server

    Benedikt, Michael; Ley, Clemens


    We study verification of systems whose transitions consist of accesses to a Web-based data-source. An access is a lookup on a relation within a relational database, fixing values for a set of positions in the relation. For example, a transition can represent access to a Web form, where the user is restricted to filling in values for a particular set of fields. We look at verifying properties of a schema describing the possible accesses of such a system. We present a language where one can describe the properties of an access path, and also specify additional restrictions on accesses that are enforced by the schema. Our main property language, AccLTL, is based on a first-order extension of linear-time temporal logic, interpreting access paths as sequences of relational structures. We also present a lower-level automaton model, Aautomata, which AccLTL specifications can compile into. We show that AccLTL and A-automata can express static analysis problems related to "querying with limited access patterns" that h...

  1. On Changes of the City Size and Restricting Factors of Cities in Southern Xinjiang In Modern Period%近代南疆城市规模的变化与制约因素论析

    Institute of Scientific and Technical Information of China (English)



    清代前中期,南疆城市发展比北疆城市缓慢。晚清时期,随着外国资本主义的渗入、新疆建省和清政府推行一系列改革,南疆城市获得了较大发展,呈现出以喀什、和阗为中心的南疆西南城市体系的雏形和以阿克苏为中心的南疆东北城市体系的雏形。民国时期,随着新疆人口的增加和经济的发展,南疆城市人口和城市空间也都有所扩大和变化,尤其是南疆东北部地区的城市变化较为突出。虽然南疆城市在此一时期有所发展,但数量仍然不多,人口规模和空间规模都普遍较小。制约南疆城市发展的因素,除了自然环境脆弱、经济不发达、交通运输落后外,社会动乱、政局变化以及民族、宗教等因素的制约也不可忽略。%In early and middle Qing dynasty, Southern Xinjiang developed slower than Northern Xin-jiang. In late Qing Dynasty, with the infiltration of foreign capitalism, the establishment of Xinjiang prov-ince, and a series of reform measures implemented by the Qing government, the southern Xinjiang cities obtained considerable development. Kashgar, Hetian and Aksu city become the centers of southern Xin-jiang’ s urban system. During the period of the Republic of China, with the increase of population in Xin-jiang and the development of economy, southern Xinjiang urban population and urban space were wid-ened and changed, especially in the northeast region of southern Xinjiang. Although the southern Xin-jiang city achieved a certain degree of development in this period, the cities are not of great number while population and spatial scale were generally small. There were other factors which hindered the urban de-velopment of cities in southern Xinjiang, such as natural geographical environment, undeveloped econo-my, inconvenient transportation, social turmoil, political change, ethnic and religious factors.

  2. IFI16 restricts HSV-1 replication by accumulating on the hsv-1 genome, repressing HSV-1 gene expression, and directly or indirectly modulating histone modifications.

    Directory of Open Access Journals (Sweden)

    Karen E Johnson


    Full Text Available Interferon-γ inducible factor 16 (IFI16 is a multifunctional nuclear protein involved in transcriptional regulation, induction of interferon-β (IFN-β, and activation of the inflammasome response. It interacts with the sugar-phosphate backbone of dsDNA and modulates viral and cellular transcription through largely undetermined mechanisms. IFI16 is a restriction factor for human cytomegalovirus (HCMV and herpes simplex virus (HSV-1, though the mechanisms of HSV-1 restriction are not yet understood. Here, we show that IFI16 has a profound effect on HSV-1 replication in human foreskin fibroblasts, osteosarcoma cells, and breast epithelial cancer cells. IFI16 knockdown increased HSV-1 yield 6-fold and IFI16 overexpression reduced viral yield by over 5-fold. Importantly, HSV-1 gene expression, including the immediate early proteins, ICP0 and ICP4, the early proteins, ICP8 and TK, and the late proteins gB and Us11, was reduced in the presence of IFI16. Depletion of the inflammasome adaptor protein, ASC, or the IFN-inducing transcription factor, IRF-3, did not affect viral yield. ChIP studies demonstrated the presence of IFI16 bound to HSV-1 promoters in osteosarcoma (U2OS cells and fibroblasts. Using CRISPR gene editing technology, we generated U2OS cells with permanent deletion of IFI16 protein expression. ChIP analysis of these cells and wild-type (wt U2OS demonstrated increased association of RNA polymerase II, TATA binding protein (TBP and Oct1 transcription factors with viral promoters in the absence of IFI16 at different times post infection. Although IFI16 did not alter the total histone occupancy at viral or cellular promoters, its absence promoted markers of active chromatin and decreased those of repressive chromatin with viral and cellular gene promoters. Collectively, these studies for the first time demonstrate that IFI16 prevents association of important transcriptional activators with wt HSV-1 promoters and suggest potential

  3. Hierarchical Cellular Structures in High-Capacity Cellular Communication Systems

    CERN Document Server

    Jain, R K; Agrawal, N K


    In the prevailing cellular environment, it is important to provide the resources for the fluctuating traffic demand exactly in the place and at the time where and when they are needed. In this paper, we explored the ability of hierarchical cellular structures with inter layer reuse to increase the capacity of mobile communication network by applying total frequency hopping (T-FH) and adaptive frequency allocation (AFA) as a strategy to reuse the macro and micro cell resources without frequency planning in indoor pico cells [11]. The practical aspects for designing macro- micro cellular overlays in the existing big urban areas are also explained [4]. Femto cells are inducted in macro / micro / pico cells hierarchical structure to achieve the required QoS cost effectively.

  4. 低出生体重早产儿宫外发育迟缓的相关因素分析%Related factors of extrauterine growth restriction in low birth weight preterm children

    Institute of Scientific and Technical Information of China (English)



    目的:探讨胎龄≤32周低出生体重早产儿宫外发育迟缓(EUGR)发生率及其相关影响因素。方法纳入126例胎龄≤32周低出生体重早产儿,记录胎龄(超声或出生时成熟度分析数据)、出生时体重、身长、头围、性别、是否低于胎龄儿、是否存在呼吸窘迫综合征、最大生理性体重减少率、恢复出生体重的天数、起始肠内喂养时间、完全肠内喂养时间(每天奶量>100 ml/kg·d),37~42周时测定早产儿体重、身长、头围,以体重、身长和头围计,分析EUGR发生率、其危险因素以及适于胎龄儿(AGA)和低于胎龄儿(SGA) EUGR发生率。结果 EUGR组胎龄、出生体重、出生身长、出生头围均低于非EUGR组(均P100 ml/kg·d) were recorded. During 37~42 weeks, weight, length, head circumference, body weight, length and head circumference of premature children were measured. Incidence of EUGR and risk factors, and incidences of EUGR in appropriate for gestational age children (AGA) and small for gestational age children (SGA) were analyzed. Results The gestational age, birth weight, birth length, and head circumference at birth of EUGR group were lower than those of the non-EUGR group (all P<0.01), while the rate of weight loss (%), time to regain birth weight, time for starting enteral feeding and giving full enteral feeding were greater than those of non-EUGR group (all P<0.01). The proportion of SGA was significantly greater than that of non-EUGR group (all P<0.05). Based on weight, length, head circumference, incidences of EUGR in all newborns were 47.6%, 39.7%and 4.8%. Toatally, extrauterine growth retardation rate of SGA was significantly higher than that of AGA (all P<0.01).Gestational age, birth weight, recovery time, and time for full enteral feeding were closely related with EUGR. Conclusion Gestation-al age, intrauterine growth retardation, poor nutritional intake and RDS are still the risk factors of EUGR in premature

  5. 医院临床药学服务能力的制约因素及对策探讨%Restricted factors of hospital clinical pharmaceutical care capability and discussion of improved countermeasures

    Institute of Scientific and Technical Information of China (English)

    孙艳; 黄翠丽; 张明华; 李德东; 王沭


    Objective:To explore effective measures for improving pharmaceutical care capability of the hospital .Methods:A questionnaire survey was made on the clinical physicians ,nurses ,dispensary pharmacists and clinical pharmacists in the 65 tertiary hospitals across the country .The contents of the survey included the scope of hospital pharmaceutical care ,the mode of clinical pharmaceutical care ,the comprehensive capability of pharmacist pharmaceutical care ,as well as the rate of recognition by medical personnel of the hospital .Then ,all the obtained data were summarized and analyzed .Results and Conclusion:Sur‐vey results indicated that the main contents of clinical pharmaceutical care by pharmacists included the review of medical orders , medication consultation of outpatients ,medication education ,drug dispensing and so on .The main factors affecting further de‐velopment of clinical pharmacists were 4 external and 6 internal factors .In view of higher demands on pharmaceutical care by clinical medical personnel ,pharmacists should improve their professional quality to satisfy increasing clinical needs .With this in view ,the pharmacy department should further improve the professional quality of clinical pharmacists and establish the phar‐maceutical care platform suitable to the situation in China ,so as to establish the new pharmaceutical care mode with the patient as the center and rational medication as the core ,and ultimately enhance the pharmaceutical care capability of pharmacists .%目的:探索提高医院药师药学服务能力的有效举措。方法:在全国范围内对65家三级甲等医院医师、护士、药房药师和临床药师进行问卷调研,调研内容主要包括医院药学工作内容、临床药学服务工作方式、药师药学服务综合能力及医护人员对药师认知度等方面,并对采集的数据进行汇总和分析。结果和结论:调研结果表明,药师在医院从事的药学服务工作

  6. On Restricting Factors and Countermeasures of the Development of Carrageenan%我国卡拉胶生产发展制约因素及其对策的探讨

    Institute of Scientific and Technical Information of China (English)

    郭善慧; 关键


    卡拉胶用作天然食品添加剂已有多年的历史,它是一种无毒而又不能被人体消化的植物纤维,用途十分广泛。国外的卡拉胶商业性生产是从20世纪20年代开始的。我国则从1985年开始生产商业用卡拉胶,其中80%用于食品或与食品有关的工业。随着食品、医疗等行业发展,国内外市场对卡拉胶需求不断扩大,但卡拉胶行业在蓬勃发展的同时遇到瓶颈。本文主要通过对卡拉胶生产发展制约因素的研究,以探讨破解瓶颈的方法和策略。%Carrageenan is used as a natural food additive has a long history, it is the plant fiber which is a non-toxic and can not be digested by, use isvery extensive. Carrageenan demand has continued to expand, but in recent years the development of carrageenan bottleneck of highlights. In this paper , through the research on the development of carrageenan production factors, to explore the methods and strategies of breaking the bottleneck.

  7. Restricting Factors and Countermeasures on College Students ’ Political Participation through Network%大学生网络政治参与的制约因素及对策研究

    Institute of Scientific and Technical Information of China (English)



    政治参与渠道的网络化为大学生提供了更加便利的条件,大学生网络政治参与已日益成为中国政治生活里不容忽视的一股力量。综观目前的发展状况,大学生在网络政治参与中受到社交网络肆意膨胀、政治参与心态不成熟、参与动机趋向功利化等方面因素的影响。面对现实,政府应完善网络立法和监管,高校应加强大学生思想政治教育,大学生要提升网络政治参与水平。%Political participation channels of the network to provide a more convenient condition for college students, college students’ network political participation has increasingly become a force to be reckoned with in the China’s political life. Throughout the current status of the development of college students in the network political participation by social networks is wanton expansion, political participation, mentality is not mature, and participation motivation tend to be utilitarian factors, the government should face it improving the Internet legislation and regulation, should strengthen the ideological and political education in colleges and universities, college students to enhance the level of network political participation.

  8. Observability in electric power networks: a method of ways of factorization in state estimation with equality restrictions; Observabilidade em redes de energia: um metodo de caminhos de fatoracao em estimacao de estado com restricoes de igualdade

    Energy Technology Data Exchange (ETDEWEB)

    Vicentino, Flavio Antonio


    A theory of network observability that mixes graph concepts and factorization of the gain matrix G has been recently developed. It uses data already available in Power System Operating Centers. That theory is easy to understand and implement and does not require subroutines other than the ones used in static state estimation. However, this new theory has been implemented only for the case of state estimation in Normal Equation Formulation (N E). However, the N E Method presents some inherent numerical difficulties. Such numerical difficulties are usually related to the disparity in the measurements weights (high values for zero-injections measurements and low values for pseudo-measurements) and the presence of short lines in the network, as well. In order to solve such numerical difficulties, new methods have come up, such as: Normal Equation Method with Equality Constraints (N E/C), where Lagrange's Multiplier Method can be applied to minimize a function while satisfying a set of constraints; Hachtel's Method, which is formulated the same way as N E/C Method, although an equation of residual vector is introduced in solution process; Hybrid Method, which is a general formulation behaving as the N E/C Method at one extreme, and as Hachtel's Method at the other. Thus, the aim of this work is to treat the adaptation of the network observability Method by using path graphs, with the state estimation in the form of a minimization problem with equality constraints. As the Hybrid Method is a generalization form of the state estimator with constraints, this formulation is used to develop the proposed theory. Extreme case (as the pure Hachtel's Method) are also considered. (author)

  9. Paternally Inherited IGF2 Mutation and Growth Restriction. (United States)

    Begemann, Matthias; Zirn, Birgit; Santen, Gijs; Wirthgen, Elisa; Soellner, Lukas; Büttel, Hans-Martin; Schweizer, Roland; van Workum, Wilbert; Binder, Gerhard; Eggermann, Thomas


    In humans, mutations in IGF1 or IGF1R cause intrauterine and postnatal growth restriction; however, data on mutations in IGF2, encoding insulin-like growth factor (IGF) II, are lacking. We report an IGF2 variant (c.191C→A, p.Ser64Ter) with evidence of pathogenicity in a multigenerational family with four members who have growth restriction. The phenotype affects only family members who have inherited the variant through paternal transmission, a finding that is consistent with the maternal imprinting status of IGF2. The severe growth restriction in affected family members suggests that IGF-II affects postnatal growth in addition to prenatal growth. Furthermore, the dysmorphic features of affected family members are consistent with a role of deficient IGF-II levels in the cause of the Silver-Russell syndrome. (Funded by Bundesministerium für Bildung und Forschung and the European Union.).

  10. Quantitative, functional, and biochemical alterations in the peritoneal cells of mice exposed to whole-body gamma irradiation. 1. Changes in cellular protein, adherence properties, and enzymatic activities associated with platelet-activating factor formation and inactivation, and arachidonate metabolism. Scientific report

    Energy Technology Data Exchange (ETDEWEB)

    Steel, L.K.; Hughes, H.N.; Walden, T.L.


    Changes in total number, differentials, cell protein, adherence properties, acetyltransferase and acetylhydrolase activities, prostaglandin E2 and leukotriene C4 production, as well as calcium (2+) ionophore A23187 stimulation were examined in resident peritoneal cells isolated from mice 2h to 10 days postexposure to a single dose (7,10 or 12 Gy) of gamma radiation. Radiation dose-related reductions in macrophage and lymphocyte numbers and increases in cellular protein and capacity to adhere to plastic surfaces were evident. In-vitro irradiation also elevated the activities of acetyltransferase and acetylhydrolase (catalyzing platelet-activating factor biosynthesis and inactivation, respectively) in adherent and nonadherent peritoneal cells, particularly 3-4 days postexposure. Blood plasma from irradiated animals did not reflect the increased cellular acetylhydrolase activity. Prostaglandin E2 and leukotriene C4 synthesis were elevated postexposure, suggesting increased substrate (arachidonate) availability and increased cyclooxygenase and lipoxygenase activities. Ionospheric stimulation of enzyme activities and eicosanoid release also differed in irradiated peritoneal cells. While the properties of adherence, platelet-activating factor synthesis/inactivation-associated enzyme activities, and eicosanoid production are generally characterized as those of macrophages, lymphocytes or their products may influence or contribute to the observed radiation-induced changes.

  11. Gentile statistics and restricted partitions

    Indian Academy of Sciences (India)

    C S Srivatsan; M V N Murthy; R K Bhaduri


    In a recent paper (Tran et al, Ann. Phys. 311, 204 (2004)), some asymptotic number theoretical results on the partitioning of an integer were derived exploiting its connection to the quantum density of states of a many-particle system. We generalise these results to obtain an asymptotic formula for the restricted or coloured partitions $p_{k}^{s} (n)$, which is the number of partitions of an integer into the summand of th powers of integers such that each power of a given integer may occur utmost times. While the method is not rigorous, it reproduces the well-known asymptotic results for = 1 apart from yielding more general results for arbitrary values of .

  12. Neurodevelopment after fetal growth restriction. (United States)

    Baschat, Ahmet A


    Fetal growth restriction (FGR) can emerge as a complication of placental dysfunction and increases the risk for neurodevelopmental delay. Marked elevations of umbilical artery (UA) Doppler resistance that set the stage for cardiovascular and biophysical deterioration with subsequent preterm birth characterize early-onset FGR. Minimal, or absent UA Doppler abnormalities and isolated cerebral Doppler changes with subtle deterioration and a high risk for unanticipated term stillbirth are characteristic for late-onset FGR. Nutritional deficiency manifested in lagging head growth is the most powerful predictor of developmental delay in all forms of FGR. Extremes of blood flow resistance and cardiovascular deterioration, prematurity and intracranial hemorrhage increase the risks for psychomotor delay and cerebral palsy. In late-onset FGR, regional cerebral vascular redistribution correlates with abnormal behavioral domains. Irrespective of the phenotype of FGR, prenatal tests that provide precise and independent stratification of risks for adverse neurodevelopment have yet to be determined.


    Institute of Scientific and Technical Information of China (English)

    Petar Petrov


    For given data (ti,yi), I= 0,1,…,n,0 = t0 <t1 <…<tn = 1we study constrained interpolation problem of Favard type inf{‖f"‖∞|f∈W2∞[0,1],f(ti)=yi,i=0,…,n,l(f;[0,1])≤l0}, wherel(f";[0,1])=∫1 0 / 1+f'2(x)dx is the arc length off in [0,1]. We prove the existence of a solution f* of the above problem, that is a quadratic spline with a second derivative f"* , which coincides with one of the constants - ‖f"*‖∞,0,‖f"*‖∞ between every two consecutive knots. Thus, we extend a result ofKarlin concerning Favard problem, to the case of restricted length interpolation.

  14. Stillbirth and fetal growth restriction. (United States)

    Bukowski, Radek


    The association between stillbirth and fetal growth restriction is strong and supported by a large body of evidence and clinically employed for the stillbirth prediction. However, although assessment of fetal growth is a basis of clinical practice, it is not trivial. Essentially, fetal growth is a result of the genetic growth potential of the fetus and placental function. The growth potential is the driving force of fetal growth, whereas the placenta as the sole source of nutrients and oxygen might become the rate limiting element of fetal growth if its function is impaired. Thus, placental dysfunction may prevent the fetus from reaching its full genetically determined growth potential. In this sense fetal growth and its aberration provides an insight into placental function. Fetal growth is a proxy for the test of the effectiveness of placenta, whose function is otherwise obscured during pregnancy.

  15. An Infinite Restricted Boltzmann Machine. (United States)

    Côté, Marc-Alexandre; Larochelle, Hugo


    We present a mathematical construction for the restricted Boltzmann machine (RBM) that does not require specifying the number of hidden units. In fact, the hidden layer size is adaptive and can grow during training. This is obtained by first extending the RBM to be sensitive to the ordering of its hidden units. Then, with a carefully chosen definition of the energy function, we show that the limit of infinitely many hidden units is well defined. As with RBM, approximate maximum likelihood training can be performed, resulting in an algorithm that naturally and adaptively adds trained hidden units during learning. We empirically study the behavior of this infinite RBM, showing that its performance is competitive to that of the RBM, while not requiring the tuning of a hidden layer size.

  16. 10 CFR 1045.16 - Criteria for evaluation of restricted data and formerly restricted data information. (United States)


    ... § 1045.16 Criteria for evaluation of restricted data and formerly restricted data information. (a) The... 10 Energy 4 2010-01-01 2010-01-01 false Criteria for evaluation of restricted data and formerly restricted data information. 1045.16 Section 1045.16 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS)...

  17. Classifying cellular automata using grossone (United States)

    D'Alotto, Louis


    This paper proposes an application of the Infinite Unit Axiom and grossone, introduced by Yaroslav Sergeyev (see [7] - [12]), to the development and classification of one and two-dimensional cellular automata. By the application of grossone, new and more precise nonarchimedean metrics on the space of definition for one and two-dimensional cellular automata are established. These new metrics allow us to do computations with infinitesimals. Hence configurations in the domain space of cellular automata can be infinitesimally close (but not equal). That is, they can agree at infinitely many places. Using the new metrics, open disks are defined and the number of points in each disk computed. The forward dynamics of a cellular automaton map are also studied by defined sets. It is also shown that using the Infinite Unit Axiom, the number of configurations that follow a given configuration, under the forward iterations of cellular automaton maps, can now be computed and hence a classification scheme developed based on this computation.

  18. Prognosis of Different Cellular Generations

    Directory of Open Access Journals (Sweden)

    Preetish Ranjan


    Full Text Available Technological advancement in mobile telephony from 1G to 3G, 4G and 5G has a very axiomatic fact that made an entire world a global village. The cellular system employs a different design approach and technology that most commercial radio and television system use. In the cellular system, the service area is divided into cells and a transmitter is designed to serve an individual cell. The system seeks to make efficient use of available channels by using low-power transmitters to allow frequency reuse at a smaller distance. Maximizing the number of times each channel can be reused in a given geographical area is the key to an efficient cellular system design. During the past three decades, the world has seen significant changes in telecommunications industry. There have been some remarkable aspects to the rapid growth in wireless communications, as seen by the large expansion in mobile systems. This paper focuses on “Past, Present & Future of Cellular Telephony” and some light has been thrown upon the technologies of the cellular systems, namely 1G, 2G, 2.5G, 3G and future generations like 4G and 5G systems as well.

  19. Restricted Interval Valued Neutrosophic Sets and Restricted Interval Valued Neutrosophic Topological Spaces

    Directory of Open Access Journals (Sweden)

    Anjan Mukherjee


    Full Text Available In this paper we introduce the concept of restricted interval valued neutrosophic sets (RIVNS in short. Some basic operations and properties of RIVNS are discussed. The concept of restricted interval valued neutrosophic topology is also introduced together with restricted interval valued neutrosophic finer and restricted interval valued neutrosophic coarser topology. We also define restricted interval valued neutrosophic interior and closer of a restricted interval valued neutrosophic set. Some theorems and examples are cites. Restricted interval valued neutrosophic subspace topology is also studied.

  20. Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response. (United States)

    Richardson, Chanté L; Delehanty, Lorrie L; Bullock, Grant C; Rival, Claudia M; Tung, Kenneth S; Kimpel, Donald L; Gardenghi, Sara; Rivella, Stefano; Goldfarb, Adam N


    The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mechanistically, the erythroid iron restriction response results from inactivation of aconitase enzymes and can be suppressed by providing the aconitase product isocitrate. Recent studies have implicated the erythroid iron restriction response in anemia of chronic disease and inflammation (ACDI), offering new therapeutic avenues for a major clinical problem; however, inflammatory signals may also directly repress erythropoiesis in ACDI. Here, we show that suppression of the erythroid iron restriction response by isocitrate administration corrected anemia and erythropoietic defects in rats with ACDI. In vitro studies demonstrated that erythroid repression by inflammatory signaling is potently modulated by the erythroid iron restriction response in a kinase-dependent pathway involving induction of the erythroid-inhibitory transcription factor PU.1. These results reveal the integration of iron and inflammatory inputs in a therapeutically tractable erythropoietic regulatory circuit.

  1. Novel Materials for Cellular Nanosensors

    DEFF Research Database (Denmark)

    Sasso, Luigi

    The monitoring of cellular behavior is useful for the advancement of biomedical diagnostics, drug development and the understanding of a cell as the main unit of the human body. Micro- and nanotechnology allow for the creation of functional devices that enhance the study of cellular dynamics...... modifications for electrochemical nanosensors for the detection of analytes released from cells. Two type of materials were investigated, each pertaining to the two different aspects of such devices: peptide nanostructures were studied for the creation of cellular sensing substrates that mimic in vivo surfaces...... and that offer advantages of functionalization, and conducting polymers were used as electrochemical sensor surface modifications for increasing the sensitivity towards relevant analytes, with focus on the detection of dopamine released from cells via exocytosis. Vertical peptide nanowires were synthesized from...

  2. Cellular phones and traffic accidents: an epidemiological approach. (United States)

    Violanti, J M; Marshall, J R


    Using epidemiological case-control design and logistic regression techniques, this study examined the association of cellular phone use in motor vehicles and traffic accident risk. The amount of time per month spent talking on a cellular phone and 18 other driver inattention factors were examined. Data were obtained from: (1) a case group of 100 randomly selected drivers involved in accidents within the past 2 years, and (2) a control group of 100 randomly selected licensed drivers not involved in accidents within the past 10 years. Groups were matched on geographic residence. Approximately 13% (N = 7) of the accident and 9% (N = 7) of the non-accident group reported use of cellular phones while driving. Data was obtained from Department of Motor Vehicles accident reports and survey information from study subjects. We hypothesized that increased use of cellular phones while driving was associated with increased odds of a traffic accident. Results indicated that talking more than 50 minutes per month on cellular phones in a vehicle was associated with a 5.59-fold increased risk in a traffic accident. The combined use of cellular phones and motor and cognitive activities while driving were also associated with increased traffic accident risk. Readers should be cautioned that this study: (1) consists of a small sample, (2) reveals statistical associations and not causal relationships, and (3) does not conclude that talking on cellular phones while driving is inherently dangerous.

  3. The structure and function of vertebrate fibroblast growth factor receptor 1. (United States)

    Groth, Casper; Lardelli, Michael


    The vertebrate fibroblast growth factor receptor 1 (FGFR1) is alternatively spliced generating multiple splice variants that are differentially expressed during embryo development and in the adult body. The restricted expression patterns of FGFR1 isoforms, together with differential expression and binding of specific ligands, leads to activation of common FGFR1 signal transduction pathways, but may result in distinctively different biological responses as a result of differences in cellular context. FGFR1 isoforms are also present in the nucleus in complex with various fibroblast growth factors where they function to regulate transcription of target genes.

  4. Cellular models for Parkinson's disease. (United States)

    Falkenburger, Björn H; Saridaki, Theodora; Dinter, Elisabeth


    Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of α-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of non-dopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to α-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Cellular models reproduce the two most salient changes of Parkinson's disease, the degeneration of dopaminergic neurons and the existence of α-synuclein aggregates. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types and treatments the aspects of Parkinson's disease they model along with technical advantages and disadvantages. Furthermore, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. This article is part of a special issue on Parkinson disease.

  5. Infectious Lassa virus, but not filoviruses, is restricted by BST-2/tetherin. (United States)

    Radoshitzky, Sheli R; Dong, Lian; Chi, Xiaoli; Clester, Jeremiah C; Retterer, Cary; Spurgers, Kevin; Kuhn, Jens H; Sandwick, Sarah; Ruthel, Gordon; Kota, Krishna; Boltz, Dutch; Warren, Travis; Kranzusch, Philip J; Whelan, Sean P J; Bavari, Sina


    Bone marrow stromal antigen 2 (BST-2/tetherin) is a cellular membrane protein that inhibits the release of HIV-1. We show for the first time, using infectious viruses, that BST-2 also inhibits egress of arenaviruses but has no effect on filovirus replication and spread. Specifically, infectious Lassa virus (LASV) release significantly decreased or increased in human cells in which BST-2 was either stably expressed or knocked down, respectively. In contrast, replication and spread of infectious Zaire ebolavirus (ZEBOV) and Lake Victoria marburgvirus (MARV) were not affected by these conditions. Replication of infectious Rift Valley fever virus (RVFV) and cowpox virus (CPXV) was also not affected by BST-2 expression. Elevated cellular levels of human or murine BST-2 inhibited the release of virus-like particles (VLPs) consisting of the matrix proteins of multiple highly virulent NIAID Priority Pathogens, including arenaviruses (LASV and Machupo virus [MACV]), filoviruses (ZEBOV and MARV), and paramyxoviruses (Nipah virus). Although the glycoproteins of filoviruses counteracted the antiviral activity of BST-2 in the context of VLPs, they could not rescue arenaviral (LASV and MACV) VLP release upon BST-2 overexpression. Furthermore, we did not observe colocalization of filoviral glycoproteins with BST-2 during infection with authentic viruses. None of the arenavirus-encoded proteins rescued budding of VLPs in the presence of BST-2. Our results demonstrate that BST-2 might be a broad antiviral factor with the ability to restrict release of a wide variety of human pathogens. However, at least filoviruses, RVFV, and CPXV are immune to its inhibitory effect.

  6. Blood Flow Restricted Exercise and Vascular Function

    Directory of Open Access Journals (Sweden)

    Masahiro Horiuchi


    Full Text Available It is established that regular aerobic training improves vascular function, for example, endothelium-dependent vasodilatation and arterial stiffness or compliance and thereby constitutes a preventative measure against cardiovascular disease. In contrast, high-intensity resistance training impairs vascular function, while the influence of moderate-intensity resistance training on vascular function is still controversial. However, aerobic training is insufficient to inhibit loss in muscular strength with advancing age; thus, resistance training is recommended to prevent sarcopenia. Recently, several lines of study have provided compelling data showing that exercise and training with blood flow restriction (BFR leads to muscle hypertrophy and strength increase. As such, BFR training might be a novel means of overcoming the contradiction between aerobic and high-intensity resistance training. Although it is not enough evidence to obtain consensus about impact of BFR training on vascular function, available evidences suggested that BFR training did not change coagulation factors and arterial compliance though with inconsistence results in endothelial function. This paper is a review of the literature on the impact of BFR exercise and training on vascular function, such as endothelial function, arterial compliance, or other potential factors in comparison with those of aerobic and resistance training.

  7. Cellular basis of Alzheimer's disease. (United States)

    Bali, Jitin; Halima, Saoussen Ben; Felmy, Boas; Goodger, Zoe; Zurbriggen, Sebastian; Rajendran, Lawrence


    Alzheimer's disease (AD) is the most common form of neurodegenerative disease. A characteristic feature of the disease is the presence of amyloid-β (Aβ) which either in its soluble oligomeric form or in the plaque-associated form is causally linked to neurodegeneration. Aβ peptide is liberated from the membrane-spanning -amyloid precursor protein by sequential proteolytic processing employing β- and γ-secretases. All these proteins involved in the production of Aβ peptide are membrane associated and hence, membrane trafficking and cellular compartmentalization play important roles. In this review, we summarize the key cellular events that lead to the progression of AD.

  8. Interferon gamma, interleukin 4 and transforming growth factor beta in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Mustafa, M; Ljungdahl, A;


    The potential role of certain important immunoregulatory and effector cytokines in autoimmune neuroinflammation have been studied. We have examined the expression of mRNA, with in situ hybridization, of interferon gamma (IFN-gamma), interleukin 4 (IL-4) and transforming growth factor beta (TGF...

  9. Diabetes mellitus: channeling care through cellular discovery. (United States)

    Maiese, Kenneth; Shang, Yan Chen; Chong, Zhao Zhong; Hou, Jinling


    Diabetes mellitus (DM) impacts a significant portion of the world's population and care for this disorder places an economic burden on the gross domestic product for any particular country. Furthermore, both Type 1 and Type 2 DM are becoming increasingly prevalent and there is increased incidence of impaired glucose tolerance in the young. The complications of DM are protean and can involve multiple systems throughout the body that are susceptible to the detrimental effects of oxidative stress and apoptotic cell injury. For these reasons, innovative strategies are necessary for the implementation of new treatments for DM that are generated through the further understanding of cellular pathways that govern the pathological consequences of DM. In particular, both the precursor for the coenzyme beta-nicotinamide adenine dinucleotide (NAD(+)), nicotinamide, and the growth factor erythropoietin offer novel platforms for drug discovery that involve cellular metabolic homeostasis and inflammatory cell control. Interestingly, these agents and their tightly associated pathways that consist of cell cycle regulation, protein kinase B, forkhead transcription factors, and Wnt signaling also function in a broader sense as biomarkers for disease onset and progression.

  10. Cellular uptake of metallated cobalamins

    DEFF Research Database (Denmark)

    Tran, MQT; Stürup, Stefan; Lambert, Ian H.;


    Cellular uptake of vitamin B12-cisplatin conjugates was estimated via detection of their metal constituents (Co, Pt, and Re) by inductively coupled plasma mass spectrometry (ICP-MS). Vitamin B12 (cyano-cob(iii)alamin) and aquo-cob(iii)alamin [Cbl-OH2](+), which differ in the β-axial ligands (CN(-...

  11. Calcium desensitizer catechin reverses diastolic dysfunction in mice with restrictive cardiomyopathy. (United States)

    Zhang, Lei; Nan, Changlong; Chen, Yuan; Tian, Jie; Jean-Charles, Pierre-Yves; Getfield, Cecile; Wang, Xiaoqing; Huang, Xupei


    Diastolic dysfunction refers to an impaired relaxation and an abnormality in ventricular blood filling during diastole while systolic function is preserved. Cardiac myofibril hypersensitivity to Ca(2+) is a major factor that causes impaired relaxation of myocardial cells. The present study investigates the effect of the green tea extract catechins on myofibril calcium desensitization and restoration of diastolic function in a restrictive cardiomyopathy (RCM) mouse model with cardiac troponin mutations. Wild type (WT) and RCM mice were treated daily with catechin (epigallocatechin-3-gallate, EGCg, 50 mg/kg body weight) for 3 months. Echocardiography and cell based assays were performed to measure cardiac structure and flow-related variables including chamber dimensions, fraction shortening, trans-mitral flow patterns in the experimental mice. In addition, myocyte contractility and calcium dynamics were measured in WT and RCM cardiomyocytes treated in vitro with 5 μM EGCg. Our data indicated that RCM mice treated with EGCg showed an improved diastolic function while systolic function remained unchanged. At the cellular level, sarcomere relaxation and calcium decay were accelerated in RCM myocardial cells treated with EGCg. These results suggest that catechin is effective in reversing the impaired relaxation in RCM myocardial cells and rescuing the RCM mice with diastolic dysfunction.

  12. Measuring Regulatory Restrictions in Logistics Services


    Claire HOLLWEG; Marn-Heong WONG


    This study measures the extent of restrictions on trade in logistics services in the ASEAN+6 economies by constructing a logistics regulatory restrictiveness index for each economy that quantifies the extent of government regulations faced by logistics service providers. This is the first study of its kind to construct a regulatory index of the entire logistics sector, which includes the main modes of international transport and customs restrictions. The indices show that large differences ex...

  13. 1,4-Naphthoquinones: From Oxidative Damage to Cellular and Inter-Cellular Signaling

    Directory of Open Access Journals (Sweden)

    Lars-Oliver Klotz


    Full Text Available Naphthoquinones may cause oxidative stress in exposed cells and, therefore, affect redox signaling. Here, contributions of redox cycling and alkylating properties of quinones (both natural and synthetic, such as plumbagin, juglone, lawsone, menadione, methoxy-naphthoquinones, and others to cellular and inter-cellular signaling processes are discussed: (i naphthoquinone-induced Nrf2-dependent modulation of gene expression and its potentially beneficial outcome; (ii the modulation of receptor tyrosine kinases, such as the epidermal growth factor receptor by naphthoquinones, resulting in altered gap junctional intercellular communication. Generation of reactive oxygen species and modulation of redox signaling are properties of naphthoquinones that render them interesting leads for the development of novel compounds of potential use in various therapeutic settings.

  14. Restrictive Factors for Economic Growth in Developing Countries


    Bucur Ion; Bucur Cristian


    Economic growth reflects the ability of an economy to produce more goods, in the structure and quality demanded by consumers. Growth influence decisive the existing living standard in a country. Developing countries are characterized in a greater extent than developed countries by insufficient financial resources designed both to increase the volume of investment resources and their efficient use. Increasing economic resources requires investments and lead to increased production.

  15. Identification of a protein that interacts with the nuclear factor-1 (NF-1) binding site in cells that do not express NF-1: comparison to NF-1, cellular distribution, and effect on transcription.


    McQuillan, J J; Rosen, G.D.; Birkenmeier, T M; Dean, D C


    We examined expression of nuclear factor-1 (NF-1) in different cell lines. Expression was low or undetectable in T and B lymphocyte cell lines, whereas fibroblasts and other adherent cell lines generally had a relatively high level of NF-1 mRNA. In cell lines that did not express NF-1, gel retardation assays, nevertheless, indicated complexes between a protein or proteins and the NF-1 site. These complexes were less abundant than those formed with NF-1, they migrated more slowly, and they app...

  16. The replicative restriction of lymphocytotropic isolates of HIV-1 in macrophages is overcome by TGF-beta. (United States)

    Lazdins, J K; Klimkait, T; Woods-Cook, K; Walker, M; Alteri, E; Cox, D; Cerletti, N; Shipman, R; Bilbe, G; McMaster, G


    In vitro exposure of human blood monocyte-derived macrophages to T-cell tropic human immunodeficiency virus (HIV) isolates fails to establish a productive viral infection. Several studies have shown that such preferential HIV-1 replication in T cells or in mononuclear phagocytes (HIV tropism) may be determined by distinct viral characteristics. In the present study it was demonstrated that transforming growth factor-beta (TGF-beta), a factor known to be produced by platelets, macrophages, and other cells present at a wound site, can act as a mediator in overcoming the lymphocytotropic restriction of several well-characterized viral isolates of HIV-1 (i.e., LAV, Z84, pLAI, NY5). Macrophages infected with these isolates show cytopathic changes comparable to those seen upon infection with the monocytotropic isolate ADA. To achieve this effect with TGF-beta, the factor must be present after the infection period. The emerging virus retains its original cellular tropism. Based on these observations the authors propose a role for TGF-beta in the establishment and progression of HIV infection and disease.

  17. The Restriction .on Educational Quality in Rural Schools

    Institute of Scientific and Technical Information of China (English)



    In order to understand the educational quality in rural schools, I went deep into Huangjia Middle School( situated in Northern China) to make the research. In this article, I focus on the restrictions on educational qualitys, which is one of the main themes about rural education. The factors influencing quality in rural schools are analyzed in this article .It is concluded that educational quality depends on the relationship of teaching and learning and its supporting context.

  18. Evolution of DNA Double-Strand Break Repair by Gene Conversion: Coevolution Between a Phage and a Restriction-Modification System (United States)

    Yahara, Koji; Horie, Ryota; Kobayashi, Ichizo; Sasaki, Akira


    The necessity to repair genome damage has been considered to be an immediate factor responsible for the origin of sex. Indeed, attack by a cellular restriction enzyme of invading DNA from several bacteriophages initiates recombinational repair by gene conversion if there is homologous DNA. In this work, we modeled the interaction between a bacteriophage and a bacterium carrying a restriction enzyme as antagonistic coevolution. We assume a locus on the bacteriophage genome has either a restriction-sensitive or a restriction-resistant allele, and another locus determines whether it is recombination/repair proficient or defective. A restriction break can be repaired by a co-infecting phage genome if one of them is recombination/repair proficient. We define the fitness of phage (resistant/sensitive and repair-positive/-negative) genotypes and bacterial (restriction-positive/-negative) genotypes by assuming random encounter of the genotypes, with given probabilities of single and double infections, and the costs of resistance, repair, and restriction. Our results show the evolution of the repair allele depends on \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}b_{1}/b_{0},\\end{equation*}\\end{document} the ratio of the burst size \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}b_{1}\\end{equation*}\\end{document} under damage to host cell physiology induced by an unrepaired double-strand break to the default burst size \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage

  19. Different modulation by dietary restriction of adipokine expression in white adipose tissue sites in the rat

    Directory of Open Access Journals (Sweden)

    Esteve Montserrat


    Full Text Available Abstract Background White adipose tissue (WAT is a disperse organ acting as energy storage depot and endocrine/paracrine controlling factor in the management of energy availability and inflammation. WAT sites response under energy-related stress is not uniform. In the present study we have analyzed how different WAT sites respond to limited food restriction as a way to better understand the role of WAT in the pathogenesis of the metabolic syndrome. Methods Overweight male rats had their food intake reduced a 40% compared with free-feeding controls. On day ten, the rats were killed; circulating glucose, insulin, leptin, adiponectin, triacylglycerols and other parameters were measured. The main WAT sites were dissected: mesenteric, retroperitoneal, epididymal and subcutaneous inguinal, which were weighed and frozen. Later all subcutaneous WAT was also dissected and weighed. Samples were used for DNA (cellularity analysis and mRNA extraction and semiquantitarive RT-PCR analysis of specific cytokine gene expressions. Results There was a good correlation between serum leptin and cumulative WAT leptin gene mRNA, but not for adiponectin. Food restriction reduced WAT size, but not its DNA content (except for epididymal WAT. Most cytokines were correlated to WAT site weight, but not to DNA. There was WAT site specialization in the differential expression (and probably secretion of adipokines: subcutaneous WAT showed the highest concentration for leptin, CD68 and MCP-1, mesenteric WAT for TNFα (and both tissues for the interleukins 1β and 6; resistin was highly expressed in subcutaneous and retroperitoneal WAT. Conclusion Food restriction induced different patterns for mesenteric and the other WAT sites, which may be directly related to both the response to intestine-derived energy availability, and an inflammatory-related response. However, retroperitoneal WAT, and to a lower extent, subcutaneous and epididymal, reacted decreasing the expression of

  20. Cellular proliferation rate and insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-3 and estradiol receptor alpha expression in the mammary gland of dairy heifers naturally infected with gastrointestinal nematodes during development. (United States)

    Perri, A F; Dallard, B E; Baravalle, C; Licoff, N; Formía, N; Ortega, H H; Becú-Villalobos, D; Mejia, M E; Lacau-Mengido, I M


    Mammary ductal morphogenesis during prepuberty occurs mainly in response to insulin-like growth factor-1 (IGF-1) and estradiol stimulation. Dairy heifers infected with gastrointestinal nematodes have reduced IGF-1 levels, accompanied by reduced growth rate, delayed puberty onset, and lower parenchyma-stroma relationship in their mammary glands. Immunohistochemical studies were undertaken to determine variations in cell division rate, IGF-1 system components, and estradiol receptors (ESR) during peripubertal development in the mammary glands of antiparasitic-treated and untreated Holstein heifers naturally infected with gastrointestinal nematodes. Mammary biopsies were taken at 20, 30, 40, and 70 wk of age. Proliferating cell nuclear antigen immunolabeling, evident in nuclei, tended to be higher in the parenchyma of the glands from treated heifers than in those from untreated. Insulin-like growth factor binding proteins (IGFBP) type 2 and type 3 immunolabeling was cytoplasmic and was evident in stroma and parenchyma. The IGFBP2-labeled area was lower in treated than in untreated heifers. In the treated group, a maximal expression of this protein was seen at 40 wk of age, whereas in the untreated group the labeling remained constant. No differences were observed for IGFBP3 between treatment groups or during development. Immunolabeling for α ESR (ESR1) was evident in parenchymal nuclei and was higher in treated than in untreated heifers. In the treated group, ESR1 peaked at 30 wk of age and then decreased. These results demonstrate that the parasite burden in young heifers negatively influence mammary gland development, affecting cell division rate and parameters related to estradiol and IGF-1 signaling in the gland.

  1. Cellular events and biomarkers of wound healing

    Directory of Open Access Journals (Sweden)

    Shah Jumaat Mohd. Yussof


    Full Text Available Researchers have identified several of the cellular events associated with wound healing. Platelets, neutrophils, macrophages, and fibroblasts primarily contribute to the process. They release cytokines including interleukins (ILs and TNF-α, and growth factors, of which platelet-derived growth factor (PDGF is perhaps the most important. The cytokines and growth factors manipulate the inflammatory phase of healing. Cytokines are chemotactic for white cells and fibroblasts, while the growth factors initiate fibroblast and keratinocyte proliferation. Inflammation is followed by the proliferation of fibroblasts, which lay down the extracellular matrix. Simultaneously, various white cells and other connective tissue cells release both the matrix metalloproteinases (MMPs and the tissue inhibitors of these metalloproteinases (TIMPs. MMPs remove damaged structural proteins such as collagen, while the fibroblasts lay down fresh extracellular matrix proteins. Fluid collected from acute, healing wounds contains growth factors, and stimulates fibroblast proliferation, but fluid collected from chronic, nonhealing wounds does not. Fibroblasts from chronic wounds do not respond to chronic wound fluid, probably because the fibroblasts of these wounds have lost the receptors that respond to cytokines and growth factors. Nonhealing wounds contain high levels of IL1, IL6, and MMPs, and an abnormally high MMP/TIMP ratio. Clinical examination of wounds inconsistently predicts which wounds will heal when procedures like secondary closure are planned. Surgeons therefore hope that these chemicals can be used as biomarkers of wounds which have impaired ability to heal. There is also evidence that the application of growth factors like PDGF will help the healing of chronic, nonhealing wounds.

  2. Reversibly assembled cellular composite materials. (United States)

    Cheung, Kenneth C; Gershenfeld, Neil


    We introduce composite materials made by reversibly assembling a three-dimensional lattice of mass-produced carbon fiber-reinforced polymer composite parts with integrated mechanical interlocking connections. The resulting cellular composite materials can respond as an elastic solid with an extremely large measured modulus for an ultralight material (12.3 megapascals at a density of 7.2 milligrams per cubic centimeter). These materials offer a hierarchical decomposition in modeling, with bulk properties that can be predicted from component measurements and deformation modes that can be determined by the placement of part types. Because site locations are locally constrained, structures can be produced in a relative assembly process that merges desirable features of fiber composites, cellular materials, and additive manufacturing.

  3. Restricted Interests and Teacher Presentation of Items (United States)

    Stocco, Corey S.; Thompson, Rachel H.; Rodriguez, Nicole M.


    Restricted and repetitive behavior (RRB) is more pervasive, prevalent, frequent, and severe in individuals with autism spectrum disorders (ASDs) than in their typical peers. One subtype of RRB is restricted interests in items or activities, which is evident in the manner in which individuals engage with items (e.g., repetitious wheel spinning),…

  4. 33 CFR 203.46 - Restrictions. (United States)


    ... Flood Control Works Damaged by Flood or Coastal Storm: The Corps Rehabilitation and Inspection Program § 203.46 Restrictions. (a) Restrictions to flood control works. Flood control works are designed and...) Non-flood related rehabilitation. Rehabilitation of flood control structures damaged by...

  5. 7 CFR 400.407 - Restricted access. (United States)


    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Restricted access. 400.407 Section 400.407 Agriculture... Social Security Account Numbers and Employer Identification Numbers § 400.407 Restricted access. The Manager, other officer, or employee of FCIC or an authorized person may have access to the SSNs and...

  6. Glycosylation regulates prestin cellular activity. (United States)

    Rajagopalan, Lavanya; Organ-Darling, Louise E; Liu, Haiying; Davidson, Amy L; Raphael, Robert M; Brownell, William E; Pereira, Fred A


    Glycosylation is a common post-translational modification of proteins and is implicated in a variety of cellular functions including protein folding, degradation, sorting and trafficking, and membrane protein recycling. The membrane protein prestin is an essential component of the membrane-based motor driving electromotility changes (electromotility) in the outer hair cell (OHC), a central process in auditory transduction. Prestin was earlier identified to possess two N-glycosylation sites (N163, N166) that, when mutated, marginally affect prestin nonlinear capacitance (NLC) function in cultured cells. Here, we show that the double mutant prestin(NN163/166AA) is not glycosylated and shows the expected NLC properties in the untreated and cholesterol-depleted HEK 293 cell model. In addition, unlike WT prestin that readily forms oligomers, prestin(NN163/166AA) is enriched as monomers and more mobile in the plasma membrane, suggesting that oligomerization of prestin is dependent on glycosylation but is not essential for the generation of NLC in HEK 293 cells. However, in the presence of increased membrane cholesterol, unlike the hyperpolarizing shift in NLC seen with WT prestin, cells expressing prestin(NN163/166AA) exhibit a linear capacitance function. In an attempt to explain this finding, we discovered that both WT prestin and prestin(NN163/166AA) participate in cholesterol-dependent cellular trafficking. In contrast to WT prestin, prestin(NN163/166AA) shows a significant cholesterol-dependent decrease in cell-surface expression, which may explain the loss of NLC function. Based on our observations, we conclude that glycosylation regulates self-association and cellular trafficking of prestin(NN163/166AA). These observations are the first to implicate a regulatory role for cellular trafficking and sorting in prestin function. We speculate that the cholesterol regulation of prestin occurs through localization to and internalization from membrane microdomains by

  7. Stochastic Nature in Cellular Processes

    Institute of Scientific and Technical Information of China (English)

    刘波; 刘圣君; 王祺; 晏世伟; 耿轶钊; SAKATA Fumihiko; GAO Xing-Fa


    The importance of stochasticity in cellular processes is increasingly recognized in both theoretical and experimental studies. General features of stochasticity in gene regulation and expression are briefly reviewed in this article, which include the main experimental phenomena, classification, quantization and regulation of noises. The correlation and transmission of noise in cascade networks are analyzed further and the stochastic simulation methods that can capture effects of intrinsic and extrinsic noise are described.

  8. Cellular fiber–reinforced concrete


    Isachenko S.; Kodzoev M.


    Methods disperse reinforcement of concrete matrix using polypropylene, glass, basalt and metal fibers allows to make the construction of complex configuration, solve the problem of frost products. Dispersed reinforcement reduces the overall weight of the structures. The fiber replaces the secondary reinforcement, reducing the volume of use of structural steel reinforcement. Cellular Fiber concretes are characterized by high-performance properties, especially increased bending strength and...

  9. Identification of Nonstationary Cellular Automata

    Institute of Scientific and Technical Information of China (English)



    The principal feature of nonstationary cellular automata(NCA) is that a local transitiol rule of each cell is changed at each time step depending on neighborhood configuration at previous time step.The identification problem for NCA is extraction of local transition rules and the establishment of mechanism for changing these rules using sequence of NCA configurations.We present serial and parallel algorithms for identification of NCA.



    Popescu, O.; Sumanovski, L. T.; I. Checiu; Elisabeta Popescu; G. N. Misevic


    Cellular interactions involve many types of cell surface molecules and operate via homophilic and/or heterophilic protein-protein and protein-carbohydrate binding. Our investigations in different model-systems (marine invertebrates and mammals) have provided direct evidence that a novel class of primordial proteoglycans, named by us gliconectins, can mediate cell adhesion via a new alternative molecular mechanism of polyvalent carbohydrate-carbohydrate binding. Biochemical characterization of...

  11. The impact of peroxisomes on cellular aging and death

    NARCIS (Netherlands)

    Manivannan, Selvambigai; Scheckhuber, Christian Quintus; Veenhuis, Marten; Klei, Ida Johanna van der; Côrte-Real, Manuela


    Peroxisomes are ubiquitous eukaryotic organelles, which perform a plethora of functions including hydrogen peroxide metabolism and β-oxidation of fatty acids. Reactive oxygen species produced by peroxisomes are a major contributing factor to cellular oxidative stress, which is supposed to significan

  12. Caveolar vesicles generate DNA damage and perpetuate cellular aging

    Institute of Scientific and Technical Information of China (English)

    Keith Wheaton


    @@ The replicative limit of human fibroblasts has long provided a model to assess the molecular mechanisms underlying cellular aging [1].In culture, fibroblasts which reach the end of their proliferative lifespan acquire profound molecular changes that limit their response to growth factors, and cause permanent exit from the cell cycle [2].

  13. Multi-cellular logistics of collective cell migration.

    Directory of Open Access Journals (Sweden)

    Masataka Yamao

    Full Text Available During development, the formation of biological networks (such as organs and neuronal networks is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.

  14. The insect cellular immune response

    Institute of Scientific and Technical Information of China (English)

    Michael R. Strand


    The innate immune system of insects is divided into humoral defenses that include the production of soluble effector molecules and cellular defenses like phagocytosis and encapsulation that are mediated by hemocytes. This review summarizes current understanding of the cellular immune response. Insects produce several terminally differentiated types of hemocytes that are distinguished by morphology, molecular and antigenic markers, and function. The differentiated hemocytes that circulate in larval or nymphal stage insects arise from two sources: progenitor cells produced during embryogenesis and mesodermally derived hematopoietic organs. Regulation of hematopoiesis and hemocyte differentiation also involves several different signaling pathways. Phagocytosis and encapsulation require that hemocytes first recognize a given target as foreign followed by activation of downstream signaling and effector responses. A number of humoral and cellular receptors have been identified that recognize different microbes and multicellular parasites. In turn, activation of these receptors stimulates a number of signaling pathways that regulate different hemocyte functions. Recent studies also identify hemocytes as important sources of a number of humoral effector molecules required for killing different foreign invaders.

  15. Progress of cellular dedifferentiation research

    Institute of Scientific and Technical Information of China (English)

    LIU Hu-xian; HU Da-hai; JIA Chi-yu; FU Xiao-bing


    Differentiation, the stepwise specialization of cells, and transdifferentiation, the apparent switching of one cell type into another, capture much of the stem cell spotlight. But dedifferentiation, the developmental reversal of a cell before it reinvents itself, is an important process too. In multicellular organisms, cellular dedifferentiation is the major process underlying totipotency, regeneration and formation of new stem cell lineages. In humans,dedifferentiation is often associated with carcinogenesis.The study of cellular dedifferentiation in animals,particularly early events related to cell fate-switch and determination, is limited by the lack of a suitable,convenient experimental system. The classic example of dedifferentiation is limb and tail regeneration in urodele amphibians, such as salamanders. Recently, several investigators have shown that certain mammalian cell types can be induced to dedifferentiate to progenitor cells when stimulated with the appropriate signals or materials. These discoveries open the possibility that researchers might enhance the endogenous regenerative capacity of mammals by inducing cellular dedifferentiation in vivo.


    Directory of Open Access Journals (Sweden)

    Tomasz Garbacz


    Full Text Available In a study of cellular injection, molding process uses polyvinylchloride PVC. Polymers modified with introducing blowing agents into them in the Laboratory of the Department of Technologies and Materiase of Technical University of Kosice. For technological reasons, blowing agents have a form of granules. In the experiment, the content of the blowing agent (0–2,0 % by mass fed into the processed polymer was adopted as a variable factor. In the studies presented in the article, the chemical blowing agents occurring in the granulated form with a diameter of 1.2 to 1.4 mm were used. The view of the technological line for cellular injection molding and injection mold cavity with injection moldings are shown in Figure 1. The results of the determination of selected properties of injection molded parts for various polymeric materials, obtained with different content of blowing agents, are shown in Figures 4-7. Microscopic examination of cross-sectional structure of the moldings were obtained using the author's position image analysis of porous structure. Based on analysis of photographs taken (Figures 7, 8, 9 it was found that the coating containing 1.0% of blowing agents is a clearly visible solid outer layer and uniform distribution of pores and their sizes are similar.

  17. Mechanisms of cellular invasion by intracellular parasites. (United States)

    Walker, Dawn M; Oghumu, Steve; Gupta, Gaurav; McGwire, Bradford S; Drew, Mark E; Satoskar, Abhay R


    Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world's population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite-host cell interactions, forming the basis of the parasite's cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality.

  18. 地方本科高校专业课程双语教学的制约因素与模式--以A学院《西方经济学》课程为例%Study on the Restrictive Factors and Methods of Bilingual Teaching in Local University --- A Case Study Based on the Teach of Western Economics in A University

    Institute of Scientific and Technical Information of China (English)



    As a typical local University in the western region ,A University has less Research and Practice in bilingual teach-ing .Many restrictive factors such as faculty、the quality of students、course selection ,teaching concept and management mode turn the bilingual teaching into a difficult subject .This paper takes the teaching of Western Economics in A University as an example . It indicates the goals of bilingual education and summarizes the main problems in bilingual teaching .Then it give some suggestion to promote undergraduate bilingual education of specialized courses .%A学院作为一所典型的西部新建地方本科高校,在双语教学的实践和研究方面才刚刚起步,在师资力量、学生素质、教材选用、教学理念、管理机制等方面存在诸多制约因素,需要从实际出发,不断研究和实践,探索出符合自身特点的双语教学模式。

  19. Caloric restriction and intermittent fasting: Two potential diets for successful brain aging


    Martin, Bronwen; Mark P. Mattson; Maudsley, Stuart


    The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span. CR and IF affect energy and oxygen radical meta...

  20. Cellular communications a comprehensive and practical guide

    CERN Document Server

    Tripathi, Nishith


    Even as newer cellular technologies and standards emerge, many of the fundamental principles and the components of the cellular network remain the same. Presenting a simple yet comprehensive view of cellular communications technologies, Cellular Communications provides an end-to-end perspective of cellular operations, ranging from physical layer details to call set-up and from the radio network to the core network. This self-contained source forpractitioners and students represents a comprehensive survey of the fundamentals of cellular communications and the landscape of commercially deployed

  1. 甘南藏区数学课堂教学中数学交流的制约因素及对策思考%Restricts in the Gannan Tibet Area Mathematics Teaching Mathematics Exchange Factor Brief Analysis and the Strategy Ponder

    Institute of Scientific and Technical Information of China (English)



    In the Gannan Tibet Area Middle school mathematics classroom instruction mathematics exchange is short of restricts one of its mathematics education lag factors. The article through analyzes in the Gannan Tibet Area Nationality Middle school mathematics classroom instruction mathematics exchange present situation, the investigation now in the classroom instruction mathematics exchange implementation condition, as well as the Tibetan national minority middle school students to mathematics exchange's understanding, to affect in the Gannan Tibet area mathematics classroom instruction mathematics exchange many factors--Exchange consciousness, the teaching art level, mathematics power of thought that mathematical linguistics ability and so on has carried on the brief analysis, had pointed out in the Gannan race area mathematics classroom instruction mathematics exchange exists the actual problem, and proposed the dealing with strategy.%甘南藏区中学数学课堂教学中数学交流欠缺是制约其数学教育滞后的因素之一.文章通过剖析甘南藏区民族中学数学课堂教学中数学交流的现状,调查当今课堂教学中数学交流实施的状况,以及藏族中学学生对数学交流的认识,对影响甘南藏区数学课堂教学中数学交流的诸多因素一交流意识、教学艺术水平、数学思维能力、数学语言能力等进行了浅析,指出了甘南族区数学课堂教学中数学交流所存在的实际问题,并提出了应对策略.

  2. Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme. (United States)

    Maroon, Joseph; Bost, Jeffrey; Amos, Austin; Zuccoli, Giulio


    Glioblastoma multiforme is the most common malignant primary brain tumor in adults and generally considered to be universally fatal. Glioblastoma multiforme accounts for 12% to 15% of all intracranial neoplasms and affects 2 to 3 adults per every 100,000 in the United States annually. In children glioblastoma multiforme accounts for only approximately 7% to 9% of central nervous system tumors. The mean survival rate in adults after diagnosis ranges from 12 to 18 months with standard therapy and 3 to 6 months without therapy. The prognosis in children is better compared to adult tumor onset with a mean survival of approximately 4 years following gross total surgical resection and chemotherapy. There have been few advances in the treatment of glioblastoma multiforme in the past 40 years beyond surgery, radiotherapy, chemotherapy, and corticosteroids. For this reason a restrictive calorie ketogenic diet, similar to that used in children to control drug resistant seizure activity, has been advanced as an alternative adjunctive treatment to help prolonged survival. This article reviews the science of tumor metabolism and discusses the mechanism of calorie restriction, cellular energy metabolism, and how dietary induced ketosis can inhibit cancer cell's energy supply to slow tumor growth.

  3. Wireless traffic steering for green cellular networks

    CERN Document Server

    Zhang, Shan; Zhou, Sheng; Niu, Zhisheng; Shen, Xuemin (Sherman)


    This book introduces wireless traffic steering as a paradigm to realize green communication in multi-tier heterogeneous cellular networks. By matching network resources and dynamic mobile traffic demand, traffic steering helps to reduce on-grid power consumption with on-demand services provided. This book reviews existing solutions from the perspectives of energy consumption reduction and renewable energy harvesting. Specifically, it explains how traffic steering can improve energy efficiency through intelligent traffic-resource matching. Several promising traffic steering approaches for dynamic network planning and renewable energy demand-supply balancing are discussed. This book presents an energy-aware traffic steering method for networks with energy harvesting, which optimizes the traffic allocated to each cell based on the renewable energy status. Renewable energy demand-supply balancing is a key factor in energy dynamics, aimed at enhancing renewable energy sustainability to reduce on-grid energy consum...

  4. Dietary restriction, mitochondrial function and aging: from yeast to humans. (United States)

    Ruetenik, Andrea; Barrientos, Antoni


    Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on health-span and lifespan. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.

  5. Complement-Opsonized HIV-1 Overcomes Restriction in Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    Wilfried Posch


    Full Text Available DCs express intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. Thus, DCs are productively infected only at very low levels with HIV-1, and this non-permissiveness of DCs is suggested to go along with viral evasion. We now illustrate that complement-opsonized HIV-1 (HIV-C efficiently bypasses SAMHD1 restriction and productively infects DCs including BDCA-1 DCs. Efficient DC infection by HIV-C was also observed using single-cycle HIV-C, and correlated with a remarkable elevated SAMHD1 T592 phosphorylation but not SAMHD1 degradation. If SAMHD1 phosphorylation was blocked using a CDK2-inhibitor HIV-C-induced DC infection was also significantly abrogated. Additionally, we found a higher maturation and co-stimulatory potential, aberrant type I interferon expression and signaling as well as a stronger induction of cellular immune responses in HIV-C-treated DCs. Collectively, our data highlight a novel protective mechanism mediated by complement opsonization of HIV to effectively promote DC immune functions, which might be in the future exploited to tackle HIV infection.

  6. The cellular composition of the marsupial neocortex. (United States)

    Seelke, Adele M H; Dooley, James C; Krubitzer, Leah A


    In the current investigation we examined the number and proportion of neuronal and non-neuronal cells in the primary sensory areas of the neocortex of a South American marsupial, the short-tailed opossum (Monodelphis domestica). The primary somatosensory (S1), auditory (A1), and visual (V1) areas were dissected from the cortical sheet and compared with each other and the remaining neocortex using the isotropic fractionator technique. We found that although the overall sizes of V1, S1, A1, and the remaining cortical regions differed from each other, these divisions of the neocortex contained the same number of neurons, but the remaining cortex contained significantly more non-neurons than the primary sensory regions. In addition, the percent of neurons was higher in A1 than in the remaining cortex and the cortex as a whole. These results are similar to those seen in non-human primates. Furthermore, these results indicate that in some respects, such as number of neurons, the neocortex is homogenous across its extent, whereas in other aspects of organization, such as non-neuronal number and percentage of neurons, there is non-uniformity. Whereas the overall pattern of neuronal distribution is similar between short-tailed opossums and eutherian mammals, short-tailed opossum have a much lower cellular and neuronal density than other eutherian mammals. This suggests that the high neuronal density cortices of mammals such as rodents and primates may be a more recently evolved characteristic that is restricted to eutherians, and likely contributes to the complex behaviors we see in modern mammals.

  7. Restriction beyond the restriction point: mitogen requirement for G2 passage

    Directory of Open Access Journals (Sweden)

    te Riele Hein


    Full Text Available Abstract Cell proliferation is dependent on mitogenic signalling. When absent, normal cells cannot pass the G1 restriction point, resulting in cell cycle arrest. Passage through the G1 restriction point involves inactivation of the retinoblastoma protein family. Consequently, loss of the retinoblastoma protein family leads to loss of the G1 restriction point. Recent work in our lab has revealed that cells possess yet another mechanism that restricts proliferation in the absence of mitogens: arrest in the G2 phase of the cell cycle. Here, we discuss the similarities and differences between these restriction points and the roles of cyclin-dependent kinase inhibitors (CKIs herein.

  8. Analysis of Restrictive Environments in the South-West Oltenia Development Region

    Directory of Open Access Journals (Sweden)

    Radu Matei Cocheci


    Full Text Available Restrictive environments can be defined as an area within a territorial system where development is constrained either by natural factors or anthropogenic factors. This paper aims to identify restrictive environments through multi-criteria analysis of Romania’s South West Oltenia development region, known for its issues regarding open-pit mining, desertification or flood risk. In order to achieve this, I proposed a typology of restrictive environments, based on an extensive literature review of natural and anthropogenic factors that can limit development. For each of the ten environmental restrictiveness types identified, several criteria were proposed, which were then weighted as a result of a questionnaire addressed to experts in the field of territorial planning. Based on the questionnaire results, an index of environmental restrictiveness is computed at LAU 2 level for the entire South-West Oltenia development region. The territorialized index highlights the environmental restrictiveness of areas susceptible to flood risk (e.g. along the Jiu valley, but also the problems faced by mining areas (Motru-Rovinari or isolated mountain areas. The computed index represents a first step towards the definition of potential inter-communal cooperation structures, that could become the object of territorial planning instruments aimed at mitigating restrictive environments.

  9. Restriction enzyme mining for SNPs in genomes. (United States)

    Chuang, Li-Yeh; Yang, Cheng-Hong; Tsui, Ke-Hung; Cheng, Yu-Huei; Chang, Phei-Lang; Wen, Cheng-Hao; Chang, Hsueh-Wei


    Many different single nucleotide polymorphisms (SNPs) genotyping methods have been developed recently. However, most of them are expensive. Using restriction enzymes for SNP genotyping is a cost-effective method. However, restriction enzyme mining for SNPs in a genome sequence is still challenging for researchers who do not have a background in genomics and bioinformatics. In this review, the basic bioinformatics tools used for restriction enzyme mining for SNP genotyping are summarized and described. The objectives of this paper include: i) the introduction of SNPs, genotyping and PCR-restriction fragment length polymorphism (RFLP); ii) a review of components for genotyping software, including tools for primer design only or restriction enzyme mining only; iii) a review of software providing the flanking sequence for primer design; iv) recent advances in PCR-RFLP tools and natural and mutagenic PCR-RFLP; v) highlighting the strategy for restriction enzyme mining for SNP genotyping; vi) a discussion of potential problems for multiple PCR-RFLP. The different implications for restriction enzymes on sense and antisense strands are also discussed. Our PCR-RFLP freeware, SNP-RFLPing, is included in this review to illustrate many characteristics of PCR-RFLP software design. Future developments will include further sophistication of PCR-RFLP software in order to provide better visualization and a more interactive environment for SNP genotyping and to integrate the software with other tools used in association studies.

  10. Urban water restrictions: Attitudes and avoidance (United States)

    Cooper, Bethany; Burton, Michael; Crase, Lin


    In most urban cities across Australia, water restrictions remain the dominant policy mechanism to restrict urban water consumption. The extensive adoption of water restrictions as a means to limit demand, over several years, means that Australian urban water prices have consistently not reflected the opportunity cost of water. Given the generally strong political support for water restrictions and the likelihood that they will persist for some time, there is value in understanding households' attitudes in this context. More specifically, identifying the welfare gains associated with avoiding urban water restrictions entirely would be a nontrivial contribution to our knowledge and offer insights into the benefits of alternative policy responses. This paper describes the results from a contingent valuation study that investigates consumers' willingness to pay to avoid urban water restrictions. Importantly, the research also investigates the influence of cognitive and exogenous dimensions on the utility gain associated with avoiding water restrictions. The results provide insights into the impact of the current policy mechanism on economic welfare.

  11. Pathologic Cellular Events in Smoking-Related Pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Thrower, Edwin [Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520 (United States); Veterans Affairs Connecticut Healthcare, West Haven, CT 06516 (United States)


    Pancreatitis, a debilitating inflammatory disorder, results from pancreatic injury. Alcohol abuse is the foremost cause, although cigarette smoking has recently surfaced as a distinct risk factor. The mechanisms by which cigarette smoke and its toxins initiate pathological cellular events leading to pancreatitis, have not been clearly defined. Although cigarette smoke is composed of more than 4000 compounds, it is mainly nicotine and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which have been extensively studied with respect to pancreatic diseases. This review summarizes these research findings and highlights cellular pathways which may be of relevance in initiation and progression of smoking-related pancreatitis.

  12. Cellular roles of ADAM12 in health and disease

    DEFF Research Database (Denmark)

    Kveiborg, Marie; Albrechtsen, Reidar; Couchman, John R;


    and it is a potential biomarker for breast cancer. It is therefore important to understand ADAM12's functions. Many cellular roles for ADAM12 have been suggested. It is an active metalloprotease, and has been implicated in insulin-like growth factor (IGF) receptor signaling, through cleavage of IGF-binding proteins...... to or from the cell interior. These ADAM12-mediated cellular effects appear to be critical events in both biological and pathological processes. This review presents current knowledge on ADAM12 functions gained from in vitro and in vivo observations, describes ADAM12's role in both normal physiology...

  13. The thorny path linking cellular senescence to organismalaging

    Energy Technology Data Exchange (ETDEWEB)

    Patil, Christopher K.; Mian, Saira; Campisi, Judith


    Half a century is fast approaching since Hayflick and colleagues formally described the limited ability of normal human cells to proliferate in culture (Hayflick and Moorhead, 1961). This finding--that normal somatic cells, in contrast to cancer cells, cannot divide indefinitely--challenged the prevailing idea that cells from mortal multicellular organisms were intrinsically ''immortal'' (Carrell, 1912). It also spawned two hypotheses, essential elements of which persist today. The first held that the restricted proliferation of normal cells, now termed cellular senescence, suppresses cancer (Hayflick, 1965; Sager, 1991; Campisi, 2001). The second hypothesis, as explained in the article by Lorenzini et al., suggested that the limited proliferation of cells in culture recapitulated aspects of organismal aging (Hayflick, 1965; Martin, 1993). How well have these hypotheses weathered the ensuing decades? Before answering this question, we first consider current insights into the causes and consequences of cellular senescence. Like Lorenzini et al., we limit our discussion to mammals. We also focus on fibroblasts, the cell type studied by Lorenzini et al., but consider other types as well. We suggest that replicative capacity in culture is not a straightforward assessment, and that it correlates poorly with both longevity and body mass. We speculate this is due to the malleable and variable nature of replicative capacity, which renders it an indirect metric of qualitative and quantitative differences among cells to undergo senescence, a response that directly alters cellular phenotype and might indirectly alter tissue structure and function.


    Directory of Open Access Journals (Sweden)

    V. V. Zarubaev


    Full Text Available Аbstract. Influenza is a highly contagious infection of humans. The use of specific antivirals leads to emergence of drug-resistant strains following by the decrease of efficacy of ethiotropic chemotherapy. In this review the data about the decrease of the level of viral replication and severity of pathological process based on the use of alternative targets of cellular instead of viral origin are presented. The medicines for decreasing the production of proinflammatory cytokines (eritoran, restricting the degranulation of mast cells (ketotifen, inhibitors of cyclooxygenases (celexocib, mesalasine, SC-560, inhibitors of sphingosine-1-phospate pathway (AAL-R and compounds increasing the capillars stability by strengthe ning the contacts between endothelial cells (Slit protein have been described in the review. The special attention is paid to the inhibitors of cellular pathways that are used by the virus to provide its reproduction, such as NF-κB, Raf/MEK/ERK, PI3K/AKT/mTOR. Information concerning anti-influenza activity of kinase and autophagy inhibitors is summarised as well as data about the preparations of combined mechanism of activity — glycirrhizic acid and dipeptide alpha-glutamyl-tryptophane. Further studies in the field of search and optimization of inhibitors of cellular components as remedies against influenza infection could lead to the development of novel antivirals with high efficacy, broad spectrum of activity and low probability of virus resistance.

  15. Parallelizing the Cellular Potts Model on graphics processing units (United States)

    Tapia, José Juan; D'Souza, Roshan M.


    The Cellular Potts Model (CPM) is a lattice based modeling technique used for simulating cellular structures in computational biology. The computational complexity of the model means that current serial implementations restrict the size of simulation to a level well below biological relevance. Parallelization on computing clusters enables scaling the size of the simulation but marginally addresses computational speed due to the limited memory bandwidth between nodes. In this paper we present new data-parallel algorithms and data structures for simulating the Cellular Potts Model on graphics processing units. Our implementations handle most terms in the Hamiltonian, including cell-cell adhesion constraint, cell volume constraint, cell surface area constraint, and cell haptotaxis. We use fine level checkerboards with lock mechanisms using atomic operations to enable consistent updates while maintaining a high level of parallelism. A new data-parallel memory allocation algorithm has been developed to handle cell division. Tests show that our implementation enables simulations of >10 cells with lattice sizes of up to 256 3 on a single graphics card. Benchmarks show that our implementation runs ˜80× faster than serial implementations, and ˜5× faster than previous parallel implementations on computing clusters consisting of 25 nodes. The wide availability and economy of graphics cards mean that our techniques will enable simulation of realistically sized models at a fraction of the time and cost of previous implementations and are expected to greatly broaden the scope of CPM applications.

  16. Spatial and functional restriction of regulatory molecules during mammalian myoblast fusion

    Energy Technology Data Exchange (ETDEWEB)

    Pavlath, Grace K., E-mail: [Department of Pharmacology, Emory University, 1510 Clifton Rd., Room 5027, Atlanta, GA 30322 (United States)


    Myoblast fusion is a highly regulated process that is key for forming skeletal muscle during development and regeneration in mammals. Much remains to be understood about the molecular regulation of myoblast fusion. Some molecules that influence mammalian muscle fusion display specific cellular localization during myogenesis. Such molecules can be localized to the contact region between two fusing cells either in both cells or only in one of the cells. How distinct localization of molecules contributes to fusion is not clear. Further complexity exists as other molecules are functionally restricted to myoblasts at later stages of myogenesis to regulate their fusion with multinucleated myotubes. This review examines these three categories of molecules and discusses how spatial and functional restriction may contribute to the formation of a multinucleated cell. Understanding how and why molecules become restricted in location or function is likely to provide further insights into the mechanisms regulating mammalian muscle fusion.

  17. CD1-Restricted T Cells at the Crossroad of Innate and Adaptive Immunity (United States)

    Pereira, Catia S.


    Lipid-specific T cells comprise a group of T cells that recognize lipids bound to the MHC class I-like CD1 molecules. There are four isoforms of CD1 that are expressed at the surface of antigen presenting cells and therefore capable of presenting lipid antigens: CD1a, CD1b, CD1c, and CD1d. Each one of these isoforms has distinct structural features and cellular localizations, which promotes binding to a broad range of different types of lipids. Lipid antigens originate from either self-tissues or foreign sources, such as bacteria, fungus, or plants and their recognition by CD1-restricted T cells has important implications in infection but also in cancer and autoimmunity. In this review, we describe the characteristics of CD1 molecules and CD1-restricted lipid-specific T cells, highlighting the innate-like and adaptive-like features of different CD1-restricted T cell subtypes. PMID:28070524

  18. Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

    Directory of Open Access Journals (Sweden)

    Marieke van de Ven


    Full Text Available How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age, including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W/XPA(-/- that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/- mouse. Specific (but not all types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

  19. Cellular immune responses to HIV (United States)

    McMichael, Andrew J.; Rowland-Jones, Sarah L.


    The cellular immune response to the human immunodeficiency virus, mediated by T lymphocytes, seems strong but fails to control the infection completely. In most virus infections, T cells either eliminate the virus or suppress it indefinitely as a harmless, persisting infection. But the human immunodeficiency virus undermines this control by infecting key immune cells, thereby impairing the response of both the infected CD4+ T cells and the uninfected CD8+ T cells. The failure of the latter to function efficiently facilitates the escape of virus from immune control and the collapse of the whole immune system.

  20. Repaglinide at a cellular level

    DEFF Research Database (Denmark)

    Krogsgaard Thomsen, M; Bokvist, K; Høy, M


    To investigate the hormonal and cellular selectivity of the prandial glucose regulators, we have undertaken a series of experiments, in which we characterised the effects of repaglinide and nateglinide on ATP-sensitive potassium ion (KATP) channel activity, membrane potential and exocytosis in rat...... pancreatic alpha-cells and somatotrophs. We found a pharmacological dissociation between the actions on KATP channels and exocytosis and suggest that compounds that, unlike repaglinide, have direct stimulatory effects on exocytosis in somatotrophs and alpha- and beta-cells, such as sulphonylureas...

  1. Game of Life Cellular Automata

    CERN Document Server

    Adamatzky, Andrew


    In the late 1960s, British mathematician John Conway invented a virtual mathematical machine that operates on a two-dimensional array of square cell. Each cell takes two states, live and dead. The cells' states are updated simultaneously and in discrete time. A dead cell comes to life if it has exactly three live neighbours. A live cell remains alive if two or three of its neighbours are alive, otherwise the cell dies. Conway's Game of Life became the most programmed solitary game and the most known cellular automaton. The book brings together results of forty years of study into computational

  2. Cellular automata a parallel model

    CERN Document Server

    Mazoyer, J


    Cellular automata can be viewed both as computational models and modelling systems of real processes. This volume emphasises the first aspect. In articles written by leading researchers, sophisticated massive parallel algorithms (firing squad, life, Fischer's primes recognition) are treated. Their computational power and the specific complexity classes they determine are surveyed, while some recent results in relation to chaos from a new dynamic systems point of view are also presented. Audience: This book will be of interest to specialists of theoretical computer science and the parallelism challenge.

  3. ING proteins in cellular senescence. (United States)

    Menéndez, Camino; Abad, María; Gómez-Cabello, Daniel; Moreno, Alberto; Palmero, Ignacio


    Cellular senescence is an effective anti-tumor barrier that acts by restraining the uncontrolled proliferation of cells carrying potentially oncogenic alterations. ING proteins are putative tumor suppressor proteins functionally linked to the p53 pathway and to chromatin regulation. ING proteins exert their tumor-protective action through different types of responses. Here, we review the evidence on the participation of ING proteins, mainly ING1 and ING2, in the implementation of the senescent response. The currently available data support an important role of ING proteins as regulators of senescence, in connection with the p53 pathway and chromatin organization.

  4. Cellular Analogs of Operant Behavior. (United States)


    ing of single units can be demonstrated, does such a cellular subset of neighboring pyramidal cells and interneurons as well as process contribute...excite dopamine neurons by -hyperpolarization of local interneurons . J. Neurosci. 12:483-488; 1992. Kosterlitz, H. W. Biosynthesis of morphine in the...II 197 1 1 ocation preltereite iindiis- HOIdlod VA. artdo \\M I . \\.ill I ’’’’i i R i l’)89) ( pioid mediationl lserilI1 reintoree-Cd bK amlphetcamine

  5. 5G Ultra-Dense Cellular Networks


    Ge, Xiaohu; Tu, Song; Mao, Guoqiang; Wang, Cheng-xiang; Han, Tao


    Traditional ultra-dense wireless networks are recommended as a complement for cellular networks and are deployed in partial areas, such as hotspot and indoor scenarios. Based on the massive multiple-input multi-output (MIMO) antennas and the millimeter wavecommunication technologies, the 5G ultra-dense cellular network is proposed to deploy in overall cellular scenarios. Moreover, a distribution network architecture is presented for 5G ultra-dense cellular networks. Furthermore, the backhaul ...

  6. Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes. (United States)

    Komatsu, Tetsuro; Will, Hans; Nagata, Kyosuke; Wodrich, Harald


    Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions as well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle.

  7. Restrictive extraocular myopathy: A presenting feature of acromegaly

    Directory of Open Access Journals (Sweden)

    Steven Heireman


    Full Text Available A 45-year-old man presented with binocular diplopia in primary gaze for 1 year. Orthoptic evaluation showed 10-prism diopter right eye hypotropia and 6-prism diopter right eye esotropia. The elevation and abduction of the right eye were mechanically restricted. This was associated with systemic features suggestive of acromegaly. Magnetic resonance imaging (MRI of the brain demonstrated a pituitary macroadenoma. An elevated serum insulin-like growth factor I level and the failure of growth hormone suppression after an oral glucose load biochemically confirmed the diagnosis of acromegaly. Computed tomography (CT of the orbit demonstrated bilateral symmetrical enlargement of the medial rectus and inferior rectus muscle bellies. All tests regarding Graves-Basedow disease were negative. Although rare, diplopia due to a restrictive extraocular myopathy could be the presenting symptom of acromegaly.

  8. Stanniocalcin 2 alters PERK signalling and reduces cellular injury during cerulein induced pancreatitis in mice

    Directory of Open Access Journals (Sweden)

    DiMattia Gabriel E


    Full Text Available Abstract Background Stanniocalcin 2 (STC2 is a secreted protein activated by (PKR-like Endoplasmic Reticulum Kinase (PERK signalling under conditions of ER stress in vitro. Over-expression of STC2 in mice leads to a growth-restricted phenotype; however, the physiological function for STC2 has remained elusive. Given the relationship of STC2 to PERK signalling, the objective of this study was to examine the role of STC2 in PERK signalling in vivo. Results Since PERK signalling has both physiological and pathological roles in the pancreas, STC2 expression was assessed in mouse pancreata before and after induction of injury using a cerulein-induced pancreatitis (CIP model. Increased Stc2 expression was identified within four hours of initiating pancreatic injury and correlated to increased activation of PERK signalling. To determine the effect of STC2 over-expression on PERK, mice systemically expressing human STC2 (STC2Tg were examined. STC2Tg pancreatic tissue exhibited normal pancreatic morphology, but altered activation of PERK signalling, including increases in Activating Transcription Factor (ATF 4 accumulation and autophagy. Upon induction of pancreatic injury, STC2Tg mice exhibited limited increases in circulating amylase levels and increased maintenance of cellular junctions. Conclusions This study links STC2 to the pathological activation of PERK in vivo, and suggests involvement of STC2 in responding to pancreatic acinar cell injury.

  9. The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing (United States)

    Shah, Priya; Pozzi, Berta; Gebhard, Leopoldo G.; Mammi, Pablo; Yanovsky, Marcelo J.; Andino, Raul; Krogan, Nevan; Srebrow, Anabella; Gamarnik, Andrea V.


    Dengue virus NS5 protein plays multiple functions in the cytoplasm of infected cells, enabling viral RNA replication and counteracting host antiviral responses. Here, we demonstrate a novel function of NS5 in the nucleus where it interferes with cellular splicing. Using global proteomic analysis of infected cells together with functional studies, we found that NS5 binds spliceosome complexes and modulates endogenous splicing as well as minigene-derived alternative splicing patterns. In particular, we show that NS5 alone, or in the context of viral infection, interacts with core components of the U5 snRNP particle, CD2BP2 and DDX23, alters the inclusion/exclusion ratio of alternative splicing events, and changes mRNA isoform abundance of known antiviral factors. Interestingly, a genome wide transcriptome analysis, using recently developed bioinformatics tools, revealed an increase of intron retention upon dengue virus infection, and viral replication was improved by silencing specific U5 components. Different mechanistic studies indicate that binding of NS5 to the spliceosome reduces the efficiency of pre-mRNA processing, independently of NS5 enzymatic activities. We propose that NS5 binding to U5 snRNP proteins hijacks the splicing machinery resulting in a less restrictive environment for viral replication. PMID:27575636

  10. Cellular senescence in normal and premature lung aging. (United States)

    Bartling, B


    The incidence of chronic respiratory diseases (e.g., chronic obstructive pulmonary disease, COPD) and interstitial lung diseases (e.g., pneumonia and lung fibrosis) increases with age. In addition to immune senescence, the accumulation of senescent cells directly in lung tissue might play a critical role in the increased prevalence of these pulmonary diseases. In the last couple of years, detailed studies have identified the presence of senescent cells in the aging lung and in diseased lungs of patients with COPD and lung fibrosis. Cellular senescence has been shown for epithelial cells of bronchi and alveoli as well as mesenchymal and vascular cells. Known risk factors for pulmonary diseases (cigarette smoke, air pollutions, bacterial infections, etc.) were identified in experimental studies as being possible mediators in the development of cellular senescence. The present findings indicate the importance of cellular senescence in normal lung aging and in premature aging of the lung in patients with COPD, lung fibrosis, and probably other respiratory diseases.

  11. Cellular blebs: pressure-driven, axisymmetric, membrane protrusions

    KAUST Repository

    Woolley, Thomas E.


    Blebs are cellular protrusions that are used by cells for multiple purposes including locomotion. A mechanical model for the problem of pressure-driven blebs based on force and moment balances of an axisymmetric shell model is proposed. The formation of a bleb is initiated by weakening the shell over a small region, and the deformation of the cellular membrane from the cortex is obtained during inflation. However, simply weakening the shell leads to an area increase of more than 4 %, which is physically unrealistic. Thus, the model is extended to include a reconfiguration process that allows large blebs to form with small increases in area. It is observed that both geometric and biomechanical constraints are important in this process. In particular, it is shown that although blebs are driven by a pressure difference across the cellular membrane, it is not the limiting factor in determining bleb size. © 2013 Springer-Verlag Berlin Heidelberg.

  12. Melanoma screening with cellular phones.

    Directory of Open Access Journals (Sweden)

    Cesare Massone

    Full Text Available BACKGROUND: Mobile teledermatology has recently been shown to be suitable for teledermatology despite limitations in image definition in preliminary studies. The unique aspect of mobile teledermatology is that this system represents a filtering or triage system, allowing a sensitive approach for the management of patients with emergent skin diseases. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigated the feasibility of teleconsultation using a new generation of cellular phones in pigmented skin lesions. 18 patients were selected consecutively in the Pigmented Skin Lesions Clinic of the Department of Dermatology, Medical University of Graz, Graz (Austria. Clinical and dermoscopic images were acquired using a Sony Ericsson with a built-in two-megapixel camera. Two teleconsultants reviewed the images on a specific web application ( where images had been uploaded in JPEG format. Compared to the face-to-face diagnoses, the two teleconsultants obtained a score of correct telediagnoses of 89% and of 91.5% reporting the clinical and dermoscopic images, respectively. CONCLUSIONS/SIGNIFICANCE: The present work is the first study performing mobile teledermoscopy using cellular phones. Mobile teledermatology has the potential to become an easy applicable tool for everyone and a new approach for enhanced self-monitoring for skin cancer screening in the spirit of the eHealth program of the European Commission Information for Society and Media.

  13. Cellular functions of the microprocessor. (United States)

    Macias, Sara; Cordiner, Ross A; Cáceres, Javier F


    The microprocessor is a complex comprising the RNase III enzyme Drosha and the double-stranded RNA-binding protein DGCR8 (DiGeorge syndrome critical region 8 gene) that catalyses the nuclear step of miRNA (microRNA) biogenesis. DGCR8 recognizes the RNA substrate, whereas Drosha functions as an endonuclease. Recent global analyses of microprocessor and Dicer proteins have suggested novel functions for these components independent of their role in miRNA biogenesis. A HITS-CLIP (high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation) experiment designed to identify novel substrates of the microprocessor revealed that this complex binds and regulates a large variety of cellular RNAs. The microprocessor-mediated cleavage of several classes of RNAs not only regulates transcript levels, but also modulates alternative splicing events, independently of miRNA function. Importantly, DGCR8 can also associate with other nucleases, suggesting the existence of alternative DGCR8 complexes that may regulate the fate of a subset of cellular RNAs. The aim of the present review is to provide an overview of the diverse functional roles of the microprocessor.

  14. Cellular automata modelling of SEIRS

    Institute of Scientific and Technical Information of China (English)

    Liu Quan-Xing; Jin Zhen


    In this paper the SEIRS epidemic spread is analysed, and a two-dimensional probability cellular automata model for SEIRS is presented. Each cellular automation cell represents a part of the population that may be found in one of five states of individuals: susceptible, exposed (or latency), infected, immunized (or recovered) and death. Here studied are the effects of two cases on the epidemic spread. i.e. the effects of non-segregation and segregation on the latency and the infected of population. The conclusion is reached that the epidemic will persist in the case of non-segregation but it will decrease in the case of segregation. The proposed model can serve as a basis for the development of algorithms to simulate real epidemics based on real data. Last we find the density series of the exposed and the infected will fluctuate near a positive equilibrium point, when the constant for the immunized is less than its corresponding constant τ0. Our theoretical results are verified by numerical simulations.

  15. The Frattini Subalgebra of Restricted Lie Superalgebras

    Institute of Scientific and Technical Information of China (English)

    Liang Yun CHEN; Dao Ji MENG; Yong Zheng ZHANG


    In the present paper, we study the Frattini subalgebra of a restricted Lie superalgebra (L, [p]). We show first that if L = A1 (⊙) A2 (⊙) … (⊙) An, then φp (L) = φp (A1) + φp (A2) +… +φp (An),where each Ai is a p-ideal of L. We then obtain two results: F(L) = φ(L) = J(L) = L(1) if and only if L is nilpotent; Fp(L) and F(L) are nilpotent ideals of L if L is solvable. In addition, necessary and sufficient conditions are found for φp-free restricted Lie superalgebras. Finally, we discuss the relationships of E-p-restricted Lie superalgebras and E-restricted Lie superalgebras.

  16. Restriction/modification polypeptides, polynucleotides, and methods

    Energy Technology Data Exchange (ETDEWEB)

    Westpheling, Janet; Chung, DaeHwan; Huddleston, Jennifer; Farkas, Joel A


    The present invention relates to the discovery of a novel restriction/modification system in Caldicellulosiruptor bescii. The discovered restriction enzyme is a HaeIII-like restriction enzyme that possesses a thermophilic activity profile. The restriction/modification system also includes a methyltransferase, M.CbeI, that methylates at least one cytosine residue in the CbeI recognition sequence to m.sup.4C. Thus, the invention provides, in various aspects, isolated CbeI or M.CbeI polypeptides, or biologically active fragments thereof; isolated polynucleotides that encode the CbeI or M.CbeI polypeptides or biologically active fragments thereof, including expression vectors that include such polynucleotide sequences; methods of digesting DNA using a CbeI polypeptide; methods of treating a DNA molecule using a M.CbeI polypeptide; and methods of transforming a Caldicellulosiruptor cell.

  17. Restricted Coherent Risk Measures and Actuarial Solvency

    Directory of Open Access Journals (Sweden)

    Christos E. Kountzakis


    Full Text Available We prove a general dual representation form for restricted coherent risk measures, and we apply it to a minimization problem of the required solvency capital for an insurance company.

  18. 7 CFR 982.50 - Restricted obligation. (United States)


    ... WASHINGTON Order Regulating Handling Control of Distribution § 982.50 Restricted obligation. (a) No handler... procedures as are necessary to facilitate the administration of this option among handlers. (d) Whenever...

  19. Crowding during restricted and free viewing. (United States)

    Wallace, Julian M; Chiu, Michael K; Nandy, Anirvan S; Tjan, Bosco S


    Crowding impairs the perception of form in peripheral vision. It is likely to be a key limiting factor of form vision in patients without central vision. Crowding has been extensively studied in normally sighted individuals, typically with a stimulus duration of a few hundred milliseconds to avoid eye movements. These restricted testing conditions do not reflect the natural behavior of a patient with central field loss. Could unlimited stimulus duration and unrestricted eye movements change the properties of crowding in any fundamental way? We studied letter identification in the peripheral vision of normally sighted observers in three conditions: (i) a fixation condition with a brief stimulus presentation of 250 ms, (ii) another fixation condition but with an unlimited viewing time, and (iii) an unrestricted eye movement condition with an artificial central scotoma and an unlimited viewing time. In all conditions, contrast thresholds were measured as a function of target-to-flanker spacing, from which we estimated the spatial extent of crowding in terms of critical spacing. We found that presentation duration beyond 250 ms had little effect on critical spacing with stable gaze. With unrestricted eye movements and a simulated central scotoma, we found a large variability in critical spacing across observers, but more importantly, the variability in critical spacing was well correlated with the variability in target eccentricity. Our results assure that the large body of findings on crowding made with briefly presented stimuli remains relevant to conditions where viewing time is unconstrained. Our results further suggest that impaired oculomotor control associated with central vision loss can confound peripheral form vision beyond the limits imposed by crowding.

  20. Feed restriction enhances the depressive effects of erythromycin on equine hindgut microbial metabolism in vitro. (United States)

    Kuhn, Manuela; Guschlbauer, Maria; Feige, Karsten; Schluesener, Michael; Bester, Kai; Beyerbach, Martin; Breves, Gerhard


    Equine typholocolitis is a sporadic diarrheal disease causing high mortality rates. One of the risk factors responsible for this is the oral application of the macrolide antibiotic erythromycin. The aim of the present in vitro study was to investigate whether erythromycin in combination with feed restriction provokes changes in microbial hindgut metabolism and could therefore be involved in the pathogenesis of equine typhlocolitis. As application of erythromycin and feed restriction are risk factors for equine typhlocolitis, both factors were chosen to investigate their individual and combined effects on hindgut microbial metabolism. The colon simulation technique (Cositec) was used to evaluate biochemical parameters of microbial metabolism. Production rates of the acetate, proprionate and butyrate were measured as quantitative parameters of microbial fermentation. Application of erythromycin (10 mg/d) predominantly decreased the production rates of propionate. Reducing the fermentable substrate to 30% induced an even more pronounced impairment. The detrimental effects of feed restriction on the production rates of short-chain fatty acids (SCFA) were enhanced when feed restriction was combined with the application of erythromycin. Irrespective of erytrhomycin, the butyrate fermentation rate was completely inhibited by feed restriction within two days after start of restriction. The reduction in butyrate fermentation rate has to be discussed as a pathophysiological factor for the onset of acute typhlocolitis.